bluuebunny/crossref_metadata_2025 huggingface dataset:
Phycoerythrin from Colaconema sp. Has Immunostimulatory Effects on the Whiteleg Shrimp Litopenaeus vannamei and Increases Resistance to Vibrio parahaemolyticus and White Spot Syndrome Virus
Authors: Lee Po-Tsang , Huang Jing , Huang Chin-Yi , Liu Zi-Xuan , Yeh Han-Yang , Huang Huai-Ting , Chen Li-Li , Nan Fan-Hua , Lee Meng-Chou
Published: August 2021

We investigated whether phycoerythrin (PE), a pigment sourced from marine algae, could act as an immunomodulatory agent in whiteleg shrimp (Litopenaeus vannamei). To this end, PE was extracted and purified from a PE-rich macroalgae, Colaconema sp. Our in vitro analysis demonstrated that PE enhanced prophenoloxidase and phagocytosis activity but inhibited the production of reactive oxygen species in hemocytes. Additionally, the PE signal could be detected using an in vivo imaging system after its injection into the ventral sinus of the cephalothorax of whiteleg shrimp. The expression profiles of fourteen immune-related genes were monitored in hemocytes from whiteleg shrimp injected with 0.30 μg of PE per gram of body weight, and crustin, lysozyme, penaiedin 4, and anti-lipopolysaccharide factor showed up-regulated post-stimulation. The induction of immune genes and enhancement of innate immune parameters by PE may explain the higher survival rates for shrimp that received different doses of PE prior to being challenged with Vibrio parahaemolyticus or white spot syndrome virus compared to controls. Combined, these results show that PE from Colaconema sp. can differentially stimulate the immune response of whiteleg shrimp in vitro and in vivo and could potentially be used as an immunomodulator in shrimp culture.
Moxifloxacin and Sulfamethoxazole-Based Nanocarriers Exhibit Potent Antibacterial Activities
Authors: Akbar Noor , Gul Jasra , Siddiqui Ruqaiyyah , Shah Muhammad Raza , Khan Naveed Ahmed
Published: August 2021

Antibiotic resistance is a major concern given the rapid emergence of multiple-drug-resistant bacteria compared to the discovery of novel antibacterials. An alternative strategy is enhancing the existing available drugs. Nanomedicine has emerged as an exciting area of research, showing promise in the enhanced development of existing antimicrobials. Herein, we synthesized nanocarriers and loaded these with available clinically approved drugs, namely Moxifloxacin and Sulfamethoxazole. Bactericidal activity against Gram-negative (Serratia marcescens, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Salmonella enterica) and Gram-positive (methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus cereus) bacteria was investigated. To characterize the nanocarriers and their drug-loaded forms, Fourier-transform infrared spectroscopy, dynamic light scattering, and atomic force microscopy were utilized. Antibacterial assays and hemolysis assays were carried out. Moreover, lactate dehydrogenase assays were performed to determine cytotoxicity against human cells. The results depicted the successful formation of drug–nanocarrier complexes. The potent antibacterial activities of the drug-loaded nanocarriers were observed and were significantly enhanced in comparison to the drugs alone. Hemolysis and cytotoxicity assays revealed minimal or negligible cytotoxic effects against human red blood cells and human cells. Overall, metronidazole-based nanocarriers loaded with Moxifloxacin and Sulfamethoxazole showed enhanced bactericidal effects against multiple-drug-resistant bacteria compared with drugs alone, without affecting human cells. Our findings show that drug-loaded nanocarriers hold promise as potent chemotherapeutic drugs against multiple-drug-resistant bacteria.
Overexpression of MnSOD Protects against Cold Storage-Induced Mitochondrial Injury but Not against OMA1-Dependent OPA1 Proteolytic Processing in Rat Renal Proximal Tubular Cells
Authors: Tobacyk Julia , KC Grishma , MacMillan-Crow Lee Ann
Published: August 2021

Kidneys from deceased donors undergo cold storage (CS) preservation before transplantation. Although CS is a clinical necessity for extending organ quality preservation, CS causes mitochondrial and renal injury. Specifically, many studies, including our own, have shown that the triggering event of CS-induced renal injury is mitochondrial reactive oxygen species (mROS). Here, we explored the role of OMA1-depedent OPA1 proteolytic processing in rat kidney proximal tubular epithelial (NRK) cells in an in vitro model of renal CS (18 h), followed by rewarming (6 h) (CS + RW). The involvement of mROS was evaluated by stably overexpressing manganese superoxide dismutase (MnSOD), an essential mitochondrial antioxidant enzyme, in NRK cells. Western blots detected rapid OPA1 proteolytic processing and a decrease in ATP-dependent cell viability in NRK cells subjected to CS + RW compared to control cells. Small interfering RNA (siRNA) knockdown of OMA1 reduced proteolytic processing of OPA1, suggesting that OMA1 is responsible for OPA1 proteolytic processing during CS + RW-induced renal injury. Overexpression of MnSOD during CS + RW reduced cell death, mitochondrial respiratory dysfunction, and ATP-dependent cell viability, but it did not prevent OMA1-dependent OPA1 processing. These data show for the first time that OMA1 is responsible for proteolytically cleaving OPA1 in a redox-independent manner during renal cell CS.
Fast and Stable Hyperspectral Multispectral Image Fusion Technique Using Moore–Penrose Inverse Solver
Authors: Long Jian , Peng Yuanxi , Zhou Tong , Zhao Liyuan , Li Jun
Published: August 2021

Fusion low-resolution hyperspectral images (LR-HSI) and high-resolution multispectral images (HR-MSI) are important methods for obtaining high-resolution hyperspectral images (HR-HSI). Some hyperspectral image fusion application areas have strong real-time requirements for image fusion, and a fast fusion method is urgently needed. This paper proposes a fast and stable fusion method (FSF) based on matrix factorization, which can largely reduce the computational workloads of image fusion to achieve fast and efficient image fusion. FSF introduces the Moore–Penrose inverse in the fusion model to simplify the estimation of the coefficient matrix and uses singular value decomposition (SVD) to simplify the estimation of the spectral basis, thus significantly reducing the computational effort of model solving. Meanwhile, FSF introduces two multiplicative iterative processes to optimize the spectral basis and coefficient matrix to achieve stable and high-quality fusion. We have tested the fusion method on remote sensing and ground-based datasets. The experiments show that our proposed method can achieve the performance of several state-of-the-art algorithms while reducing execution time to less than 1% of such algorithms.
Reinforcement Learning with Self-Attention Networks for Cryptocurrency Trading
Authors: Betancourt Carlos , Chen Wen-Hui
Published: August 2021

This work presents an application of self-attention networks for cryptocurrency trading. Cryptocurrencies are extremely volatile and unpredictable. Thus, cryptocurrency trading is challenging and involves higher risks than trading traditional financial assets such as stocks. To overcome the aforementioned problems, we propose a deep reinforcement learning (DRL) approach for cryptocurrency trading. The proposed trading system contains a self-attention network trained using an actor-critic DRL algorithm. Cryptocurrency markets contain hundreds of assets, allowing greater investment diversification, which can be accomplished if all the assets are analyzed against one another. Self-attention networks are suitable for dealing with the problem because the attention mechanism can process long sequences of data and focus on the most relevant parts of the inputs. Transaction fees are also considered in formulating the studied problem. Systems that perform trades in high frequencies cannot overlook this issue, since, after many trades, small fees can add up to significant expenses. To validate the proposed approach, a DRL environment is built using data from an important cryptocurrency market. We test our method against a state-of-the-art baseline in two different experiments. The experimental results show the proposed approach can obtain higher daily profits and has several advantages over existing methods.
Multi-Destination Path Planning Method Research of Mobile Robots Based on Goal of Passing through the Fewest Obstacles
Authors: Zhuang Hongchao , Dong Kailun , Qi Yuming , Wang Ning , Dong Lei
Published: August 2021

In order to effectively solve the inefficient path planning problem of mobile robots traveling in multiple destinations, a multi-destination global path planning algorithm is proposed based on the optimal obstacle value. A grid map is built to simulate the real working environment of mobile robots. Based on the rules of the live chess game in Go, the grid map is optimized and reconstructed. This grid of environment and the obstacle values of grid environment between each two destination points are obtained. Using the simulated annealing strategy, the optimization of multi-destination arrival sequence for the mobile robot is implemented by combining with the obstacle value between two destination points. The optimal mobile node of path planning is gained. According to the Q-learning algorithm, the parameters of the reward function are optimized to obtain the q value of the path. The optimal path of multiple destinations is acquired when mobile robots can pass through the fewest obstacles. The multi-destination path planning simulation of the mobile robot is implemented by MATLAB software (Natick, MA, USA, R2016b) under multiple working conditions. The Pareto numerical graph is obtained. According to comparing multi-destination global planning with single-destination path planning under the multiple working conditions, the length of path in multi-destination global planning is reduced by 22% compared with the average length of the single-destination path planning algorithm. The results show that the multi-destination global path planning method of the mobile robot based on the optimal obstacle value is reasonable and effective. Multi-destination path planning method proposed in this article is conducive to improve the terrain adaptability of mobile robots.
On-Site Monitoring for the Stability Evaluation of a Highway Tunnel above Goaves of Multi-Layer Coal Seams
Authors: Cai Guangtao , Sui Wanghua , Wu Shenglin , Wang Jilin , Chen Jiaxing
Published: August 2021

This paper presents the on-site monitoring of a medium–long highway tunnel constructed above a goaf of a multi-layer coal seam, in order to evaluate and maintain safety during operation. The case study of the Tianzimiao medium–long highway tunnel in Shanxi province was conducted above a goaf of a multi-layer coal seam with typical geological and engineering conditions in China, where a total of four coal seams (seam no. 3, 8, 12, and 15) were mined out with a total thickness of up to 11 m. Methods including data collection, engineering geological survey, drilling, geophysical prospecting, testing, and on-site monitoring were adopted, and a geo-mechanical model was established to conduct the research. Stratified monitoring was applied to investigate the individual settlement and deformation of the four layers of the goaf below, and a prediction of the possible deformation in tunnel floor ground was made based on the stratified measurements. The settlement of the tunnel sidewall, the internal stress in the fractured zone of the surrounding rock, and the deformation above the tunnel entrance were also monitored, and the monitoring data were compared with the numerical simulation results for the safety evaluation of the tunnel. The results show that the current tunnel deformation values and trend are both within the safety scope of the evaluation and prediction. The stability evaluation method for the multi-layer goaf used in this paper and the long-term on-site monitoring and timely feedback during operation is helpful to ensure the safe use of the tunnels above the goaves of multi-layer thick coal seams.
Adsorption of Natural Organic Matter and Phosphorus from Surface Water Using Heated Aluminum Oxide (Predeposited) Dynamic Membrane Adsorber
Authors: Malczewska Beata
Published: August 2021

The paper reports the removal of phosphorus and natural organic matter (NOM) from surface water by dynamic membrane (DM) adsorber. DM filter builds up as a layer of particles deposited via permeation through the membrane’s surface. This study reports the application of Heated Aluminium Oxide Particles (HAOPs) as a dynamic membrane adsorber. Filtration experiments were conducted with surface water and batch tests were carried out with synthetic water. The efficiency of phosphorus removal along with the efficiency of organics (represented as UV-254) removal was evaluated. Additionally, the impact of HAOPs surface loading on the changes of transmembrane pressure (TMP), the kinetics, isotherm modeling of the adsorption and the effect of the pH, the effect of ionic strength, the effect of coexisting organic matter on phosphorus removal efficiency were studied. In the case of phosphorus removal in batch adsorption experiments, its sorption kinetic and isotherm data were analyzed using pseudo-first- and pseudo-second-order models and Langmuir and Freundlich models, respectively. The results indicated that Langmuir adsorption isotherm fits the experimental data best (0.9894). The kinetics of phosphorus adsorption on HAOPs was best described by the pseudo-second-order model and the best removal was achieved at the pH 6–7 (96.65% on average). An increase in ionic strength did not impact the efficiency of phosphorus removal significantly. The outcome of this study highlights HAOPs efficiency in NOM removal up to 92% in filtration experiments. In the case of phosphorous, removal efficiency varied. For the highest HAOPs dose, the degree of phosphorus removal ranged up to 93 ± 5%. The same removal efficiency was observed for the lowest dose while for 17 g/m2 of HAOPs the fluctuations were larger and varied from 64.7% to 92%. The results demonstrate that HAOPs could potentially be applied in the removal of phosphorus from surface water, especially when there is a high concentration of phosphorus in the water. However, this process requires further research and optimization of its parameters.
Overview of Approaches to Improve Rhizoremediation of Petroleum Hydrocarbon-Contaminated Soils
Authors: Alotaibi Fahad , Hijri Mohamed , St-Arnaud Marc
Published: August 2021

Soil contamination with petroleum hydrocarbons (PHCs) has become a global concern and has resulted from the intensification of industrial activities. This has created a serious environmental issue; therefore, there is a need to find solutions, including application of efficient remediation technologies or improvement of current techniques. Rhizoremediation is a green technology that has received global attention as a cost-effective and possibly efficient remediation technique for PHC-polluted soil. Rhizoremediation refers to the use of plants and their associated microbiota to clean up contaminated soils, where plant roots stimulate soil microbes to mineralize organic contaminants to H2O and CO2. However, this multipartite interaction is complicated because many biotic and abiotic factors can influence microbial processes in the soil, making the efficiency of rhizoremediation unpredictable. This review reports the current knowledge of rhizoremediation approaches that can accelerate the remediation of PHC-contaminated soil. Recent approaches discussed in this review include (1) selecting plants with desired characteristics suitable for rhizoremediation; (2) exploiting and manipulating the plant microbiome by using inoculants containing plant growth-promoting rhizobacteria (PGPR) or hydrocarbon-degrading microbes, or a combination of both types of organisms; (3) enhancing the understanding of how the host–plant assembles a beneficial microbiome, and how it functions, under pollutant stress. A better understanding of plant–microbiome interactions could lead to successful use of rhizoremediation for PHC-contaminated soil in the future.
Measurement of NORM in Building Materials to Assess Radiological Hazards to Human Health and Develop the Standard Guidelines for Residents in Thailand: Case Study in Sand Samples Collected from Seven Northeastern Thailand Provinces
Authors: Sola Phachirarat , Injarean Uthaiwan , Picha Roppon , Kranrod Chutima , Kukusamude Chunyapuk , Tokonami Shinji
Published: August 2021

A total of 223 sand samples collected from seven provinces in Northeastern Thailand were analyzed for their gamma radioactivity from naturally occurring radioactive materials (NORMs), and the data were used to calculate the concentrations of Ra-226, Th-232, and K-40. Radiological safety indicators such as the indoor external dose rates (Din), the annual indoor effective dose (Ein), the activity concentration index (I), the radium equivalent activity (Raeq), the external hazard index (Hex), the internal haphazard index (Hin), and the excess lifetime cancer risk (ELCR) were calculated. The activity concentrations were found to be 36 ± 10 Bq/kg for Ra-226, 2.64 ± 0.58 Bq/kg for Th-232, and 323 ± 168  Bq/kg for K-40. Din is 62 ± 23 nGy/h. The Ein is 0.30 ± 0.11 mSv/y. The activity concentrations and other indicators were reported by each province and compared with the safety standards and are found to be within the safe limits in this study. The results can be used to develop the standard guideline levels for choosing building materials in Thailand.
Carbon Monoliths with Hierarchical Porous Structure for All-Vanadium Redox Flow Batteries
Authors: Vivo-Vilches Jose Francisco , Karakashov Blagoj , Celzard Alain , Fierro Vanessa , El Hage Ranine , Brosse Nicolas , Dufour Anthony , Etienne Mathieu
Published: August 2021

Carbon monoliths were tested as electrodes for vanadium redox batteries. The materials were synthesised by a hard-templating route, employing sucrose as carbon precursor and sodium chloride crystals as the hard template. For the preparation process, both sucrose and sodium chloride were ball-milled together and molten into a paste which was hot-pressed to achieve polycondensation of sucrose into a hard monolith. The resultant material was pyrolysed in nitrogen at 750 °C, and then washed to remove the salt by dissolving it in water. Once the porosity was opened, a second pyrolysis step at 900 °C was performed for the complete conversion of the materials into carbon. The products were next characterised in terms of textural properties and composition. Changes in porosity, obtained by varying the proportions of sucrose to sodium chloride in the initial mixture, were correlated with the electrochemical performances of the samples, and a good agreement between capacitive response and microporosity was indeed observed highlighted by an increase in the cyclic voltammetry curve area when the SBET increased. In contrast, the reversibility of vanadium redox reactions measured as a function of the difference between reduction and oxidation potentials was correlated with the accessibility of the active vanadium species to the carbon surface, i.e., was correlated with the macroporosity. The latter was a critical parameter for understanding the differences of energy and voltage efficiencies among the materials, those with larger macropore volumes having the higher efficiencies.
Epigenetics for Crop Improvement in Times of Global Change
Authors: Kakoulidou Ioanna , Avramidou Evangelia V. , Baránek Miroslav , Brunel-Muguet Sophie , Farrona Sara , Johannes Frank , Kaiserli Eirini , Lieberman-Lazarovich Michal , Martinelli Federico , Mladenov Velimir , Testillano Pilar S. , Vassileva Valya , Maury Stéphane
Published: August 2021

Epigenetics has emerged as an important research field for crop improvement under the on-going climatic changes. Heritable epigenetic changes can arise independently of DNA sequence alterations and have been associated with altered gene expression and transmitted phenotypic variation. By modulating plant development and physiological responses to environmental conditions, epigenetic diversity—naturally, genetically, chemically, or environmentally induced—can help optimise crop traits in an era challenged by global climate change. Beyond DNA sequence variation, the epigenetic modifications may contribute to breeding by providing useful markers and allowing the use of epigenome diversity to predict plant performance and increase final crop production. Given the difficulties in transferring the knowledge of the epigenetic mechanisms from model plants to crops, various strategies have emerged. Among those strategies are modelling frameworks dedicated to predicting epigenetically controlled-adaptive traits, the use of epigenetics for in vitro regeneration to accelerate crop breeding, and changes of specific epigenetic marks that modulate gene expression of traits of interest. The key challenge that agriculture faces in the 21st century is to increase crop production by speeding up the breeding of resilient crop species. Therefore, epigenetics provides fundamental molecular information with potential direct applications in crop enhancement, tolerance, and adaptation within the context of climate change.
Serum Selenium Level and 10-Year Survival after Melanoma
Authors: Rogoża-Janiszewska Emilia , Malińska Karolina , Baszuk Piotr , Marciniak Wojciech , Derkacz Róża , Lener Marcin , Jakubowska Anna , Cybulski Cezary , Huzarski Tomasz , Masojć Bartłomiej , Gronwald Jacek , Rudnicka Helena , Kram Andrzej , Kiedrowicz Magdalena , Boer Magdalena , Dębniak Tadeusz , Lubiński Jan
Published: August 2021

Melanoma is one of the most aggressive human malignancies. The determination of prognostic biomarkers is important for the early detection of recurrence and for the enrollment of the patients into different treatment regimens. Herein, we report the 10-year survival of 375 melanoma patients depending on their serum selenium levels. The study group was followed up from the date of melanoma diagnosis until death or 2020. Patients were assigned to one of four categories, in accordance with the increasing selenium level (I–IV quartiles). The subgroup with low selenium levels had a significant lower survival rate in relation to patients with high selenium levels, HR = 8.42; p = 0.005 and HR = 5.83; p = 0.02, for uni- and multivariable models, respectively. In the univariable analysis, we also confirmed the association between Breslow thickness, Clark classification and age at melanoma prognosis. In conclusion, a low serum selenium level was associated with an increased mortality rate in the 10 years following melanoma diagnosis. Future studies in other geographic regions with low soil selenium levels should be conducted to confirm our findings.
Simply Adding Oxygen during Hypothermic Machine Perfusion to Combat the Negative Effects of Ischemia-Reperfusion Injury: Fundamentals and Current Evidence for Kidneys
Authors: Darius Tom , Nath Jay , Mourad Michel
Published: August 2021

The use of high-risk renal grafts for transplantation requires optimization of pretransplant preservation and assessment strategies to improve clinical outcomes as well as to decrease organ discard rate. With oxygenation proposed as a resuscitative measure during hypothermic machine preservation, this review provides a critical overview of the fundamentals of active oxygenation during hypothermic machine perfusion, as well as the current preclinical and clinical evidence and suggests different strategies for clinical implementation.
SARS-CoV-2 RdRp Inhibitors Selected from a Cell-Based SARS-CoV-2 RdRp Activity Assay System
Authors: Min Jung Sun , Kwon Sunoh , Jin Young-Hee
Published: August 2021

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), urgently needs effective prophylactic and therapeutic drugs. RNA-dependent RNA polymerase (RdRp), essential for replicating and transcribing a viral RNA genome, is highly conserved in coronaviruses; thus, it is a potential target for inhibiting coronavirus infection. In this study, we generated the cell-based SARS-CoV-2 RdRp activity assay system by modifying a previously reported cell-based MERS-CoV RdRp activity assay system to screen for SARS-CoV-2 RdRp inhibitors. The assay system consisted of an expression plasmid encoding SARS-CoV-2 RdRp and an RdRp activity reporter plasmid. RdRp activity in the cells could be conveniently detected by luminescence after transfection. We confirmed that SARS-CoV-2 RdRp replicated double-stranded RNA using immunofluorescence staining and the inhibition of RdRp activity by remdesivir and lycorine using this system. Moreover, the Z-factor of this system was calculated to be 0.798, suggesting the reproducibility and reliability of the high-throughput screening system. Finally, we screened nucleoside and nucleotide analogs and identified adefovir dipivoxil, emtricitabine, telbivudine, entecavir hydrate, moroxydine and rifampin as novel SARS-CoV-2 RdRp inhibitors and therapeutic candidates for COVID-19 This system provides an effective high-throughput screening system platform for developing potential prophylactic and therapeutic drugs for COVID-19 and emerging coronavirus infections.
The Effect of Judgement Bias on Cue Utilization for Shot Prediction in Basketball Athletes
Authors: Li Yawei , Feng Tian
Published: August 2021

Background: Concerning the judgments bias and cue utilization in basketball athletes, previous shot anticipation tasks were hard to examine in regards to whether the experts’ judgement bias relies more on the cue of the player’s body or the ball trajectory. Methods: Four types of body–ball cues shots were employed: IN–IN, IN–OUT, OUT–IN, and OUT–OUT. Four temporal stages (i.e., shooting, rising, high point, and falling) were divided during a shot. Forty-two participants predicted the fate of the ball after watching the shot videos. Results: The results suggested that for the shooting, rising, and high point phase, compared to the non-athletes, the experts provided superior predictions for IN–IN condition and OUT–IN condition but fewer accurate predictions for IN–OUT condition and OUT–OUT condition. Moreover, a higher bias toward predicting the shots as “in” for the athletes than the non-athletes under early temporal conditions was confirmed. Conclusions: These findings strengthen the idea that the IN cues from both body information and ball trajectory could elicit the experts’ judgement bias for made shots and then influence their response, thus rendered two distinct (e.g., impeding and facilitating) effects for the incongruent body–ball cues, respectively.
Designing and Building Robust Innovative Learning Environments
Authors: Frelin Anneli , Grannäs Jan
Published: August 2021

Prior research shows that creating innovative learning spaces that work well for pupils and teachers is a challenge which implicates different stakeholders. The aim of this article is to inquire into how educational visions evolve and are expressed through the different phases of two school design processes as well as visualize how stakeholders’ roles in the processes result in innovative learning environments and practices that work well. The data consists of photographs from school visits, briefs, and interviews. The material is analyzed with a particular focus on educational vision, organization, and working methods. An analytical model showing the stakeholders’ levels of participation at each stage is revised and developed. The results indicate four common themes: Continuity (several stakeholders involved in more than one phase); Preparation (processes were long-term, continuous, and iterative, with future users testing and evaluating prototypes and other innovative interior design elements to be used in the new spaces); Alignment (early and extensive considerations of the school’s organization and working methods); and Participation (multi-professional teams with representation of a pedagogical perspective at the higher levels of participation). From this, it can be concluded that achieving robust, innovative learning environments involves stakeholders’ regard to the aspects of knowledge, education, organization, and economy.
Receptor-Mediated Mitophagy Rescues Cancer Cells under Hypoxic Conditions
Authors: Abdrakhmanov Alibek , Yapryntseva Maria A. , Kaminskyy Vitaliy O. , Zhivotovsky Boris , Gogvadze Vladimir
Published: August 2021

Targeting mitochondria with thenoyltrifluoroacetone (TTFA), an inhibitor of Complex II in the respiratory chain, stimulated cisplatin-induced apoptosis in various cell lines in normoxia but not in hypoxia. This can be explained by the elimination of mitochondria involved in triggering apoptotic cell death by mitophagy, either Parkin-dependent or receptor-mediated. Treatment with TTFA alone or in combination with cisplatin did not cause accumulation of PINK1, meaning that under hypoxic conditions cells survive through activation of a receptor-mediated pathway. Hypoxia triggers the accumulation of BNIP3 and BNIP3L (also known as NIX), key participants in receptor-mediated mitophagy. Under hypoxic conditions, stimulation of autophagy, as assessed by the accumulation of lipidated form of LC3 (LC3II), was observed. To exclude the contribution of canonical macroautophagy in LC3II accumulation, experiments were performed using U1810 cells lacking ATG13, a key enzyme of macroautophagy. Despite the absence of ATG13, hypoxia-mediated accumulation of LC3II was not affected, underlying the importance of the receptor-mediated pathway. In order to prove the protective role of BNIP3 against cisplatin-induced apoptosis, BNIP3-deficient A549 cells were used. Surprisingly, a BNIP3 knockout did not abolish hypoxia-induced protection; however, in cells lacking BNIP3, a compensatory upregulation of BNIP3L was detected. Thus, in the absence of BNIP3, mitophagy could be maintained by BNIP3L and lead to cell death suppression due to the elimination of proapoptotic mitochondria. When both BNIP3 and BNIP3L were knocked out, the inhibitory effect of hypoxia on apoptosis was diminished, although not abolished completely. Undoubtedly, receptor-mediated mitophagy is likely to be one of the mechanisms responsible for cell death suppression under hypoxic conditions.
Circulating miRNAs as Novel Non-Invasive Biomarkers to Aid the Early Diagnosis of Suspicious Breast Lesions for Which Biopsy Is Recommended
Authors: Giussani Marta , Ciniselli Chiara Maura , De Cecco Loris , Lecchi Mara , Dugo Matteo , Gargiuli Chiara , Mariancini Andrea , Mancinelli Elisa , Cosentino Giulia , Veneroni Silvia , Paolini Biagio , Orlandi Rosaria , Gennaro Massimiliano , Iorio Marilena Valeria , Depretto Catherine , Ferranti Claudio , Sozzi Gabriella , Sensi Marialuisa , Colombo Mario Paolo , Scaperrotta Gianfranco , Tagliabue Elda , Verderio Paolo
Published: August 2021

In population-based screens, tissue biopsy remains the standard practice for women with imaging that suggests breast cancer. We examined circulating microRNAs as minimally invasive diagnostic biomarkers to discriminate malignant from benign breast lesions. miRNAs were analyzed by OpenArray in a retrospective cohort of plasma samples including 100 patients with malignant (T), 89 benign disease (B), and 99 healthy donors (HD) divided into training and testing sets and a prospective cohort (BABE) of 289 women with suspicious imaging findings who underwent tissue biopsy. miRNAs associated with disease status were identified by univariate analysis and then combined into signatures by multivariate logistic regression models. By combining 16 miRNAs differentially expressed in the T vs. HD comparison, 26 signatures were also able to significantly discriminate T from B disease. Seven of them, involving 5 specific miRNAs (miR-625, miR-423-5p, miR-370-3p, miR-181c, and miR-301b), were statistically validated in the testing set. Among the 7 signatures, the discriminatory performances of 5 were confirmed in the prospective BABE Cohort. This study identified 5 circulating miRNAs that, properly combined, distinguish malignant from benign breast disease in women with a high likelihood of malignancy.
Leveraging Genomics, Transcriptomics, and Epigenomics to Understand the Biology and Chemoresistance of Ovarian Cancer
Authors: Muñoz-Galván Sandra , Carnero Amancio
Published: August 2021

Ovarian cancer is a major cause of fatality due to a gynecological malignancy. This lethality is largely due to the unspecific clinical manifestations of ovarian cancer, which lead to late detection and to high resistance to conventional therapies based on platinum. In recent years, we have advanced our understanding of the mechanisms provoking tumor relapse, and the advent of so-called omics technologies has provided exceptional tools to evaluate molecular mechanisms leading to therapy resistance in ovarian cancer. Here, we review the contribution of genomics, transcriptomics, and epigenomics techniques to our knowledge about the biology and molecular features of ovarian cancers, with a focus on therapy resistance. The use of these technologies to identify molecular markers and mechanisms leading to chemoresistance in these tumors is discussed, as well as potential further applications.
Enhancement of Radiosurgical Treatment Outcome Prediction Using MRI Radiomics in Patients with Non-Small Cell Lung Cancer Brain Metastases
Authors: Liao Chien-Yi , Lee Cheng-Chia , Yang Huai-Che , Chen Ching-Jen , Chung Wen-Yuh , Wu Hsiu-Mei , Guo Wan-Yuo , Liu Ren-Shyan , Lu Chia-Feng
Published: August 2021

The diagnosis of brain metastasis (BM) is commonly observed in non-small cell lung cancer (NSCLC) with poor outcomes. Accordingly, developing an approach to early predict BM response to Gamma Knife radiosurgery (GKRS) may benefit the patient treatment and monitoring. A total of 237 NSCLC patients with BMs (for survival prediction) and 256 patients with 976 BMs (for prediction of local tumor control) treated with GKRS were retrospectively analyzed. All the survival data were recorded without censoring, and the status of local tumor control was determined by comparing the last MRI follow-up in patients’ lives with the pre-GKRS MRI. Overall 1763 radiomic features were extracted from pre-radiosurgical magnetic resonance images. Three prediction models were constructed, using (1) clinical data, (2) radiomic features, and (3) clinical and radiomic features. Support vector machines with a 30% hold-out validation approach were constructed. For treatment outcome predictions, the models derived from both the clinical and radiomics data achieved the best results. For local tumor control, the combined model achieved an area under the curve (AUC) of 0.95, an accuracy of 90%, a sensitivity of 91%, and a specificity of 89%. For patient survival, the combined model achieved an AUC of 0.81, an accuracy of 77%, a sensitivity of 78%, and a specificity of 80%. The pre-radiosurgical radiomics data enhanced the performance of local tumor control and survival prediction models in NSCLC patients with BMs treated with GRKS. An outcome prediction model based on radiomics combined with clinical features may guide therapy in these patients.
Novel Prognostic Immunohistochemical Markers in Uveal Melanoma-Literature Review
Authors: Gajdzis Malgorzata , Kaczmarek Radoslaw , Gajdzis Pawel
Published: August 2021

Uveal melanoma is the most common primary intraocular neoplasm in adults. As there are currently no effective methods of treating the disease in the metastatic stage, there is a need to search for new prognostic factors that would enable a reliable assessment of the patient’s condition and constitute a possible therapeutic target. In this review, we have prepared the results of English-language studies on new prognostic factors determined with immunohistochemical methods. We found 64 articles in which the expression of various proteins was associated in a statistically significant manner with the histopathological and clinical prognostic factors identified by AJCC. The results of our work clearly show that the biology of uveal melanoma is extraordinarily complex. Numerous studies have shed new light on the complexity of the processes involved in the development of this cancer. Moreover, a careful analysis of the expression of individual proteins may allow the identification of homogeneous groups of patients requiring different treatment regimens.
Hyaluronic Acid-Functionalized Nanomicelles Enhance SAHA Efficacy in 3D Endometrial Cancer Models
Authors: Edwards Kadie , Yao Seydou , Pisano Simone , Feltracco Veronica , Brusehafer Katja , Samanta Sumanta , Oommen Oommen P. , Gazze S. Andrea , Paravati Roberta , Maddison Holly , Li Chao , Gonzalez Deyarina , Conlan R. Steven , Francis Lewis
Published: August 2021

Histone Deacetylase (HDAC) enzymes are upregulated in cancer leading to the development of HDAC inhibiting compounds, several of which are currently in clinical trials. Side effects associated with toxicity and non-specific targeting indicate the need for efficient drug delivery approaches and tumor specific targeting to enhance HDAC efficacy in solid tumor cancers. SAHA encapsulation within F127 micelles functionalized with a surface hyaluronic acid moiety, was developed to target endometrial cancer cells expressing elevated levels of CD44. In vitro viability and morphology analyses was conducted in both 2D and 3D models to assess the translational potential of this approach. Encapsulation enhanced SAHA delivery and activity, demonstrating increased cytotoxic efficacy in 2D and 3D endometrial cancer models. High-content imaging showed improved nanoparticle internalization in 2D and CD44 enhanced penetration in 3D models. In addition, the nano-delivery system enhanced spheroid penetration resulting in cell growth suppression, p21 associated cell cycle arrest, as well as overcoming the formation of an EMT associated phenotype observed in free drug treated type II endometrial cancer cells. This study demonstrates that targeted nanoparticle delivery of SAHA could provide the basis for improving its efficacy in endometrial cancer. Using 3D models for endometrial cancer allows the elucidation of nanoparticle performance and CD44 targeting, likely through penetration and retention within the tumor model.
Lung Cancer Surgery after Neoadjuvant Immunotherapy
Authors: Stefani Dirk , Plönes Till , Viehof Jan , Darwiche Kaid , Stuschke Martin , Schuler Martin , Aigner Clemens
Published: August 2021

In early-stage lung cancer, recurrences are observed even after curative resection. Neoadjuvant immunotherapy might be a promising approach to eliminate micrometastasis and to potentially reduce recurrence rates and improve survival. Early trials have shown encouraging rates of pathologic response to neoadjuvant therapy and have demonstrated that surgery can be safely performed after neoadjuvant immunotherapy with various agents and in combination with chemo-(radio)therapy. However, whether these response rates translate into improved disease-free survival rates and overall survival rates remains to be determined by ongoing phase III studies.
Perioperative Therapy for Non-Small Cell Lung Cancer with Immune Checkpoint Inhibitors
Authors: Soh Junichi , Hamada Akira , Fujino Toshio , Mitsudomi Tetsuya
Published: August 2021

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadjuvant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improvement in 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that adjuvant PT-DC followed by maintenance atezolitumab significantly prolonged disease-free survival over adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote immunogenic cell death, releasing tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. The Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than of neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.
Hypothalamic–Pituitary Autoimmunity in Patients Treated with Anti-PD-1 and Anti-PD-L1 Antibodies
Authors: Bellastella Giuseppe , Carbone Carla , Scappaticcio Lorenzo , Cirillo Paolo , Troiani Teresa , Morgillo Floriana , Vietri Maria Teresa , Della Corte Carminia Maria , De Falco Vincenzo , Napolitano Stefania , Maiorino Maria Ida , De Bellis Annamaria , Esposito Katherine
Published: August 2021

Background: Autoimmune hypophysitis is a frequent immune-related adverse event (irAE) in cancer patients treated with immunecheckpoint inhibitors. Studies seeking anti-pituitary (APA) and anti-hypothalamus (AHA) antibodies in patients treated with anti-PD-1 and anti-PD-L1 are scarce. The aim of this study is to search for APA and AHA and related pituitary dysfunction in patients treated with these agents. Methods:Cross-sectional and preliminary longitudinal studies were conducted at the Medical Oncology Unit and Endocrinology and Metabolic Diseases Unit of the University of Campania “Luigi Vanvitelli”. Fifty-four cancer patients on treatments with anti-PD-1 or anti-PD-L1 (Group 1) and 50 healthy controls were enrolled for a cross-sectional study; 13 cancer patients (Group 2) were enrolled for our preliminary longitudinal study. APA/AHA titers and changes in biochemical and hormonal profile were evaluated in Group 1; in Group 2, they were evaluated before and after nine weeks from the start of immunotherapy. Results: Patients of Group 1 showed a higher prevalence of APA and AHA than controls: 21 of them had APA, 16 had AHA, and 11 had both autoantibodies. In total, 7 of 13 patients in Group 2 became APA-positive and 3 became AHA-positive after nine weeks of immunotherapy, showing an increase in prolactin and a decrease in ACTH and IGF-1 levels compared with basal values. Conclusions:Anti-pituitary and anti-hypothalamus antibodies seem to play a pivotal role in hypothalamic–pituitary autoimmunity and secondary endocrine-related alterations evoked by anti-PD-1 and PD-L1 antibodies.
Protective and Therapeutic Effects of an IL-15:IL-15Rα-Secreting Cell-Based Cancer Vaccine Using a Baculovirus System
Authors: Do-Thi Van Anh , Lee Hayyoung , Jeong Hye Jin , Lee Jie-Oh , Kim Young Sang
Published: August 2021

This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization with this IL-15:IL-15Rα cancer vaccine delayed tumor growth in mice by inducing effector memory CD4+ and CD8+ cells and effector NK cells which are tumor-infiltrating. It caused strong antitumor immune responses of CD8+ effector cells in a tumor-antigen specific manner both in vitro and in vivo and significantly attenuated Treg cells which a control virus-infected cancer vaccine could induce. Post-treatment with this cancer vaccine after a live cancer cell injection also prominently delayed the growth of the tumor. Collectively, we demonstrate a vaccine platform consisting of BacMam virus-infected B16F10 or CT26 cancer cells that secrete IL-15:IL-15Rα. This study is the first demonstration of a functionally competent soluble IL-15:IL-15Rα complex-related cancer vaccine using a baculovirus system and advocates that the BacMam system can be used as a secure and rapid method of producing a protective and therapeutic cancer vaccine.
PI3K/Akt Pathway: The Indestructible Role of a Vintage Target as a Support to the Most Recent Immunotherapeutic Approaches
Authors: Caforio Matteo , de Billy Emmanuel , De Angelis Biagio , Iacovelli Stefano , Quintarelli Concetta , Paganelli Valeria , Folgiero Valentina
Published: August 2021

Pathologic activation of PI3Ks and the subsequent deregulation of its downstream signaling pathway is among the most frequent events associated with cellular transformation, cancer, and metastasis. PI3Ks are also emerging as critical factors in regulating anti-tumor immunity by either promoting an immunosuppressive tumor microenvironment or by controlling the activity and the tumor infiltration of cells involved in the immune response. For these reasons, significant pharmaceutical efforts are dedicated to inhibiting the PI3K pathway, with the main goal to target the tumor and, at the same time, to enhance the anti-tumor immunity. Recent immunotherapeutic approaches involving the use of adoptive cell transfer of autologous genetically modified T cells or immune check-point inhibitors showed high efficacy. However, mechanisms of resistance to these kinds of therapy are emerging, due in part to the inhibition of effector T cell functions exerted by the immunosuppressive tumor microenvironment. Here, we first describe how inhibition of PI3K/Akt pathway contribute to enhance anti-tumor immunity and further discuss how inhibitors of the pathway are used in combination with different immunomodulatory and immunotherapeutic agents to improve anti-tumor efficacy.
Time from Diagnosis and Correlates of Health-Related Quality of Life among Young Adult Colorectal Cancer Survivors
Authors: Miller Kimberly A. , Stal Julia , Gallagher Phuong , Weng Zhen , Freyer David R. , Kaslander Jonathan N. , Marin Priscilla , Lenz Heinz-Josef , Milam Joel E. , Govaerts Lauren , Barzi Afsaneh
Published: August 2021

The incidence of colorectal cancer (CRC) is rising among young adults. Health-related quality of life (HRQoL) in survivorship is not well-described in this population. We assessed HRQoL among young adult CRC survivors diagnosed from age 18–39 (AYAs) to examine differences by time from diagnosis, and to identify key correlates. A cross-sectional online survey was administered in collaboration with a national patient advocacy organization. The Functional Assessment of Cancer Therapy (FACT-C) was used to measure HRQoL, which assesses HRQoL globally and across 4 domains: emotional, physical, social, and functional. T-tests were conducted to compare HRQoL between survivors who were 6–18 months versus 19–36 months from diagnosis or relapse and multiple linear regression was conducted to identify correlates. The sample (n = 196) had a mean age of 32.2(SD ± 4.5); 116 (59.9%) were male; and the self-reported tumor location was colon (39.3%) or rectal (60.7%). The majority (56.4%) were diagnosed with stage 2 disease; 96.9% were non-metastatic. The mean global HRQoL score was 67.7 out of a possible score of 136. Across domains, mean scores were low. Emotional and physical well-being were significantly higher among survivors who were 19–36 months from diagnosis/relapse compared to those 6–18 months from diagnosis/relapse. Longer time from diagnosis and older current age were associated with higher HRQoL, while more intensive treatment and higher clinical disease stage were negatively associated, particularly in the emotional and physical domains. Overall, HRQoL was low in this population, and further research is needed to inform age-appropriate interventions to improve HRQoL for AYA CRC survivors.