bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Method for Optimizing the Cabin Layout of Manned Submersibles
Authors: Wang Wenzhong , Zhang Shusheng , Ye Cong , Chen Dengkai , Fan Hao
Published: December 2020

In order to reduce the misoperation of submersible pilots in the complex environment of deep sea and improve human reliability, it is a very important method to optimize the cabin space of manned submersible. In this paper, manned submersible Jiaolong is taken as an example to describe the breakthrough of traditional modes for optimizing the cabin layout of manned submersible with an aesthetic perspective of deconstruction and reconstruction thinking; the layout is optimized based on deconstruction and reconstruction from the cultural perspective of interdisciplinary. The experimental results show that the layout of manned submersible cabin is optimized by combining the theory of deconstruction and reconstruction aesthetics and human factors engineering, and the feasibility and effectiveness of this method are verified by multiobjective genetic algorithm. Deconstruction and reconfiguration layout optimization improves the human reliability of divers. It is a new method for the optimization of manned submersible cabin layout and also provides a reference for studies on the layout of similar small space.
Mathematical Analysis of TB Model with Vaccination and Saturated Incidence Rate
Authors: Mengistu Ashenafi Kelemu , Witbooi Peter J.
Published: December 2020

The model system of ordinary differential equations considers two classes of latently infected individuals, with different risk of becoming infectious. The system has positive solutions. By constructing a Lyapunov function, it is proved that if the basic reproduction number is less than unity, then the disease-free equilibrium point is globally asymptotically stable. The Routh-Hurwitz criterion is used to prove the local stability of the endemic equilibrium when

R

0

>
1

. The model is illustrated using parameters applicable to Ethiopia. A variety of numerical simulations are carried out to illustrate our main results.
Keratorefractive Surgery Outcomes in Keratoconus Suspect Patients
Authors: Abdolahian Milad , Moalem Mohammad Ali , Jahady Hoseiny Mohammadreza , Noorizadeh Farsad , Zareei Athar
Published: December 2020

Purpose. To examine the outcomes of keratorefractive surgeries in keratoconus suspect patients. Methods. This study included 192 keratoconus suspects (351 eyes), treated with photorefractive keratectomy (PRK) (211 eyes), Lasik (96 eyes), and Femto-Lasik (44 eyes) surgeries in an eye clinic. The best spectacle-corrected visual acuity (BSCVA) and subjective refraction were evaluated preoperatively and postoperatively (three months and five years after the procedure). The Orbscan II topography system was also used preoperatively and five years after the procedure. Results. The patients’ mean age was 31.6 ± 5.49 years (range: 21–47 years) in the last follow-up. There was no significant difference between the preoperative and postoperative mean values of BSCVA in any of the surgical methods (P = 0.49). The mean spherical equivalent, cylindrical power, corneal curvature, the thinnest corneal thickness, and the central corneal thickness decreased significantly in the last follow-up (P < 0.001). Four patients (3.50%) in the PRK group and one patient (1.85%) in the Lasik group needed glasses in the last follow-up. Eleven cases of corneal ectasia were detected in the last follow-up (six eyes of four patients [2.84%] and five eyes of four patients [5.20%] in the PRK and Lasik groups, respectively). Conclusion. In the present study, the high risk of postoperative ectasia was detected in keratoconus suspects following PRK and Lasik surgeries. According to the results, it can be concluded that Femto-Lasik surgery provides better outcomes than Lasik and PRK. Overall, the surgical criteria are suggested to be evaluated case by case, and the patients must be followed up over time to assess the corneal topography and refraction stability.
Study on Foundation Pit Construction Cost Prediction Based on the Stacked Denoising Autoencoder
Authors: Liu Lanjun , Liu Denghui , Wu Han , Wang Junwu
Published: December 2020

To accurately predict the construction costs of foundation pit projects, a model based on the stacked denoising autoencoder (SDAE) is constructed in this work. The influencing factors of foundation pit project construction costs are identified from the four attributes of construction cost management, namely, engineering, the environment, the market, and management. Combined with Chinese national standards and the practice of foundation pit project management, a method of the quantization of the influencing factors is presented. 60 deep foundation pit projects in China are selected to obtain 13 main characteristic factors affecting these project construction cost by using the rough set. Then, considering the advantages of the SDAE in dealing with complex nonlinear problems, a prediction model of foundation pit project construction costs is created. Finally, this paper employs these 60 projects for a case analysis. The case study demonstrates that, compared with the actual construction costs, the calculation error of the proposed method is less than 3%, and the average error is only 1.54%. In addition, three error analysis tools commonly used in machine learning (the determination coefficient, root mean square error, and mean absolute error) emphasize that the calculation accuracy of the proposed method is notably higher than those of other methods (Chinese national code, the multivariate return method, the BP algorithm, the BP model optimized by the genetic algorithm, the support vector machine, and the RBF model). The relevant research results of this paper provide a useful reference for the prediction of the construction costs of foundation pit projects.
An Unequal Image Privacy Protection Method Based on Saliency Detection
Authors: Tu Rongxin , Wen Wenying , Hua Changsheng
Published: December 2020

Cloud platforms provide a good stage for storing and sharing big image data for users, although some privacy issues arise. Image encryption technology can prevent privacy leakage and can ensure secure image data sharing on cloud platforms. Hence, in this paper, an unequal encryption scheme based on saliency detection is proposed. First, based on the mechanism of visual perception and the theory of feature integration, the visual attention model is employed to realize the recognition of significant regions and insignificant regions. Then, a dynamic DNA encryption algorithm is proposed to exploit heavyweight encryption for significant regions, while semi-tensor product compressed sensing is introduced to exploit lightweight encryption and compression for insignificant regions. Experimental results demonstrate that the proposed framework can serve to secure big image data services.
Simultaneous Determination of Ropivacaine and 3‐Hydroxy Ropivacaine in Cerebrospinal Fluid by UPLC‐MS/MS
Authors: Chen Siyuan , Ma Jianshe , Wang Xianqin , Zhou Quan
Published: December 2020

In this paper, a UPLC‐MS/MS method was developed for the determination of ropivacaine and its metabolite 3‐hydroxy ropivacaine in cerebrospinal fluid. The cerebrospinal fluid was processed by ethyl acetate liquid‐liquid extraction. The multiple reaction monitoring (MRM) mode was used for quantitative analysis by monitoring the transitions of m/z 275.3 → 126.2 for ropivacaine, m/z 291.0 → 126.0 for 3‐hydroxy ropivacaine, and m/z 290.2 → 198.2 for the internal standard. Standard curves for ropivacaine and 3‐hydroxy ropivacaine in cerebrospinal fluid were conducted over the concentration range of 0.2–2000 ng/mL, demonstrating excellent linearity, and the lower limit of quantification was 0.2 ng/mL. The intraday precision of ropivacaine and 3‐hydroxy ropivacaine was less than 11%, while the interday precision was less than 7%. The accuracy ranged between 87% and 107%, the average extraction efficiency was higher than 79%, and the matrix effect was between 89% and 98%. The developed method was then applied to a case of suspected poisoning of ropivacaine.
Analytical Solution of System of Volterra Integral Equations Using OHAM
Authors: Akbar Muhammad , Nawaz Rashid , Ahsan Sumbal , Baleanu Dumitru , Nisar Kottakkaran Sooppy
Published: December 2020

In this work, a reliable technique is used for the solution of a system of Volterra integral equations (VIEs), called optimal homotopy asymptotic method (OHAM). The proposed technique is successfully applied for the solution of different problems, and comparison is made with the relaxed Monto Carlo method (RMCM) and hat basis function method (HBFM). The comparisons show that the present technique is more suitable and reliable for the solution of a system of VIEs. The presented technique uses auxiliary function containing auxiliary constants, which control the convergence. Moreover, OHAM does not require discretization like other numerical methods and is also free from small or large parameter.
Research on Variable Universe Fuzzy PID Control Strategy of Pipe Lining Induction Heating System
Authors: Wang Yuzhong , Wei Min , Hu Xue , Jiang Minghong , Zhang Lixin
Published: December 2020

It is a promising heat supply strategy to use induction heating for the pipe lining process, but temperature control is hindering its application. In this study, we designed the variable universe fuzzy PID controller, and the lining induction heating system model was used to verify its performance. First, the transfer function parameters of the lining induction heating system are obtained by the step response method. Then, a point-by-point convergent interpolator is established through the contraction-expansion factors to realize the adaptive expansion of the fuzzy universe. Finally, the performance of PID, fuzzy PID, and variable universe fuzzy PID are compared through simulation experiments, and the ability of the controller to resist disturbance is verified by adding interference. The results show that the variable universe fuzzy PID controller can greatly improve the performance of fuzzy PID in response speed and settle time. The average stability error is smaller than PID and fuzzy PID control. It can meet the speed and accuracy requirements of the lining induction heating system. This research can be used as a reference for induction heating precise control and evidence that the variable universe fuzzy PID control can satisfy the lining induction heating process.
Effects of Human Factors on Public Use of Standing-Type Personal Mobility Vehicle
Authors: Hashimoto Naohisa , Tomita Kohji , Matsumoto Osamu , Boyali Ali
Published: December 2020

To significantly reduce the occurrence of severe traffic accidents, reducing the number of vehicles in urban areas should be considered. Personal mobility is essential for realizing this reduction, which requires consideration of the last-/first-mile problem. The overall objective of our research is to solve this problem using standing-type personal mobility vehicles as transportation devices; however, to evaluate the feasibility of such vehicles as future mobility devices, it is necessary to evaluate their operation under real-world conditions. Therefore, in this study, experimental and survey data relating to the velocity, stability, safety, and comfort of a standing-type personal mobility device are obtained to evaluate its performance in three different scenarios. The results show that the personal mobility vehicle is socially well received and can be safely operated on sidewalks, irrespective of the gender or age of the driver; moreover, the results suggest that subjects who routinely use a bicycle are adept at avoiding and absorbing the impacts of small holes and bumps, thereby yielding reduced acceleration values (in all directions) and pitch, roll, and yaw rates. This is anticipated to benefit the future development of personal mobility devices and help realize effective and accessible public transport systems, as well as reduce the number of vehicles in urban areas.
Binary File’s Visualization and Entropy Features Analysis Combined with Multiple Deep Learning Networks for Malware Classification
Authors: Guo Hui , Huang Shuguang , Huang Cheng , Shi Fan , Zhang Min , Pan Zulie
Published: December 2020

In recent years, the research on malware variant classification has attracted much more attention. However, there are still many challenges, including the low accuracy of classification of samples of similar malware families, high time, and resource consumption. This paper proposes a new method of malware classification based on multiple visual features of malware and deep learning algorithms. In prior research, visualization techniques and entropy demonstrated exemplary performance in many areas. This paper extracts numerous visual features from the raw bytes and entropy sequence of the malware, which makes it more sensitive to malware samples of similar families and endows it the ability to classify malware variants more accurately. To evaluate the proposed method, this paper conducted a series of experiments on two malware datasets with a total of more than 20,000 samples provided by the Malware Research Lab and Microsoft Research. Through experiments, the method showed its superiority compared with some leading malware visual classification methods, achieving good performance on the accuracy with at least 1% improvement. The accuracy of the method even could reach 99.73% and 99.54%, respectively, on the two datasets.
Vibrations of Plates with Complex Shape: Experimental Modal Analysis, Finite Element Method, and R-Functions Method
Authors: Zippo Antonio , Iarriccio Giovanni , Pellicano Francesco , Shmatko Tetyana
Published: December 2020

In this paper, the dynamic behavior of 3D-printed plates with different shapes and boundary conditions is investigated. The natural frequencies and mode shapes were determined using three different methods: the experimental analysis, the finite element method, using Nastran, and the R-functions method. The experimental and theoretical results are compared. The specimens tested included four cases. The test procedure is deeply described, and the material properties of the plates are given. The fixed-fixed configuration shows a better agreement both in the rectangular plate and in the plate with rectangular cuts, and the R-functions method gives better convergence with respect to the experimental and finite element analysis. The simply supported arrangement indicates some uncertainty in the boundary realization of the specimen.
The Association of Fasting C-peptide with Corneal Neuropathy in Patients with Type 2 Diabetes
Authors: Zuo Anju , Wang Chuan , Li Lili , Qu Jingru , Cao Juan , Chen Li , Tesfaye Solomon , Li Wenjuan , Hou Xinguo
Published: December 2020

Purpose. Damage to corneal nerve fibers has been demonstrated in people with type 2 diabetes mellitus (T2DM) that further progresses with increasing severity of diabetic peripheral neuropathy. However, the role of C-peptide in corneal nerve damage has not been reported in T2DM. The present study investigated the relationship of fasting C-peptide levels with corneal neuropathy evaluated by corneal confocal microscopy (CCM) in patients with T2DM. Methods. 160 T2DM patients (72 females) aged 34-78 with duration ranging from 0 to 40 years underwent CCM to measure corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), and corneal nerve branch density (CNBD). Pearson correlation analysis and multiple linear regression analysis were used to explore the association of fasting C-peptide levels with corneal nerve parameters. Partial correlation analysis (adjusted for age and gender) was also conducted to analyze the correlation of metabolic indexes with these three corneal nerve parameters. The relationship between fasting C-peptide levels and duration of diabetes was also explored by Pearson correlation analysis. Results. With an increase in fasting C-peptide levels, the values of CNFL, CNFD, and CNBD also showed a corresponding trend for an increase. Partial correlation analysis revealed that fasting C-peptide levels were positively associated with CNFL (

r
=
0.245

,

P
=
0.002

), CNFD (

r
=
0.180

,

P
=
0.024

), and CNBD (

r
=
0.214

,

P
=
0.008

) after adjusting for age and gender. Using multiple linear regression analysis, fasting C-peptide levels were also closely associated with CNFL (

P
=
0.047

) and CNBD (

P
=
0.038

) after multiple adjustments. However, this association disappeared after further adjusting for duration of diabetes. Further analysis indicated that fasting C-peptide levels declined with duration of diabetes (

r
=
−
0.267

,

P
=
0.001

). Conclusions. C-peptide was closely associated with corneal neuropathy and disease duration in T2DM. C-peptide levels might be both an indicator of beta-cell function and a marker of disease severity (such as diabetic corneal neuropathy) and duration.
Contribution of Tocols to Food Sensorial Properties, Stability, and Overall Quality
Authors: Delgado Amélia , Al-Hamimi Said , Ramadan Mohamed Fawzy , Wit Maryna De , Durazzo Alessandra , Nyam Kar Lin , Issaoui Manel
Published: December 2020

This paper reviews the contribution of tocopherols and tocotrienols (tocols) to food quality as well as their bioactivity and health-promoting properties, which have attracted researchers and food technologists. Tocols are lipophilic phenolic antioxidants encompassing tocopherols that are characterized by a saturated side chain and tocotrienols with an unsaturated isoprenoid side chain. Tocols are natural constituents of several foods like dairy, vegetable oils, nuts, and grains. Their presence in foods, namely, as food additives, helps prevent lipid oxidation, which negatively affects the sensorial quality of foods, and even the nutritional value and safety. Supplementation of animals’ diets with tocopherols has proven its effectiveness in preserving fresh color and flavor of the meat. Although alfa-tocopherol displays much higher vitamin E activity than other tocols, health outcomes have been reported for tocotrienols, thus calling for more studies.
A New Multichannel Parallel Network Framework for the Special Structure of Multilead ECG
Authors: Lu Peng , Xi Hao , Zhou Bing , Zhang Hongpo , Lin Yusong , Chen Liwei , Gao Yang , Zhang Yabin , Hu Yanhua
Published: December 2020

Electrocardiogram (ECG) contains the rhythmic features of continuous heartbeat and morphological features of ECG waveforms and varies among different diseases. Based on ECG signal features, we propose a combination of multiple neural networks, the multichannel parallel neural network (MLCNN-BiLSTM), to explore feature information contained in ECG. The MLCNN channel is used in extracting the morphological features of ECG waveforms. Compared with traditional convolutional neural network (CNN), the MLCNN can accurately extract strong relevant information on multilead ECG while ignoring irrelevant information. It is suitable for the special structures of multilead ECG. The Bidirectional Long Short-Term Memory (BiLSTM) channel is used in extracting the rhythmic features of ECG continuous heartbeat. Finally, by initializing the core threshold parameters and using the backpropagation algorithm to update automatically, the weighted fusion of the temporal-spatial features extracted from multiple channels in parallel is used in exploring the sensitivity of different cardiovascular diseases to morphological and rhythmic features. Experimental results show that the accuracy rate of multiple cardiovascular diseases is 87.81%, sensitivity is 86.00%, and specificity is 87.76%. We proposed the MLCNN-BiLSTM neural network that can be used as the first-round screening tool for clinical diagnosis of ECG.
ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia
Authors: Oravecz-Wilson Katherine , Rossi Corinne , Zajac Cynthia , Sun Yaping , Li Lu , Decoville Thomas , Fujiwara Hideaki , Kim Stephanie , Peltier Daniel , Reddy Pavan
Published: December 2020

Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild-type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T-cell allo-immunity, we generated T-cell–specific Atg5 knock-out mice. Deficiency of ATG5-dependent autophagy reduced T-cell proliferation and increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T-cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5-dependent autophagy uncouples T-cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT.

Significance:

These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.
The FABRIC Cancer Portal: A Ranked Catalogue of Gene Selection in Tumors Over the Human Coding Genome
Authors: Kelman Guy , Brandes Nadav , Linial Michal
Published: December 2020

Contemporary catalogues of cancer driver genes rely primarily on high mutation rates as evidence for gene selection in tumors. Here, we present The Functional Alteration Bias Recovery In Coding-regions Cancer Portal, a comprehensive catalogue of gene selection in cancer based purely on the biochemical functional effects of mutations at the protein level. Gene selection in the portal is quantified by combining genomics data with rich proteomic annotations. Genes are ranked according to the strength of evidence for selection in tumor, based on rigorous and robust statistics. The portal covers the entire human coding genome (∼18,000 protein-coding genes) across 33 cancer types and pan-cancer. It includes a selected set of cross-references to the most relevant resources providing genomics, proteomics, and cancer-related information. We showcase the portal with known and overlooked cancer genes, demonstrating the utility of the portal via its simple visual interface, which allows users to pivot between gene-centric and cancer type views. The portal is available at fabric-cancer.huji.ac.il.

Significance:

A new cancer portal quantifies and presents gene selection in tumor over the entire human coding genome across 33 cancer types and pan-cancer.
Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium
Authors: Chen Chung-Hsin , Grollman Arthur P. , Huang Chao-Yuan , Shun Chia-Tung , Sidorenko Viktoriya S. , Hashimoto Keiji , Moriya Masaaki , Turesky Robert J. , Yun Byeong Hwa , Tsai Karen , Wu Stephanie , Chuang Po-Ya , Tang Chao-Hsiun , Yang Wen-Horng , Tzai Tzong-Shin , Tsai Yuh-Shyan , Dickman Kathleen G. , Pu Yeong-Shiau
Published: December 2020

Background:

Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC).

Methods:

Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases.

Results:

In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC.

Conclusions:

Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan.

Impact:

This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.
Vaccine-Induced Intratumoral Lymphoid Aggregates Correlate with Survival Following Treatment with a Neoadjuvant and Adjuvant Vaccine in Patients with Resectable Pancreatic Adenocarcinoma
Authors: Zheng Lei , Ding Ding , Edil Barish H. , Judkins Carol , Durham Jennifer N. , Thomas Dwayne L. , Bever Katherine M. , Mo Guanglan , Solt Sara E. , Hoare Jessica A. , Bhattacharya Raka , Zhu Qingfeng , Osipov Arsen , Onner Beth , Purtell Katrina A. , Cai Hongyan , Parkinson Rose , Hacker-Prietz Amy , Herman Joseph M. , Le Dung T. , Azad Nilofer S. , De Jesus-Acosta Ana M.C. , Blair Alex B. , Kim Victoria , Soares Kevin C. , Manos Lindsey , Cameron John L. , Makary Martin A. , Weiss Matthew J. , Schulick Richard D. , He Jin , Wolfgang Christopher L. , Thompson Elizabeth D. , Anders Robert A. , Sugar Elizabeth , Jaffee Elizabeth M. , Laheru Daniel A.
Published: December 2020

Purpose:

Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX).

Patients and Methods:

Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS).

Results:

The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA.

Conclusions:

It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.
A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers
Authors: Kawakami Masanori , Mustachio Lisa Maria , Chen Yulong , Chen Zibo , Liu Xiuxia , Wei Cheng-Hsin , Roszik Jason , Kittai Adam S. , Danilov Alexey V. , Zhang Xiaoshan , Fang Bingliang , Wang Jing , Heymach John V. , Tyutyunyk-Massey Liliya , Freemantle Sarah J. , Kurie Jonathan M. , Liu Xi , Dmitrovsky Ethan
Published: December 2020

Cyclin-dependent kinase 2 (CDK2) antagonism inhibits clustering of excessive centrosomes at mitosis, causing multipolar cell division and apoptotic death. This is called anaphase catastrophe. To establish induced anaphase catastrophe as a clinically tractable antineoplastic mechanism, induced anaphase catastrophe was explored in different aneuploid cancers after treatment with CYC065 (Cyclacel), a CDK2/9 inhibitor. Antineoplastic activity was studied in preclinical models. CYC065 treatment augmented anaphase catastrophe in diverse cancers including lymphoma, lung, colon, and pancreatic cancers, despite KRAS oncoprotein expression. Anaphase catastrophe was a broadly active antineoplastic mechanism. Reverse phase protein arrays (RPPAs) revealed that along with known CDK2/9 targets, focal adhesion kinase and Src phosphorylation that regulate metastasis were each repressed by CYC065 treatment. Intriguingly, CYC065 treatment decreased lung cancer metastases in in vivo murine models. CYC065 treatment also significantly reduced the rate of lung cancer growth in syngeneic murine and patient-derived xenograft (PDX) models independent of KRAS oncoprotein expression. Immunohistochemistry analysis of CYC065-treated lung cancer PDX models confirmed repression of proteins highlighted by RPPAs, implicating them as indicators of CYC065 antitumor response. Phospho-histone H3 staining detected anaphase catastrophe in CYC065-treated PDXs. Thus, induced anaphase catastrophe after CYC065 treatment can combat aneuploid cancers despite KRAS oncoprotein expression. These findings should guide future trials of this novel CDK2/9 inhibitor in the cancer clinic.
Cabozantinib Unlocks Efficient In Vivo Targeted Delivery of Neutrophil-Loaded Nanoparticles into Murine Prostate Tumors
Authors: Chaudagar Kiranj Kishor , Landon-Brace Natalie , Solanki Aniruddh , Hieromnimon Hanna M. , Hegermiller Emma , Li Wen , Shao Yue , Joseph John , Wilkins Devan J. , Bynoe Kaela M. , Li Xiang-Ling , Clohessy John G. , Ullas Soumya , Karp Jeffrey M. , Patnaik Akash
Published: December 2020

A major barrier to the successful application of nanotechnology for cancer treatment is the suboptimal delivery of therapeutic payloads to metastatic tumor deposits. We previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anticancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of BSA-coated polymeric nanoparticles (BSA-NPs) into murine PTEN/p53-deficient prostate tumors. On the basis of the observation that BSA coating of NPs enhanced association and internalization by activated neutrophils by approximately 6-fold in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pretreated with cabozantinib. Flow cytometric analysis revealed an approximately 4-fold increase of neutrophil-associated BSA-NPs and an approximately 32-fold increase in mean fluorescent dye uptake following 3 days of cabozantinib/BSA-NP administration, relative to BSA-NP alone. Strikingly, neutrophil depletion with Ly6G antibody abolished dye-loaded BSA-NP accumulation within tumors to baseline levels, demonstrating targeted neutrophil-mediated intratumoral NP delivery. Furthermore, we observed an approximately 13-fold decrease in accumulation of BSA-NPs in the liver, relative to uncoated NPs, post-cabozantinib treatment, suggesting that BSA coating of NPs can significantly enhance cabozantinib-induced, neutrophil-mediated targeted intratumoral drug delivery, while mitigating off-target toxicity. Collectively, we demonstrate a novel targeted nano-immunotherapeutic strategy for enhanced intratumoral delivery of BSA-NPs, with translational potential to significantly augment therapeutic indices of cancer medicines, thereby overcoming current pharmacologic barriers commonly encountered in preclinical/early-phase drug development.
Abstract PO-080: Increasing of emergency presentation on colorectal cancer patients during COVID-19 pandemic: A retrospective study on single-center academic hospital
Authors: Bagus Budhi Ida , Bagus Metria Ida , Ayu Setyawati Ida , Kade Mastini Ida Ayu
Published: December 2020

Background: Colorectal cancer was the most common cancer found in the GI tract; the two most common clinical emergency presentations were intestinal obstruction and perforation on the tumor site or proximally to the distal tumor. During the COVID-19 pandemic, we must face the new condition; we should modify the clinical outpatients’ schedule, which could address the other problem, that colorectal cancer patients refuse to continue treatment planning and that elective and well-prepared operations will be decreased.

Methods: We will report the clinical presentation of our colorectal cancer patients during the last 2 months from March until May 2020. All patients with emergency presentation of colorectal cancer will be included; any comorbidities will be recorded on this study. Patients with emergency colorectal cancer who could not fit for emergency operation will be excluded. Inpatient mortality and postoperative complications will be evaluated.

Results: During the 2-month period, we evaluated 26 cases of emergency colorectal cancer patients. Most of the patients came with total intestinal obstruction on the emergency presentation (22 cases); the others (4 cases) came with diffuse peritonitis due to colonic perforation. All patients were reported negative for COVID-19 on rapid test. Exploratory laparotomy was done in this emergency setting; 10 patients had sigmoid colon cancer, 15 patients had rectal cancer, and 6 patients had right colonic cancer. Intestinal perforation was found on rectal cancer patients. Tumor resection and primary anastomosis were done on 18 patients, and the others had stoma diversion. Inpatient mortality reported on 4 patients of perforation cases and had cardiopulmonary complication postoperatively.

Conclusion: During the COVID-19 pandemic, emergency presentation of colorectal patients increased, and intestinal perforation was the risk factor of inpatient mortality.

Citation Format: Budhi Ida Bagus, Metria Ida Bagus, Setyawati Ida Ayu, Mastini Ida Ayu Kade. Increasing of emergency presentation on colorectal cancer patients during COVID-19 pandemic: A retrospective study on single-center academic hospital [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-080.
Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women
Authors: Zhang Xiaotao , Hoffman Kristi L. , Wei Peng , Elhor Gbito Kplola Y. , Joseph Reji , Li Fangyu , Scheet Paul , Chang Shine , Petrosino Joseph F. , Daniel Carrie R.
Published: December 2020

Given the increasing evidence that the oral microbiome is involved in obesity, diabetes, and cancer risk, we investigated baseline oral microbiota profiles in relation to all-cancer incidence among nonsmoking women enrolled in a Texas cohort of first- and second-generation immigrants of Mexican origin. We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 305 nonsmoking women, ages 20–75 years. We evaluated within- (alpha) and between-sample (beta) diversity by incident cancer status and applied linear discriminant analysis (LDA) effect size analysis to assess differentially abundant taxa. Diversity and candidate taxa in relation to all-cancer incidence were evaluated in multivariable-adjusted Cox regression models. Over 8.8 median years of follow-up, 31 incident cancer cases were identified and verified. Advanced age, greater acculturation, and cardiometabolic risk factors were associated with all-cancer incidence. Higher alpha diversity (age-adjusted Pdifference < 0.01) and distinct biological communities (Pdifference = 0.002) were observed by incident cancer status. Each unit increase in the Shannon diversity index yielded >8-fold increase in all-cancer and obesity-related cancer risk [multivariable-adjusted HR (95% confidence interval), 8.11 (3.14–20.94) and 10.72 (3.30–34.84), respectively] with similar findings for the inverse Simpson index. Streptococcus was enriched among women who did not develop cancer, while Fusobacterium, Prevotella, Mogibacterium, Campylobacter, Lachnoanaerobaculum, Dialister, and Atopobium were higher among women who developed cancer (LDA score ≥ 3; q-value < 0.01). This initial study of oral microbiota and overall cancer risk in nonsmoking Mexican American women suggests the readily accessible oral microbiota as a promising biomarker.

Prevention Relevance:

Mexican American women suffer a disproportionate burden of chronic health conditions that increase cancer risk. Few investigations of the microbiome, a key determinant of host health, have been conducted among this group. Oral microbiota profiles may provide early and accessible cancer biomarker data on invasive bacteria or community disruptions.
Targeting of CD40 and PD-L1 Pathways Inhibits Progression of Oral Premalignant Lesions in a Carcinogen-induced Model of Oral Squamous Cell Carcinoma
Authors: Monteiro de Oliveira Novaes Jose A. , Hirz Taghreed , Guijarro Irene , Nilsson Monique , Pisegna Marlese A. , Poteete Alissa , Barsoumian Hampartsoum B. , Fradette Jared J. , Chen Limo N. , Gibbons Don L. , Tian Xiangjun , Wang Jing , Myers Jeffrey N. , McArthur Mark J. , Bell Diana , William William N. , Heymach John V.
Published: December 2020

We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1–knockout (PD-L1ko) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1ko, also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting.

Prevention Relevance:

PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.
Cryosurgery as a Single Agent and in Combination with Intralesional Corticosteroids Is Effective on Young, Small Keloids and Induces Characteristic Histological and Immunohistological Changes: A Prospective Randomized Trial
Authors: Zouboulis Christos C. , Zouridaki Eftychia
Published: December 2020

Background: As the pathogenesis of keloids is poorly understood, there is no sound biological basis of keloid management. Few controlled therapeutic studies have been published, and recurrences are a major reason for treatment failure. Objective: To detect efficacy and safety of cryosurgery regimens on keloids and the occurring biological changes caused by the treatment. Methods: This prospective randomized study compared efficacy and tolerability as well as histological/immunohistochemical effects of liquid nitrogen contact cryosurgery as a single regimen (group A) and combined with intralesional corticosteroids (group B) on young (<2 years old), small (≤10 cm2) keloids in 40 patients (2-sided effect, α-error 1%, power 95%). Results: Marked flattening of the lesions was achieved by both regimens. Median lesional volumes decreased from 106 to 7 mm3 in group A (p = 0.001) and from 138 to 6 mm3 in group B (p < 0.0001; ns, between groups). Good to excellent responses were registered in 83.3 and 90% of patients in groups A and B, respectively, by evaluating the lesional volume, in 80 and 95% of patients by the physician’s evaluation and in 95% of patients in either group by the patient’s assessment. Follow-up of 6–36 months revealed no further significant changes. Cryosurgery was generally well tolerated, with minor pain during treatment not requiring (27.5%) or requiring local anaesthesia (5%) – but not analgesics –, and hypopigmentation (25%). Histological examination showed increased vessel number and lumen dilatation after treatment in group B and reduction of rete ridge length in both groups with more prominent changes in group A. Tenascin C staining demarcated keloids from normal skin before therapy, while after therapy the entire treated tissue was labelled. Interferon-γ expression was significantly decreased after therapy both regarding positively stained cells and intensity in both groups. Conclusion: Cryosurgery without and with intralesional corticosteroids is effective and safe on young, small keloids not only as a destructive physical procedure, but also by inducing biochemical and immunological scar rejuvenation.
Prevalence of Childhood Obesity in Portugal: A Narrative Review of the Literature
Authors: Frade Fátima , Carteiro Dora , Pereira Fátima , Marques Joana , Frade João
Published: December 2020

Background: The number of childhood obesity cases has been increasing in several countries around the world. In view of all the associated complications at an early stage of child development, it becomes urgent to understand this problem in depth. Objective: The aim of this work was to describe the prevalence of childhood obesity in Portugal and analyze the trend of its evolution in recent years. Materials and Methods: This is a narrative review of the literature in the databases on the following platforms: Academic Google, Scientific Electronic Library Online (SciELO), EBSCO Host, and Biblioteca Virtual em Saúde (BVS). The keywords used were: Prevalence, Pediatric Obesity, Child Overweight, and Portugal. Results and Discussion: Data on the prevalence of childhood obesity in Portugal are presented, describing the results of studies conducted at national and district level, in the different age groups and by sex. Conclusions: The data reveal that the prevalence of overweight in Portugal ranges between 20 and 40%, and of obesity between 10 and 15%, which reinforces the urgent need for monitoring and implementing preventive measures.
Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis
Authors: Koh Jin-Sin , Hung Olivia Y. , Eshtehardi Parham , Kumar Arnav , Rabah Rani , Raad Mohamad , Kumar Sonali , Chaudhry Sundeep , Gupta Sonu , Hosseini Hossein , Brilakis Emmanouil , Corban Michel , Sabbak Nabil , Burnett Grady Murphy , Liu Chang , Mehta Puja K. , Quyyumi Arshed A. , Samady Habib
Published: December 2020

Background:

Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease.

Methods:

In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed.

Results:

No significant differences in ΔSAQ angina frequency scores (
P
=0.53) or Duke Activity Status Index (
P
=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (
P
=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO
2
max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 (
P
=0.02).

Conclusions:

Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02147067.