bluuebunny/crossref_metadata_2025 huggingface dataset:
Zinc Oxide Nanoparticle Reinforced Waste Buffing Dust Based Composite Insole and Its Antimicrobial Activity
Authors: Dey Thuhin K. , Hossain Arman , Jamal Mamun , Layek Rama K. , Uddin Md. Elias
Published: January 2022

The objective of this research is to use zinc oxide nanoparticles (ZnONPs) combined with buffing dust to develop footwear insole with antibacterial properties. In addition, performance analysis (mechanical, chemical, and thermal) of fabricated insole is also the integral consideration of this study. With such aim, antimicrobial composite insoles were fabricated via simple solution mixing of ZnONPs and natural rubber latex (NRL) binder along with buffing dusts with optimum ratio. Then, removal of water was considered by mechanical pressing followed by natural drying in sunlight. The chemical bonding and material interactions of composites were investigated using FT-IR and XRD, respectively. TGA analysis confirmed the thermal stability of composites, while SEM and OTR are elucidating the surface morphology and gas barrier properties, respectively. Tensile strength, elongation, flexibility, hardness, and water absorption of prepared composite with optimum NRL content were increased by 39, 31, 30, 38, and 28%, respectively. Finally, 78% antimicrobial performance was achieved against the suspension of (

1.5
×

10

6

 
CFU
/
mL

) bacterial strain Staphylococcus aureus.
Adaptive Neural Tracking Control for a Two‐Joint Robotic Manipulator with Unknown Time‐Varying Delays
Authors: Wang Jiayao , Cui Yang
Published: January 2022

This paper presents an adaptive neural tracking control approach for a two‐joint robotic manipulator with unknown time‐varying delays. In order to work out the effect of unknown time‐varying delays on the two‐joint robotic manipulator, the appropriate Lyapunov–Krasovskii functionals (LKFs) and separation technology are chosen to settle this matter. The neural networks work as an approximator that has the advantage of estimating the unknown function in the system. In this paper, Lyapunov stability analysis can prove that all signals of the closed‐loop system are semiglobal uniformly ultimately bounded and the tracking error can converge to a compact neighborhood with respect to zero. The simulation consequences demonstrate the availability of the feedforward control approach.
Analysis of the Effectiveness of Music Therapy on Mental Health of College Students
Authors: Wenqin Li
Published: January 2022

Music therapy is a relatively mature marginal subject at present, and it is also a relatively common treatment method. This kind of treatment can better help college students get rid of bad psychology and guide their psychology to develop in a healthy direction. Mental health is one of the important indicators to measure the comprehensiveness of human quality and plays an important role in the sustainable development of human beings. Music therapy plays a very important role in college students’ mental health education. As a marginal subject, music therapy combines music, medicine, and psychology, which is beneficial to alleviate students’ bad emotions and psychological problems, and helps college students form a sound personality. Using music therapy can let college students vent their emotions in a suitable environment and atmosphere and then guide them correctly. This paper introduces the effectiveness of music therapy in college students’ mental health education and then puts forward important measures to promote the implementation of music therapy in college students’ mental health education.
China’s Energy Demand Forecasting Based on the Hybrid PSO-LSSVR Model
Authors: Yang Yifei , Han Lu , Wang Yarong , Wang Jianzhong
Published: January 2022

Forecasting energy demand accurately is the basis for the formulation and implementation of energy planning. In this paper, energy demand influencing factors are mainly decomposed into scale economy effect, population size effect, energy structure effect, and residential consumption effect based on the Logarithmic Mean Divisia Index (LMDI). Then, the Cointegration and Granger Causality tests are used to discover the influencing factors of energy demand in China. On this basis, a hybrid optimization algorithm, the least-squares support-vector regression optimized by particle swarm optimization (PSO-LSSVR), is proposed to forecast the energy demand of China. Then, three scenarios are set up to analyze the further development of drive factors of energy demand. Finally, in accordance with the forecasting results, some suggestions related to China’s energy development policy are given. The main results are as follows. First, gross domestic product (GDP), the total population at the end of the year (POP), the coal consumption ratio in energy (CCR), and residential consumption levels (RCLs) are dominant indicators of energy demand in China. Second, the improved PSO-LSSVR model has significant superiority than other models in energy demand forecasting, a complex and nonlinear system with small samples. Third, China’s energy demand will peak in 2022, which is 4.9 million tce in all scenarios.
Effect of MMF Immunosuppression Based on CNI Reduction on CNI-Related Renal Damage after Lung Transplantation
Authors: Tang Chunxai , Wang Wei , Xue Yuxi , Yang Junwei
Published: January 2022

In this paper, numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation are evaluated thoroughly. For this purpose, 110 lung transplant recipients who were treated in our hospital from March 2016 to January 2018 were randomly selected. All patients took prednisone acetate tablets or rapamycin at the same time or not at the same time. MMF is 1 g every time, twice a day, and adjusted according to the re-examination. According to the different drugs taken by 110 patients, they were divided into cyclosporine A group and tacrolimus group. Among them, 92 patients in cyclosporine A group took cyclosporine A; 18 patients in tacrolimus group took tacrolimus. The clinical data of age and gender of the two groups were collected, To observe and compare the occurrence of CNI-related renal damage in lung transplant recipients and different immunosuppressants. The CNI dosage of tacrolimus group and cyclosporine A group was compared before and after MMF. The changes of serum creatinine level and serum creatinine clearance rate were measured before MMF administration and 30, 60, and 90 days after MMF administration, to observe the complications of CNI-related renal damage after lung transplantation. Experimental results showed that there were 16 cases (14.55%) of CNI-related renal damage in lung transplant recipients and different immunosuppressants, including 10 cases (11.36%) in males, 6 cases (27.27%) in females, 11 cases (12.09%) in tacrolimus group, and 5 cases (26.32%) in cyclosporine A group. There was no significant difference between the two groups (

P
>
0.05

). Compared with MMF before and after administration, CNI dosage of cyclosporine A group and tacrolimus group decreased significantly (

P
<
0.01

). Compared with MMF before administration, serum creatinine level decreased and serum creatinine clearance rate increased significantly (

P
<
0.05

). In the follow-up, 16 patients with CNI-related renal damage were found to be immune rejection before the adjustment of immunosuppression program, no complications such as immune rejection, myelosuppression, and infection occurred within 15 months after the adjustment of immunosuppression program, blood glucose increased in 3 patients within 2 years after operation, blood lipid increased in 1 patient, urea increased in 1 patient, and uric acid increased in 1 patient. MMF immunosuppressive therapy based on CNI reduction is a safe and effective immunosuppressive therapy, which can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.
Research on Voice-Driven Facial Expression Film and Television Animation Based on Compromised Node Detection in Wireless Sensor Networks
Authors: Wen Shi-Jiang , Wu Hao , Yang Jong-Hoon
Published: January 2022

With the continuous development of social economy, film and television animation, as the spiritual needs of ordinary people, is more and more popular. Especially for the development of emerging technologies, the corresponding voice can be used to change AI expression. But at the same time, how to ensure the synchronization of language sound and facial expression is one of the difficulties in animation transformation. Relying on the compromised node detection of wireless sensor networks, this paper combs the synchronous traffic flow between the speech signals and facial expressions, finds the pattern distribution of facial motion based on unsupervised classification, realizes training and learning through neural networks, and realizes one-to-one mapping to facial expressions by using the rhyme distribution of speech features. It avoids the defect of robustness of speech recognition, improves the learning ability of speech recognition, and realizes the driving analysis of facial expression film and television animation. The simulation results show that the compromised node detection in wireless sensor networks is effective and can support the analysis and research of speech-driven facial expression film and television animation.
Effect of Implant Angulation on the Rotational Displacement of a 3-Unit Bridge after Digital Impression
Authors: Arshad Mahnaz , Asgari Amirmohsen , Kharazifard Mohamad Javad , Ameri Narges
Published: January 2022

Objectives. This study aimed to assess the effect of implant angulation on the rotational displacement of a 3-unit bridge following a digital impression. Materials and Methods. This in vitro experimental study evaluated 3 master models of the maxilla with Kennedy’s class III partial edentulism and bilateral three-unit implant-supported fixed partial dentures. Two implants were placed with 0° (first model), 15° (second model), and 30° (third model) interimplant angles. The implants were placed bilaterally at the sites of first premolars and first molars from the posterior towards the anterior region and coded A (posterior) and B (anterior) in the left, and C (posterior) and D (anterior) in the right side. Next, their position was recorded using a coordinate measuring machine to serve as a reference. The models were then scanned by both 3Shape and Sirona digital scanners (12 times by each scanner). The obtained data were compared with the reference data three-dimensionally using GOM Inspect software to determine the rotational displacement of the implants. Data were analyzed by repeated-measures ANOVA, one-way ANOVA, paired sample t-test, and independent sample t-test (

P

 < 0.05). Results. Since repeated-measures ANOVA showed that the interaction effect was significant (

P

 = 0.010), the data were analyzed by subgroup analysis. The 3Shape scanner showed significantly higher accuracy for C-D region in model 2 (

P

 = 0.001), and A-B region in model 1 (

P

 ≤ 0.01). In the use of the 3Shape scanner, model 3 showed a lower error rate in the A-B region, compared with models 1 and 2. Model 1 showed higher error rate than models 2 and 3 in the C-D region (

P

 ≤ 0.01). In the use of the Sirona scanner, model 1 showed a higher error rate than models 2 (

P

 = 0.031) and 3 (

P

 = 0.004) in the C-D region. Conclusion. In digital impressions of angulated implants in 3-unit bridges by using 3Shape and Sirona scanners, the rotational error decreases as the interimplant angle increases.
Research on English Achievement Analysis Based on Improved CARMA Algorithm
Authors: Hu Lin
Published: January 2022

This paper uses data mining technology to analyze students’ English scores. In view of the influence of many factors on students’ English performance, the analysis is realized by using the association rule algorithm. The thesis analyzes and applies students’ English scores based on association rules and mainly does the following work: (1) at present, the problem of the CARMA algorithm is low operating efficiency. The combination of the genetic algorithm’s crossover, mutation, and the CARMA algorithm realizes the fast search of the algorithm. The simulation results show that the operation performance of the algorithm is greatly improved after the crossover and mutation operations in the genetic algorithm are applied to the CARMA algorithm. The simulation results show that the mining accuracy of the improved algorithm is 97.985%, and the mining accuracy before the improvement is 92.221%, indicating that the improved algorithm can improve the accuracy of mining. (2) By comparing the mining time of the improved CARMA algorithm, the traditional CARMA algorithm, the FP-Growth algorithm, and the Apriori algorithm, the results show that when the number is 6,500, the mining efficiency of the improved CARMA algorithm is twice that of the other three algorithms. As the amount of data increases, the effect of improving mining efficiency gradually increases. (3) By using the improved CARMA algorithm to analyze students’ English performance, it is found that the quality of student performance is strongly related to the quality of daily homework, and if it is related to the teacher’s gender, professional title, etc., it is recommended that schools should pay more attention to homework during the teaching process.
A Systematic Pipelaying Control Method Based on the Sliding Matrix for Dynamically Positioned Surface Vessels
Authors: Li Xinfei , Jin Zhongyu , Wang Lihui
Published: January 2022

A pipelaying control method is presented in this paper which includes path planning, path guidance, and path tracking controller for dynamically positioned (DP) surface vessels based on the characteristics of the predefined path in marine pipelaying operation. The pipelaying control method depends on path coding, path selection logic system, and a sliding matrix. The sliding matrix contains a vessel local path and its specified control requirements, which can be updated by sliding down the waypoint table line by line as the vessel is traveling from one path to the next. A line of sight (LOS) algorithm is developed to calculate the desired vessel position and heading on a circular arc path. The motion controller, which can simultaneously control the vessel speed at the directions of surge and sway, is designed by decomposing the desired inertial resulting velocity into the desired body velocity components. A DP simulator for pipelaying operation is developed, and in order to verify the proposed method, a pipelaying simulation is carried out. The simulation results show that the proposed method enables the vessel to move along the desired path while maintaining a set crab angle, a specified speed, and a turning radius. The pipeline can be laid onto the specified waypoints even when the vessel is subjected to drift forces caused by ocean currents, wind, and waves.
LncRNA MAGI2-As3 Suppresses the Proliferation and Invasion of Cervical Cancer by Sponging MiR-15b
Authors: Chai Yiqing , Wang Lili , Qu Yanwen , Hu Zhixia
Published: January 2022

Background. Cervical cancer is the leading cause of cancer deaths among women, and more than 85% of cervical cancer deaths occur in low and middle-income countries. The purpose of this study is to investigate the functions of MAGI2-AS3 and miR-15b in cervical cancer. Materials and Methods. The mRNA levels of MAGI2-AS3, miR-15b, and CCNE1 were evaluated using RT-qPCR assay. Dual-luciferase reporter gene assay was used to confirm whether miR-15b binds to CCNE1. Results. LncRNA MAGI2-AS3 was downregulated, while miR-15b was upregulated in cervical cancer. Cervical cancer patients with low expression of MAGI2-AS3 have a poor prognosis. Upregulation of MAGI2-AS3 inhibited proliferative and invasive abilities of HeLa cells via regulating the expression of miRNA-15b. MiR-15b inhibitor suppressed cell proliferation and invasion. CCNE1 was a direct target gene of miR-15b, which binds to the 3’-UTR of its mRNA. MiR-15b partially reversed the inhibitory effect of overexpression of MAGI2-AS3 on the proliferation and invasion of HeLa cells. MAGI2-AS3 mediated the expression of CCNE1 in HeLa cells. Conclusion. LncRNA MAGI2-AS3 inhibits the proliferation and invasion of cervical cancer cells via the miRNA-15/CCNE1 axis. Our results illustrates that MAGI2-AS3 can be used as a useful clinical predictor for early diagnosis and prognosis assessment of cervical cancer.
Emerging Pollutants in Moroccan Wastewater: Occurrence, Impact, and Removal Technologies
Authors: Jari Yassine , Roche Nicolas , Necibi Mohamed Chaker , El Hajjaji Souad , Dhiba Driss , Chehbouni Abdelghani
Published: January 2022

The rapid growth of anthropogenic activities in recent decades has resulted in the appearance of numerous new chemical compounds in the environment, known as “emerging pollutants” (EPs) or “contaminants of emerging concern” (CECs). Although partially or not yet regulated or monitored, there is growing research interest in these EPs among the scientific community because of their bioaccumulation, persistence, and adverse effects. Among these, endocrine disruptors, pesticides, and pharmaceuticals can have harmful impacts on human health and the ecosystem. Conventional wastewater treatment technologies are not effective in removing these contaminants, allowing them to be released into the receiving environment. In order to improve the understanding of emerging pollutants, this review discusses the source, occurrence, and impacts of bisphenol A, atrazine, amoxicillin, and paracetamol as model molecules of emerging environmental pollutants, an issue that remains underrepresented in Morocco. Then, treatment methods for EPs are reviewed, including adsorption, advanced oxidation processes, biodegradation, and hybrid treatment. It is proposed that adsorption and photocatalysis can be used as simple, effective, and environmentally friendly technologies for their removal. Thus, we summarize some of the adsorbent and photocatalyst materials applied in recent work to control these pollutants. Towards the end of this paper, the development of inexpensive and locally available (Morocco) materials to remove these compounds from wastewater is considered.
Musculoskeletal Adverse Events Associated with PCSK9 Inhibitors: Disproportionality Analysis of the FDA Adverse Event Reporting System
Authors: Ding Lingqing , Chen Congqin , Yang Yongkuan , Fang Jie , Cao Longxing , Liu Yige
Published: January 2022

Background. Some studies suggest that potential safety issues about PCSK9 inhibitors have not been sufficiently explored in clinical trials, including musculoskeletal adverse events (MAEs). Objective. To examine the association between use of PCSK9 inhibitors with and without concurrent statins and risk of MAEs. Patients and Methods. FDA Adverse Event Reporting System (FAERS) dataset of PCSK9 inhibitors and statins from October 2015 to June 2021 was queried. The reporting odds ratio (ROR) with relevant 95% confidence interval (95% CI) was calculated as the index of disproportionality. Outcome of MAEs of different PCSK9 inhibitors regimens was also investigated. Results. 3,185 cases of PCSK9 inhibitor-associated MAEs were recorded. PCSK9 inhibitor class alone demonstrated a strong link to MAEs (ROR 5.92; 95% CI 5.70-6.15), and evolocumab was associated with more reports of MAEs than alirocumab. Concomitant use with statins leaded to an increased occurrence of MAEs (ROR 32.15 (25.55-40.46)), and the risk differed among different statins. The PCSK9 inhibitors were safer than statins in terms of hospitalization rate and death rate (15.64% vs. 36.83%; 0.72% vs. 3.53%). Conclusions. This pharmacovigilance investigation suggests that PCSK9 inhibitors are associated with MAEs. The risk significantly increases when combined with statins. Increased laboratory and clinical monitoring are required to timely diagnose and manage MAEs.
Artificial Intelligence-Based Smart Comrade Robot for Elders Healthcare with Strait Rescue System
Authors: Dilip Golda , Guttula Ramakrishna , Rajeyyagari Sivaram , S Hemalatha , Pandey Radha Raman , Bora Ashim , R Kshirsagar Pravin , M M Khanapurkar , Sundramurthy Venkatesa Prabhu
Published: January 2022

A rising proportion of older people has more demand on services including hospitals, retirement homes, and assisted living facilities. Regaining control of this population’s expectations will pose new difficulties for lawmakers, medical professionals, and the society at large. Smart technology can help older people to have independent and fulfilling lives while still living safely and securely in the community. In the last several decades, the number of sectors using robots has risen. Comrade robots have made their appearance in old human life, with the most recent notable appearance being in their care. The number of elderly individuals is increasing dramatically throughout the globe. The source of the story is the use of robots to help elderly people with day-to-day activities. Speech data and facial recognition model are done with AI model. Here, with the Comrade robotic model, elder people’s healthcare system is designed with better analysis state. The aim is to put in place a simple robotic buddy to determine the health of the old person via a headband that has been given to them. Comrade robot may do things like senior citizens home automation, home equipment control, safety, and wellbeing sensing, and, in emergency situation, routine duties like navigating in the outside world. The fear that robotics and artificial intelligence would eventually eliminate most of the jobs is increasing. It is anticipated that, in order to survive and stay relevant in the constantly shifting environment of work, workers of the future will need to be creative and versatile and prepared to identify new business possibilities and change industry to meet challenges of the world. According to the research, reflective practice, time management, communicating, and collaboration are important in fostering creativity.
Functional Analysis of MET Exon 14 Skipping Alteration in Cancer Invasion and Metastatic Dissemination
Authors: Wang Feng , Liu Yang , Qiu Wanglong , Shum Elaine , Feng Monica , Zhao Dejian , Zheng Deyou , Borczuk Alain , Cheng Haiying , Halmos Balazs
Published: January 2022

MET exon 14 skipping alteration (METΔ14Ex) is an actionable oncogenic driver that occurs in 2% to 4% of non–small cell lung cancer (NSCLC) cases. The precise role of METΔ14Ex in tumor progression of NSCLC is poorly understood. Using multiple isogenic METΔ14Ex cell models established with CRISPR editing, we demonstrate that METΔ14Ex expression increases receptor kinase activity and downstream signaling by impairing receptor internalization and endocytic degradation, significantly boosting cell scatter, migration, and invasion capacity in vitro as well as metastasis in vivo. RNA sequencing analysis revealed that METΔ14Ex preferentially activates biological processes associated with cell movement, providing novel insights into its unique molecular mechanism of action. Activation of PI3K/Akt/Rac1 signaling and upregulation of multiple matrix metallopeptidases (MMP) by METΔ14Ex induced cytoskeleton remodeling and extracellular matrix disassembly, which are critical functional pathways that facilitate cell invasion and metastasis. Therapeutically, MET inhibitors dramatically repressed METΔ14Ex-mediated tumor growth and metastasis in vivo, indicating potential therapeutic options for METΔ14Ex-altered NSCLC patients. These mechanistic insights into METΔ14Ex-mediated invasion and metastasis provide a deeper understanding of the role of METΔ14Ex in NSCLC.

Significance:

These findings reveal the mechanistic function of METΔ14Ex alteration in driving metastasis and define novel metastasis-related pathways that could be targeted for more effective treatment of lung cancer with METΔ14Ex alterations.
Alterations of the Mdm2 C-Terminus Differentially Impact Its Function In Vivo
Authors: Pant Vinod , Aryal Neeraj K. , Xiong Shunbin , Chau Gilda P. , Fowlkes Natalie W. , Lozano Guillermina
Published: January 2022

Murine double minute 2 (Mdm2) is the principal E3-ubiquitin ligase for p53 and contains a C2H2C4 type RING domain wherein the last cysteine residue is followed by an evolutionarily conserved 13 amino acid C-terminal tail. Previous studies have indicated that integrity of the C-terminal tail is critical for Mdm2 function. Recently, a mutation extending the MDM2 length by five amino acids was identified and associated with enhanced p53 response in fibroblasts and premature aging in a human patient. To investigate the importance of the conserved Mdm2 C-terminal length on p53 regulatory function in vivo, we engineered three novel mouse alleles using CRISPR–Cas9 technology. Genetic studies with these murine models showed that curtailing Mdm2 C-terminal length by even a single amino acid leads to p53-dependent embryonic lethality. Extension of the Mdm2 C-terminal length by five amino acids (QLTCL) yielded viable mice that are smaller in size, exhibit fertility problems, and have a shortened life span. Analysis of early passage mouse embryonic fibroblasts indicated impaired Mdm2 function correlates with enhanced p53 activity under stress conditions. Furthermore, analysis in mice showed tissue-specific alterations in p53 target gene expression and enhanced radiosensitivity. These results confirm the physiological importance of the evolutionarily conserved Mdm2 C-terminus in regulating p53 functions.

Significance:

This in vivo study highlights that alterations to the C-terminus of Mdm2 perturb its regulation of the tumor suppressor p53.
A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer
Authors: Dylgjeri Emanuela , Kothari Vishal , Shafi Ayesha A. , Semenova Galina , Gallagher Peter T. , Guan Yi F. , Pang Angel , Goodwin Jonathan F. , Irani Swati , McCann Jennifer J. , Mandigo Amy C. , Chand Saswati , McNair Christopher M. , Vasilevskaya Irina , Schiewer Matthew J. , Lallas Costas D. , McCue Peter A. , Gomella Leonard G. , Seifert Erin L. , Carroll Jason S. , Butler Lisa M. , Holst Jeff , Kelly William K. , Knudsen Karen E.
Published: January 2022

Purpose:

DNA-dependent protein kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer, and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. Although DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes.

Experimental Design:

Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacologic and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE).

Results:

Key findings reveal: (i) the first-in-field DNA-PK protein interactome; (ii) numerous DNA-PK novel partners involved in glycolysis; (iii) DNA-PK interacts with, phosphorylates (in vitro), and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2; (iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate; (v) DNA-PK regulates glycolysis in vitro, in vivo, and ex vivo; and (vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease.

Conclusions:

Findings herein unveil novel DNA-PK partners, substrates, and function in prostate cancer. DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK–mediated aggressive disease phenotypes.
Bone Marrow Surveillance of Pediatric Cancer Survivors Identifies Clones that Predict Therapy-Related Leukemia
Authors: Spitzer Barbara , Rutherford Kayleigh D. , Gundem Gunes , McGovern Erin M. , Millard Nathan E. , Arango Ossa Juan E. , Cheung Irene Y. , Gao Teng , Levine Max F. , Zhang Yanming , Medina-Martínez Juan S. , Feng Yi , Ptashkin Ryan N. , Bolton Kelly L. , Farnoud Noushin , Zhou Yangyu , Patel Minal A. , Asimomitis Georgios , Cobbs Cassidy C. , Mohibullah Neeman , Huberman Kety H. , Arcilla Maria E. , Kushner Brian H. , Modak Shakeel , Kung Andrew L. , Zehir Ahmet , Levine Ross L. , Armstrong Scott A. , Cheung Nai Kong V. , Papaemmanuil Elli
Published: January 2022

Purpose:

Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children.

Experimental Design:

We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor.

Results:

We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3–32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes.

Conclusions:

These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients.
Targeting Refractory Mantle Cell Lymphoma for Imaging and Therapy Using C-X-C Chemokine Receptor Type 4 Radioligands
Authors: Kwon Daniel , Takata Katsuyoshi , Zhang Zhengxing , Chong Lauren , Fraser Bryan , Zeisler Jutta , Miyata-Takata Tomoko , Merkens Helen , Rousseau Julie , Aoki Tomohiro , Kuo Hsiou-Ting , Tan Ruiyan , Zhang Chengcheng , Lau Joseph , Villa Diego , Uribe Carlos F. , Lin Kuo-Shyan , Steidl Christian , Benard Francois
Published: January 2022

Purpose:

Mantle cell lymphoma (MCL) is associated with poor survival. The purpose of this study was to assess whether the C-X-C chemokine receptor type 4 (CXCR4) is a useful target for imaging and radioligand therapy of MCL, using a novel pair of radioligands, [68Ga]Ga and [177Lu]Lu-BL02.

Experimental Design:

We performed a retrospective analysis of 146 patients with MCL to evaluate CXCR4 expression and its correlation with outcomes. Guided by in silico methods, we designed BL02, a new radioligand labelled with 68Ga or 177Lu for PET imaging and therapy, respectively. We performed imaging and biodistribution studies in xenograft models with varying CXCR4 expression. We evaluated [177Lu]Lu-BL02 in MCL models, and evaluated its potential for therapy in Z138 MCL xenografts.

Results:

Phosphorylated and nonphosphorylated CXCR4 expression were correlated with poor survival in patients with MCL and characterized by unique underlying molecular signatures. [68Ga]Ga-BL02 uptake correlated with CXCR4 expression, and localized lesions in a metastatic xenograft model. [177Lu]Lu-BL02 showed high uptake in MCL xenografts. Therapy studies with a single dose in the Z138 model showed tumor regression and improved survival compared with a control group. Upon regrowth, the treated mice experienced concurrent metastasis alongside localized xenograft regrowth, and recurrent lesions showed enhanced CXCR4 signaling.

Conclusions:

CXCR4 is an independent factor of poor prognosis for MCL and a promising target for imaging and radioligand therapy. [68Ga]Ga-BL02 showed high contrast to visualize CXCR4-expressing xenografts for PET imaging and [177Lu]Lu-BL02 induced rapid tumor regression in a preclinical model of MCL.
Comparing Somatostatin Analogs in the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors
Authors: Allaw Mohammed B. , Switchenko Jeffrey M. , Khalil Lana , Wu Christina , Alese Olatunji B. , Akce Mehmet , Draper Amber , Jones Aaron T. , El-Rayes Bassel , Shaib Walid
Published: January 2022

Background: The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study’s objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. Results: A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6–18 months) and 10.8 months (95% CI, 6–15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. Conclusions: Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.
De novo Splice Site Mutation of the CHD7 Gene in a Chinese Patient with Typical CHARGE Syndrome
Authors: Wang Shujuan , Lin Ying , Liang Pengfei , Li Qiong , Li Wei , Wang Zhaoxia , Wang Jian , Chen Jun , Zha Dingjun
Published: January 2022

Introduction: CHARGE syndrome (CS, OMIM 214800) is a rare genetic disease characterized by multiple congenital abnormalities, including coloboma, heart defect, atresia of the choanae, retardation of development, genital anomalies, and ear anomalies/deafness. The syndrome is mainly caused by a heterozygous variant in the chromodomain helicase DNA-binding protein 7 (CHD7) gene that encodes the CHD7 protein, involved in the ATP-dependent remodeling of chromatin. Methods: In this study, the next-generation sequencing targeted panel was used to detect a de novo variant c.3523-2A>G in the CHD7 gene in a patient with severe CS, congenital heart disease, left coloboma of the choroid, cryptorchidism, and congenital deafness. The Sanger sequencing confirmed the variant and clarified it as de novo variant by short tandem repeat analysis in the patient family. We analyzed the effect of a variant by Minigene assay to evaluate the pathogenicity of the variant. Results: In summary, cDNA analysis confirmed that c.3523-2A>G variant activates a cryptic splice site, resulting in 172 base pair missing in exon 15, leading to the premature truncation of the CHD7 protein (p.V1175Afs*11). Conclusion: The present study functionally characterized the novel c.3523-2A>G variant in CHD7, providing further confirmatory evidence that it is associated with CS.
Anthocyanins Inhibit Airway Inflammation by Downregulating the NF-κB Pathway via the miR-138-5p/SIRT1 Axis in Asthmatic Mice
Authors: Liu Yi , Zhang Mingqiang , Zhang Huijuan , Qian Xiaosen , Luo Lan , He Zhiwei
Published: January 2022

Objective: Asthma, caused by chronic inflammation, is a common disease. Anthocyanins are involved in asthma treatment. This study explored the mechanism of anthocyanins on airway inflammation in asthmatic mice by regulating nuclear factor-κB (NF-κB) via the miR-138-5p/sirtuin-1 (SIRT1) axis. Methods: The asthmatic mouse model was established by ovalbumin (OVA) induction and treated with anthocyanins or simultaneously injected with the lentivirus miR-138-5p mimic, followed by the measurement of lung inflammatory injury and IL-4, IL-5, IL-13, and IFN-γ levels in bronchoalveolar lavage fluid. Human bronchial epithelial (HBE) cells 16HBE14o-160 were induced by OVA to establish an asthmatic cell model, treated with anthocyanins and manipulated with miR-138-5p mimic and pcDNA3.1-SIRT1. The releases of inflammatory cytokines, the nuclear translocation of p-p65/p65 in the NF-κB pathway, and the levels of miR-138-5p and SIRT1 mRNA were detected. Results: In vivo experiments showed that anthocyanins could reduce the OVA-induced airway hyperresponsiveness and airway inflammation, improve the inflammatory infiltration and mucus in lung tissues, and diminish the miR-138-5p level in asthmatic mice. Infection with the miR-138-5p mimic averted the remission effect of anthocyanins in asthmatic mice. In vitro experiments showed that in HBE cells exposed to OVA, anthocyanins reduced the miR-138-5p level, increased the SIRT1 level, inhibited the release of inflammatory factors, and reduced the nuclear translocation of NF-κB p65. miR-138-5p targeted SIRT1. miR-138-5p overexpression partially reversed the therapeutic effect of anthocyanins, while SIRT1 overexpression antagonized the effect of miR-138-5p overexpression. Conclusion: Anthocyanins inhibited the NF-κB pathway by regulating the miR-138-5p/SIRT1 axis, thus inhibiting airway inflammation in asthmatic mice.
Lack of CD44 and Sox-2 Overexpression as Two Independent Favourable Prognostic Factors in HPV Positive Patients with Oropharyngeal Cancers
Authors: Kołodziej-Rzepa Marta , Biesaga Beata , Janecka-Widła Anna , Mucha-Małecka Anna
Published: January 2022

Introduction: In our earlier publications, in the group of 63 patients with oropharyngeal cancer, we have found HPV16 infection (assessed by qPCR) in 25 tumours (39.7%), immunohistochemical overexpression of CD44, CD98, ALDH1/2 and Nanog in, respectively: 43 (68.2%), 30 (47.6%), 33 (52.4%), and 53 (84.1%) cancers. Analysing CD44, CD98, ALDH1/2, we have also shown that lack of CD44 overexpression indicates excellent prognosis in patients with HPV16 positivity. The aim of the present study was to compare prognostic potential of Nanog, Oct3/4, Sox-2 expression in relation to CD44, CD98, ALDH1/2 immunoreactivity (assessed by us earlier) and clinicopathological features in the subgroups of patients: with HPV16 positivity and HPV16 negativity. Methods: Status of Oct3/4 and Sox-2 expression was assessed for 63 patients with oropharyngeal cancers based on immunohistochemistry. In survival analysis, two endpoints were applied: overall survival (OS) and disease-free survival (DFS). Results: Overexpression of Oct3/4 and Sox-2 was found in 0 (0.0%) and 27 (42.9%) of patients. In the subgroup with HPV16 positivity, the DFS for patients with lack of Sox-2 overexpression was significantly (p = 0.003) higher than for patients with Sox-2 overexpression. In the subgroup with HPV16 negativity, Nanog and Sox-2 immunoexpression did not significantly influence OS and DFS. In multivariate analysis performed for the subgroup with HPV16 positivity, lack of CD44 overexpression (p = 0.012) and lack of Sox-2 overexpression (p = 0.027) were positive independent prognostic factors. Conclusion: Based on CD44 and Sox-2 immunoreactivity, it is possible to differentiate the prognosis of HPV16-positive patients with oropharyngeal cancers.
Prediction of Respiratory Failure and Mortality in COVID-19 Patients Using Long Pentraxin PTX3
Authors: Hansen Cecilie Bo , Sandholdt Håkon , Møller Maria Elizabeth Engel , Pérez-Alós Laura , Pedersen Lise , Bastrup Israelsen Simone , Garred Peter , Benfield Thomas
Published: January 2022

The course of COVID-19 is unpredictable, ranging from asymptomatic to respiratory failure and death. Prognostic biomarkers are urgently needed. We hypothesized that long pentraxin PTX3 could be a valuable plasma biomarker due to its essential role in inflammatory processes. In a prospective hospitalized COVID-19 derivation cohort (n = 126) during the spring of 2020, we measured PTX3 within 4 days of admission. The predictive value of mechanical ventilation (MV) and 30-day mortality compared with clinical parameters and other markers of inflammation were assessed by logistic regression analysis and expressed as odds ratio (OR) with 95% confidence interval (CI). Analyses were repeated in a prospective validation cohort (n = 112) of hospitalized patients with COVID-19 treated with remdesivir and dexamethasone. Thirty-day mortality in the derivation cohort was 26.2%. In patients who died, the median PTX3 concentration upon admission was 19.5 ng/mL (IQR: 12.5–33.3) versus 6.6 ng/mL (IQR 2.9–12.3) (p < 0.0001) for survivors. After adjustment for covariates, the odds of 30-day mortality increased two-fold for each doubling of PTX3 (OR 2.03 [95% CI: 1.23–3.34], p = 0.006), which was also observed in the validation cohort (OR 1.70 [95% CI: 1.09–2.67], p = 0.02). Similarly, PTX3 levels were associated with MV. After adjustment for covariates, OR of MV was 2.34 (95% CI: 1.33–4.12, p = 0.003) in the derivation cohort and 1.64 (95% CI: 1.03–2.62, p = 0.04) in the validation cohort. PTX3 appears to be a useful clinical biomarker to predict 30-day respiratory failure and mortality risk in COVID-19 patients treated with and without remdesivir and dexamethasone.
Genetic Variant of CXCR1 (rs2234671) Associates with Clinical Outcome in Perihilar Cholangiocarcinoma
Authors: Lurje Isabella , Czigany Zoltan , Bednarsch Jan , Gaisa Nadine Therese , Dahl Edgar , Knüchel Ruth , Miller Hannah , Ulmer Tom Florian , Strnad Pavel , Trautwein Christian , Tacke Frank , Neumann Ulf Peter , Lurje Georg
Published: January 2022

Background: Perihilar cholangiocarcinoma (pCCA) is a rare primary liver malignancy. Even in patients amenable to surgery, outcomes are often dismal. Here, we aimed to identify prognostic markers for patient outcomes by analyzing functionally relevant single-nucleotide polymorphisms (SNPs) in genes with a role in tumor inflammation and angiogenesis. We analyzed 11 polymorphisms in the inflammation-angiogenesis axis (VEGF, EGF, EGFR, IL-1b, IL-6, CXCL8 (IL-8), IL-10, CXCR1, HIF1A, and COX2 genes) for their prediction of tumor recurrence and survival in pCCA patients undergoing surgery in a curative intent. Methods: Samples were obtained from 111 patients with pCCA undergoing liver resection in curative intent. DNA was extracted and analyzed using polymerase chain reaction-restriction fragment length polymorphism protocols and correlated with patients’ outcomes. Results: Out of the assessed variants, only the CXCR1 (also: interleukin-8-receptor alpha – IL-8RA) +860C>G heterozygous polymorphism (rs2234671) was associated with decreased disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) (18/111 (16.2%), median DFS 14 months, log-rank p = 0.007; median CSS 31 months, log-rank p = 0.007; and median OS 6 months, log-rank p = 0.002), compared to the GG genotype (92/111 (82.9%), median DFS 55 months, median CSS 63 months, and median OS 33 months). In the multivariate analysis, +860C>G remained an independent prognostic factor for DFS (adjusted p = 0.008), CSS (adjusted p = 0.001), and OS (adjusted p = 0.001). Conclusion: Genetic variant of CXCR1 +860C>G may serve as a molecular marker for DFS, CSS, and OS in patients undergoing curative-intent surgery for pCCA, indicating that the analysis of SNPs in genes involved in immune-mediated angiogenesis may help to identify patient subgroups at high risk for dismal oncological and overall outcome.
DNMT3A and TET2; Potential Estimates of Generic DNA Methylation in Children and Adolescents with Obesity; Relation to Metabolic Dysregulation
Authors: Salah Nouran , Salem Lamyaa , Taha Sara , Youssef Mariam , Annaka Layla , Hassan Safeya , Mahmoud Rana
Published: January 2022

Introduction: The role of DNA methylation in metabolic dysregulation is emerging. However, the functional role of methylation in obesity and metabolic dysregulation is poorly understood. Aim: The aim of this study was to compare DNA methyltransferase-3A (DNMT3A) and ten-eleven translocase-2 (TET2) levels in children and adolescents with obesity to normal-weighed children and adolescents and to correlate them to various metabolic parameters. Methods: Fifty children and adolescents with obesity were compared to 50 matched normal-weighed children and adolescents. Participants underwent assessment for anthropometric measurements, Tanner staging, acanthosis nigricans, and mean blood pressure percentile on three different occasions. TET2, DNMT3A, fasting lipids, and insulin were measured with calculation of the homeostatic model assessment insulin resistance (HOMA-IR). Results: The median BMI SDS of the studied children and adolescents with obesity was 3.40, their mean TET2 was 178.40 ng/mL, and their mean DNMT3A was 2.18 ng/mL. TET2 is significantly lower (p = 0.009), while DNMT3A is significantly higher (p < 0.001) in children and adolescents with obesity than controls. Children and adolescents with obesity and insulin resistance have significantly lower TET2 (p = 0.012) and significantly higher DNMT3A (p = 0.013) than those without insulin resistance. Diastolic blood pressure percentile and HOMA-IR are positively correlated to DNMT3A (p < 0.001) and negatively correlated to TET-2 (p < 0.001). Multivariate logistic regression analysis revealed that TET2 and DNMT3A are independently associated with diastolic blood pressure percentile (p = 0.03 and p = 0.014, respectively) and HOMA-IR (p = 0.003 and p = 0.001, respectively). Conclusions: Children and adolescents with obesity have significantly higher DNMT3A and significantly lower TET2 than controls. This is more evident in those having insulin resistance than those without. DNMT3A and TET2 are independently associated with systemic hypertension and insulin resistance in children with obesity.