bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Environmental Regulation on Efficiency of Green Innovation in China
Authors: Shen Tongtong , Li Dongju , Jin Yuanyuan , Li Jie
Published: May 2022

The implementation of a reasonable and effective environmental regulation policy can compensate for the dual externalities of green technology innovation and improve green innovation efficiency. Therefore, environmental regulation policy has gradually become an effective means of solving ecological environment problems and achieving green industrial transformation. This paper measures the green innovation efficiency of 30 provinces in China from 2009 to 2019 using the SBM (slacks-based measure) of super-efficiency based on the undesirable output. The dynamic panel regression model is established to explore the impact of different environmental regulations on green innovation efficiency and regional differences. The results reveal that the green innovation efficiency of the 30 provinces shows a fluctuating upward trend, but that differences among provinces are relatively significant. There is a nonlinear relationship between environmental regulation and green innovation efficiency. The impact of command-control and market incentive environmental regulations on green innovation efficiency shows inverted N-shaped and U-shaped patterns, respectively. In different regions, the impact of environmental regulation on green innovation efficiency is also different. In order to ensure that environmental regulation promotes green innovation efficiency, some recommendations are proposed for the government, enterprises, and three regions, respectively.
Sources and Variability of Plutonium in Chinese Soils: A Statistical Perspective with Moving Average
Authors: Li Sixuan , Ni Youyi , Guo Qiuju
Published: May 2022

We investigated the different sources and their corresponding impact areas of Pu in Chinese surface soils to illustrate the state-of-the-art of the sources, levels and distributions of 240Pu/239Pu atom ratios as well as 239+240Pu activity concentrations in China. For the first time a moving average strategy in combination with statistical analysis was employed to partition geographic areas in China based on the reported 240Pu/239Pu atom ratio and 239+240Pu concentration data from public literature. During the partitioning, the median (MED) of the dataset was basically employed as a criteria in place of the commonly used arithmetic average (AM). Concisely, three areas were partitioned according to the different influences of Pu from the Lop Nor (LNTS) and Semipalatinsk (STS) test sites and the global fallout. The partitioned Ternary area (80° E–105° E, 35° N–50° N) was supposed to have multiple sources of Pu including the STS and LNTS besides the global fallout, which was characterized with slightly lower 240Pu/239Pu atom ratios (MED = 0.174) as well as elevated 239+240Pu concentrations (MED = 0.416 mBq/g). Meanwhile, the Binary area (35° N–45° N, 100° E–115° E) was considered to have received the extra contribution from the high-yield nuclear tests at the LNTS besides the global fallout, resulting in the highest 240Pu/239Pu atom ratios (MED = 0.200) across China. The remaining area was marked as the Unitary area, where it only received the exclusive contribution of global fallout. Furthermore, through the statistical analysis of the 240Pu/239Pu data in the Unitary area, we recommended a value of 0.186 ± 0.021 (AM ± SD) as a representative or area-specific 240Pu/239Pu atom ratio baseline to characterize the global fallout derived Pu in Chinese soils.
Sensitivity to Different Reanalysis Data on WRF Dynamic Downscaling for South China Sea Wind Resource Estimations
Authors: Thankaswamy Anandh , Xian Tao , Ma Yong-Feng , Wang Lian-Ping
Published: May 2022

As the world is moving toward greener forms of energy, to mitigate the effects of global warming due to greenhouse gas emissions, wind energy has risen as the most invested-in renewable energy. China, as the largest consumer of world energy, has started investing heavily in wind energy resources. Most of the wind farms in China are located in Northern China, and they possess the disadvantage of being far away from the energy load. To mitigate this, recently, offshore wind farms are being proposed and invested in. As an initial step in the wind farm setting, a thorough knowledge of the wind energy potential of the candidate region is required. Here, we conduct numerical experiments with Weather Research and Forecasting (WRF) model forced by analysis (NCEP-FNL) and reanalysis (ERA-Interim and NCEP-CFSv2) to find the best choice in terms of initial and boundary data for downscale in the South China Sea. The simulations are validated by observation and several analyses. Specific locations along China’s coast are analyzed and validated for their wind speed, surface temperature, and energy production. The analysis shows that the model forced with ERA-Interim data provides the best simulation of surface wind speed characteristics in the South China Sea, yet the other models are not too far behind. Moreover, the analysis indicates that the Taiwan Strait along the coastal regions of China is an excellent region to set up wind farms due to possessing the highest wind speeds along the coast.
Decellularised Cartilage ECM Culture Coatings Drive Rapid and Robust Chondrogenic Differentiation of Human Periosteal Cells
Authors: Vas Wollis J. , Shah Mittal , Roberts Helen C. , Roberts Scott J.
Published: May 2022

The control of cell behaviour in an effort to create highly homogeneous cultures is becoming an area of intense research, both to elucidate fundamental biology and for regenerative applications. The extracellular matrix (ECM) controls many cellular processes in vivo, and as such is a rich source of cues that may be translated in vitro. Herein, we describe the creation of cell culture coatings from porcine decellularised hyaline cartilage through enzymatic digestion. Surprisingly, heat-mediated sterilisation created a coating with the capacity to rapidly and robustly induce chondrogenic differentiation of human periosteal cells. This differentiation was validated through the alteration of cell phenotype from a fibroblastic to a cuboidal/cobblestone chondrocyte-like appearance. Moreover, chondrogenic gene expression further supported this observation, where cells cultured on heat sterilised ECM-coated plastic displayed higher expression of COL2A1, ACAN and PRG4 (p < 0.05) compared to non-coated plastic cultures. Interestingly, COL2A1 and ACAN expression in this context were sensitive to initial cell density; however, SOX9 expression appeared to be mainly driven by the coating independent of seeding density. The creation of a highly chondrogenic coating may provide a cost-effective solution for the differentiation and/or expansion of human chondrocytes aimed towards cartilage repair strategies.
Obesogens in Foods
Authors: Kladnicka Iva , Bludovska Monika , Plavinova Iveta , Muller Ludek , Mullerova Dana
Published: May 2022

Obesogens, as environmental endocrine-disrupting chemicals, are supposed to have had an impact on the prevalence of rising obesity around the world over the last forty years. These chemicals are probably able to contribute not only to the development of obesity and metabolic disturbances in individuals, but also in their progeny, having the capability to epigenetically reprogram genetically inherited set-up points for body weight and body composition control during critical periods of development, such as fetal, early life, and puberty. In individuals, they may act on myriads of neuro-endocrine–immune metabolic regulatory pathways, leading to pathophysiological consequences in adipogenesis, lipogenesis, lipolysis, immunity, the influencing of central appetite and energy expenditure regulations, changes in gut microbiota–intestine functioning, and many other processes. Evidence-based medical data have recently brought much more convincing data about associations of particular chemicals and the probability of the raised risk of developing obesity. Foods are the main source of obesogens. Some obesogens occur naturally in food, but most are environmental chemicals, entering food as a foreign substance, whether in the form of contaminants or additives, and they are used in a large amount in highly processed food. This review article contributes to a better overview of obesogens, their occurrence in foods, and their impact on the human organism.
Comparative Analysis of rRNA Removal Methods for RNA-Seq Differential Expression in Halophilic Archaea
Authors: Pastor Mar Martinez , Sakrikar Saaz , Rodriguez Deyra N. , Schmid Amy K.
Published: May 2022

Despite intense recent research interest in archaea, the scientific community has experienced a bottleneck in the study of genome-scale gene expression experiments by RNA-seq due to the lack of commercial and specifically designed rRNA depletion kits. The high rRNA:mRNA ratio (80–90%: ~10%) in prokaryotes hampers global transcriptomic analysis. Insufficient ribodepletion results in low sequence coverage of mRNA, and therefore, requires a substantially higher number of replicate samples and/or sequencing reads to achieve statistically reliable conclusions regarding the significance of differential gene expression between case and control samples. Here, we show that after the discontinuation of the previous version of RiboZero (Illumina, San Diego, CA, USA) that was useful in partially or completely depleting rRNA from archaea, archaeal transcriptomics studies have experienced a slowdown. To overcome this limitation, here, we analyze the efficiency for four different hybridization-based kits from three different commercial suppliers, each with two sets of sequence-specific probes to remove rRNA from four different species of halophilic archaea. We conclude that the key for transcriptomic success with the currently available tools is the probe-specificity for the rRNA sequence hybridization. With this paper, we provide insights into the archaeal community for selecting certain reagents and strategies over others depending on the archaeal species of interest. These methods yield improved RNA-seq sensitivity and enhanced detection of low abundance transcripts.
PVR (CD155) Expression as a Potential Prognostic Marker in Multiple Myeloma
Authors: Lee Byung-Hyun , Kim Ji-Hea , Kang Ka-Won , Lee Se-Ryeon , Park Yong , Sung Hwa-Jung , Kim Byung-Soo
Published: May 2022

Poliovirus receptor (PVR, CD155) is upregulated during tumor progression, and PVR expression is associated with poor prognosis in cancer patients; however, prognostic implications for PVR in multiple myeloma (MM) have not been investigated. PVR plays an immunomodulatory role by interacting with CD226, CD96, and TIGIT. TIGIT is a checkpoint inhibitory receptor that can limit adaptive and innate immunity, and it binds to PVR with the highest affinity. We used immunohistochemistry, ELISA, qPCR, and flow cytometry to investigate the role of PVR in MM. PVR was highly expressed in patients with MM, and membrane PVR expression showed a significant correlation with soluble PVR levels. PVR expression was significantly associated with the Revised-International Staging System stage, presence of extramedullary plasmacytoma and bone lesion, percentage of bone marrow plasma cells (BMPCs), and β2-microglobulin levels, suggesting a possible role in advanced stages and metastasis. Furthermore, TIGIT expression was significantly correlated with the percentage of BMPCs. Patients with high PVR expression had significantly shorter overall and progression-free survival, and PVR expression was identified as an independent prognostic factor for poor MM survival. These findings indicate that PVR expression is associated with MM stage and poor prognosis, and is a potential prognostic marker for MM.
The First Neocentric, Discontinuous, and Complex Small Supernumerary Marker Chromosome Composed of 7 Euchromatic Blocks Derived from 5 Different Chromosomes
Authors: Weber André , Liehr Thomas , Al-Rikabi Ahmed , Bilgen Simal , Heinrich Uwe , Schiller Jenny , Stumm Markus
Published: May 2022

Background: The majority of small supernumerary marker chromosomes (sSMCs) are derived from one single chromosome. Complex sSMCs instead consist of two to three genomic segments, originating from different chromosomes. Additionally, discontinuous sSMCs have been seen; however, all of them are derived from one single chromosome. Here, we reported a 41 year-old patient with infertility, hypothyroidism, rheumatism, and degenerative spine and schizoaffective disorder, being a carrier of a unique, complex, and discontinuous sSMC. Methods: The sSMC was characterized in detail by banding and molecular cytogenetics including fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (aCGH), as well as by optical genome mapping (OGM). Results: The neocentric sSMC characterized here contained seven portions of five different chromosomes and was present in ~50% of both peripheral blood cells and buccal mucosa cells. aCGH and OGM revealed gains of 8q12.3q12.3, 8q22.3–8q23.1, 9q33.3–9q34.11, 14q21.1–14q21.1, 14q21.1–14q21.2, 15q21.2–15q21.2, and 21q21.1–21q21.1. Furthermore, glass-needle based microdissection and reverse FISH, as well as FISH with locus-specific probes confirmed these results. The exact order of the involved euchromatic blocks could be decoded by OGM. Conclusions: Among the >7000 reported sSMCs in the literature, this is the only such complex, discontinuous, and neocentric marker with a centric minute shape.
Two-Dimensional Material-Based Electrochemical Sensors/Biosensors for Food Safety and Biomolecular Detection
Authors: Li Tao , Shang Dawei , Gao Shouwu , Wang Bo , Kong Hao , Yang Guozheng , Shu Weidong , Xu Peilong , Wei Gang
Published: May 2022

Two-dimensional materials (2DMs) exhibited great potential for applications in materials science, energy storage, environmental science, biomedicine, sensors/biosensors, and others due to their unique physical, chemical, and biological properties. In this review, we present recent advances in the fabrication of 2DM-based electrochemical sensors and biosensors for applications in food safety and biomolecular detection that are related to human health. For this aim, firstly, we introduced the bottom-up and top-down synthesis methods of various 2DMs, such as graphene, transition metal oxides, transition metal dichalcogenides, MXenes, and several other graphene-like materials, and then we demonstrated the structure and surface chemistry of these 2DMs, which play a crucial role in the functionalization of 2DMs and subsequent composition with other nanoscale building blocks such as nanoparticles, biomolecules, and polymers. Then, the 2DM-based electrochemical sensors/biosensors for the detection of nitrite, heavy metal ions, antibiotics, and pesticides in foods and drinks are introduced. Meanwhile, the 2DM-based sensors for the determination and monitoring of key small molecules that are related to diseases and human health are presented and commented on. We believe that this review will be helpful for promoting 2DMs to construct novel electronic sensors and nanodevices for food safety and health monitoring.
Lowering the Sampling Rate: Heart Rate Response during Cognitive Fatigue
Authors: Lee Kar Fye Alvin , Chan Elliot , Car Josip , Gan Woon-Seng , Christopoulos Georgios
Published: May 2022

Cognitive fatigue is a mental state characterised by feelings of tiredness and impaired cognitive functioning due to sustained cognitive demands. Frequency-domain heart rate variability (HRV) features have been found to vary as a function of cognitive fatigue. However, it has yet to be determined whether HRV features derived from electrocardiogram data with a low sampling rate would remain sensitive to cognitive fatigue. Bridging this research gap is important as it has substantial implications for designing more energy-efficient and less memory-hungry wearables to monitor cognitive fatigue. This study aimed to examine (1) the level of agreement between frequency-domain HRV features derived from lower and higher sampling rates, and (2) whether frequency-domain HRV features derived from lower sampling rates could predict cognitive fatigue. Participants (N = 53) were put through a cognitively fatiguing 2-back task for 20 min whilst their electrocardiograms were recorded. Results revealed that frequency-domain HRV features derived from sampling rate as low as 125 Hz remained almost perfectly in agreement with features derived from the original sampling rate at 2000 Hz. Furthermore, frequency domain features, such as normalised low-frequency power, normalised high-frequency power, and the ratio of low- to high-frequency power varied as a function of increasing cognitive fatigue during the task across all sampling rates. In conclusion, it appears that sampling at 125 Hz is more than adequate for frequency-domain feature extraction to index cognitive fatigue. These findings have significant implications for the design of low-cost wearables for detecting cognitive fatigue.
BDNF and Pro-BDNF in Amyotrophic Lateral Sclerosis: A New Perspective for Biomarkers of Neurodegeneration
Authors: Riolo Giulia , Ricci Claudia , De Angelis Nicoletta , Marzocchi Carlotta , Guerrera Gisella , Borsellino Giovanna , Giannini Fabio , Battistini Stefania
Published: May 2022

Amyotrophic Lateral Sclerosis (ALS) is characterized by the progressive degeneration of upper or lower motor neurons, leading to muscle wasting and paralysis, resulting in respiratory failure and death. The precise ALS aetiology is poorly understood, mainly due to clinical and genetic heterogeneity. Thus, the identification of reliable biomarkers of disease could be helpful in clinical practice. In this study, we investigated whether the levels of brain-derived neurotrophic factor (BDNF) and its precursor Pro-BDNF in serum and cerebrospinal fluid (CSF) may reflect the pathological changes related to ALS. We found higher BDNF and lower Pro-BDNF levels in ALS sera compared to healthy controls. BDNF/Pro-BDNF ratio turned out to be accurate in distinguishing ALS patients from controls. Then, the correlations of these markers with several ALS clinical variables were evaluated. This analysis revealed three statistically significant associations: (1) Patients carrying the C9orf72 expansion significantly differed from non-carrier patients and showed serum BDNF levels comparable to control subjects; (2) BDNF levels in CSF were significantly higher in ALS patients with faster disease progression; (3) lower serum levels of Pro-BDNF were associated with a shorter survival. Therefore, we suggest that BDNF and Pro-BDNF, alone or in combination, might be used as ALS prognostic biomarkers.
Core Signs and Symptoms in Children with Autism Spectrum Disorder Improved after Starting Risperidone and Aripiprazole in Combination with Standard Supportive Therapies: A Large, Single-Center, Retrospective Case Series
Authors: Alsayouf Hamza A. , Talo Haitham , Biddappa Marisa L.
Published: May 2022

Background: There are a number of medications prescribed to address comorbid challenging behaviors in children with autism spectrum disorder (ASD), including risperidone and aripiprazole. This retrospective case series reports the use of these drugs in children aged 2 to 13 years. Methodology: A total of 82 children (mean age, 5 years; 79% male) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai between January 2020 and September 2021 were included in this retrospective case series. All patients had comorbid challenging behaviors that were resistant to standard supportive therapies alone and warranted pharmacological intervention. The Childhood Autism Rating Scale—2nd Edition Standard form (CARS2-ST) and the Clinical Global Impression (CGI)—Severity (CGI-S) and CGI—Improvement (CGI-I) scales were used to assess the severity of ASD at baseline and to monitor response to treatment with risperidone or aripiprazole. Results: Besides the expected improvement in comorbid challenging behaviors, 79/82 patients (96%) attained a CGI-I score of 2 or 1 following treatment, and 35/82 patients (43%) achieved both a CGI-I score of 1 and minimal-to-no symptoms as per the CARS2-ST test, with complete resolution of their ASD signs and symptoms. The differences in the overall mean CARS2-ST and CGI-S scores pre- and post-treatment were statistically significant (Z = −7.86, p < 0.0001 for both), with pre- and post-treatment mean values of 42 and 23 for CARS2-ST, respectively, and 6 and 2 for CGI-S, respectively. The main side effects were asymptomatic elevated prolactin (n = 12) and excessive weight gain (n = 2). Conclusions: ASD core symptoms and comorbid behaviors in young children improved following chronic treatment with antipsychotic medications, either with or without medications for attention deficit hyperactivity disorder, when combined with standard supportive therapies. Double-blind, placebo-controlled clinical trials are needed to verify these findings.
The Contribution of Psychological Factors to Inter-Individual Variability in Conditioned Pain Modulation Is Limited in Young Healthy Subjects
Authors: Graeff Philipp , Stacheneder Regina , Alt Laura , Ruscheweyh Ruth
Published: May 2022

Conditioned pain modulation (CPM) describes the decrease in pain perception of a test stimulus (TS) when presented together with a heterotopic painful conditioning stimulus (CS). Inter-individual differences in CPM are large and have been suggested to reflect differences in endogenous pain modulation. In a previous analysis, we demonstrated that in young, healthy participants, inter-individual differences account for about one-third of CPM variance, with age and sex together explaining only 1%. Here, we investigated if psychological factors explain significant amounts of inter-individual variance in CPM. Using the same dataset as before, we performed both cross-sectional (n = 126) and repeated measures (n = 52, 118 observations) analysis and the corresponding variance decompositions, using results of psychological questionnaires assessing depression, trait anxiety and pain catastrophizing. Psychological factors did not significantly predict CPM magnitude, neither directly nor when interactions with the CPM paradigm were assessed; however, the interaction between depression and the paradigm approached significance. Variance decomposition showed that the interaction between depression and the CPM paradigm explained an appreciable amount of variance (3.0%), but this proportion seems small when compared to the residual inter-individual differences (35.4%). The main effects of the psychological factors and the interactions of anxiety or catastrophizing with the CPM paradigm are explained at <0.1% each. These results show that the contribution of psychological factors to inter-individual CPM differences in healthy participants is limited and that the large inter-individual variability in the CPM effect remains largely unexplained.
Visual Affective Stimulus Database: A Validated Set of Short Videos
Authors: Li Qiuhong , Zhao Yiran , Gong Bingyan , Li Ruyue , Wang Yinqiao , Yan Xinyuan , Wu Chao
Published: May 2022

Two hundred and ninety-nine videos representing four categories (people, animals, objects, and scenes) were standardized using Adobe Premiere Pro CC 2018, with a unified duration of 3 s, a resolution of 1080 pixels/inch, and a size of 1920 × 1080 mm2. One-hundred and sixteen participants (mean age 22.60 ± 2.06 years; 51 males) assessed the videos by scoring, on a self-reported 9-point scale, three dimensions of emotion: valence, arousal, and dominance. The content was attributed a specific valence (positive, neutral, or negative) if more than 60% of the participants identified it with an emotion category. Results: In total, 242 short videos, including 112 positive videos, 47 neutral videos, and 83 negative videos, were retained in the video stimuli database. In the three-dimensional degree of emotion, the distribution relationship between them conformed to the fundamental characteristics of emotion. The internal consistency reliability coefficient for valence, arousal, and dominance was 0.968, 0.984, and 0.970. The internal consistency reliability of the emotional dimensions for people and faces, animals, objects, and scenes ranged between 0.799 and 0.968. Conclusions: The emotion short-video system contains multi-scene dynamic stimuli with good reliability and scoring distribution and is applicable in emotion and emotion-related research.
Analysis of Buckling Deformation for the Side Plate of Rectangular CSFT Column Based on Plate Theory with Bi-Axial Loads
Authors: Xu Bing , Wang Lang , Xiang Chunyan , Han Zhenyu
Published: May 2022

In this paper, under the condition of bidirectional stress, the buckling deformation of the side plate in a rectangular concrete-filled steel tube (CFST) column has been studied in detail. We have conducted a theocratical analysis, an experimental validation and a finite element simulation to investigate the influences of the height-width ratios and Nominal Poisson’s ratios on the buckling form of the side plate, and we also try to explain the change of buckling form between unidirectional and bidirectional stress, both of them can provide a good reference and basis for design and application of the CFST column. The specific work can be summarized as follows: Firstly, a theoretical analysis has been conducted to study the buckling coefficient solution method of the thin plate under the conditions of axial compress and transverse tension. Then, under the conditions of the unidirectional and the bidirectional stress, a comparative study is carried out to investigate the changing relationship of the buckling coefficient (k) of the side plate; the results indicate that the buckling characteristic is changed due to the bidirectional stress, meanwhile, the buckling coefficient and the number of buckling half-wave will increase. Furthermore, the existing outcomes and the numerical simulations are adopted to study the relevance between the number of the elastic buckling half-wave in the side plate and the corresponding height-width ratio of the component; the results indicate that the former is larger than the latter. Finally, based on the obtained, the buckling relationship curve, the conclusion can be drawn as follows: when the bidirectional stress has been applied to the side plate, there is an equal interval between the different buckling half-waves; meanwhile, the interval shows a quadratic function reduce trend with the increase of nominal Poisson’s ratio.
Drivers towards Adopting Modular Integrated Construction for Affordable Sustainable Housing: A Total Interpretive Structural Modelling (TISM) Method
Authors: Khan Ayaz , Yu Rongrong , Liu Tingting , Guan Hong , Oh Erwin
Published: May 2022

This study features the development of a framework to identify drivers towards increasing adoption of modular integrated construction (MiC) methods for affordable sustainable housing (ASH). The rise of offsite construction (OSC) techniques, especially MiC, has been evident in recent years. MiC’s adoption in ASH is still underdeveloped; however, due to various benefits of MiC over conventional construction methods, it is envisioned to be a significant emerging approach for tackling growing housing demand, and ASH in particular. Although a few prior studies identified some factors for utilization of MiC towards ASH, studies to date have not provided a holistic review of drivers or a comprehensive framework of the interrelationships between such drivers. To address this issue, this study utilizes a three-way process including a systematic literature review, semi-structured interviews and the Total Interpretive Structure Modelling (TISM) method to study the drivers for MiC adoption in ASH. Initially, 111 drivers were extracted from a review of 40 studies in the existing literature. Following that, the significant drivers of MiC adoption for ASH were grouped into cost, time, productivity, quality, environmental, social, policy and demand. Drawing on concepts of systems thinking and graph theory, the TISM model for eight drivers was developed from both the literature review and the interview results. Four levels of hierarchy were found among drivers containing linkage, driving, depending and autonomous. Succeeding the steps of TISM and Reachability Matrix (RM) and Matrice d’ Impacts Croises-Multipication Appliqué a Classement (MICMAC) analysis, social drivers were found to have the highest driving and lowest dependency power, followed by productivity and policy drivers. This signifies the importance of social factors for enhancing MiC adoption for ASH. In addition, a strategic framework of boosting MiC adoption in ASH is also presented, highlighting the key stakeholders and strategies for transformation along with conclusions. This study delivers a wider landscape of drivers for MiC-ASH synergy that may assist practitioners, policy makers and relevant stakeholders to better understand the relationships between the drivers.
Regulation of Carcinogenesis by Sensory Neurons and Neuromediators
Authors: Erin Nuray , Shurin Galina V. , Baraldi James H. , Shurin Michael R.
Published: May 2022

Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
Analysis of Selected Nutritional Parameters in Patients with HPV-Related and Non-HPV-Related Oropharyngeal Cancer before and after Radiotherapy Alone or Combined with Chemotherapy
Authors: Brewczyński Adam , Jabłońska Beata , Mazurek Agnieszka Maria , Mrochem-Kwarciak Jolanta , Mrowiec Sławomir , Śnietura Mirosław , Kentnowski Marek , Kotylak Anna , Kołosza Zofia , Składowski Krzysztof , Rutkowski Tomasz
Published: May 2022

Background: Radiotherapy plays an essential role in the treatment of oropharyngeal carcinoma (OPC). The aim of this study was to assess and compare the nutritional status (NS) of patients with HPV-related (HPV+) and non-HPV-related (HPV-) OPC before and after radiotherapy (RT) or chemoradiotherapy (CRT). Methods: The analysis included 127 patients with OPC who underwent radiotherapy (RT) alone, or in combination with chemotherapy (CRT), in the I Radiation and Clinical Oncology Department of Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland. Patients were divided according to HPV status. Confirmation of HPV etiology was obtained from FFPE (formalin-fixed, paraffin-embedded) tissue material and/or extracellular circulating HPV DNA. Basic anthropometric and biochemical parameters before and after RT/CRT were compared between the HPV- and HPV+ groups. The effect of NS on survival was also analyzed. Results: In both groups, a significant decrease in all analyzed nutritional parameters was noted after RT/CRT (p < 0.01). CRT caused significant weight loss and decreases in BMI, albumin, total lymphocyte count (TLC), and hemoglobin concentration, as well as an increase in the Nutritional Risk Score (NRS) 2002, in HPV- and HPV+ patients. A significant decrease in prealbumin levels after CRT was noted only in HPV+ patients. RT caused a significant decrease in hemoglobin concentration and TLC in HPV- patients. There were no significant differences regarding other nutritional parameters after RT in either group. RT did not have negative impact on body mass index (BMI), weight, NRS, CRP, Alb, Prealb, or PNI. Overall survival (OS) and disease-free survival (DFS) were significantly better in patients with a higher BMI in the HPV- group (OS, p = 0.011; DFS, p = 0.028); DFS was significantly better in patients with C-reactive protein (CRP) < 3.5 g/dL in the HPV- (p = 0.021) and HPV+ (p = 0.018) groups, and with total lymphocyte count (TLC) >1.28/mm3 in the HPV+ group (p = 0.014). Higher NRS 2002 was an independent adverse prognostic factor for OS and DFS in HPV-, but not in the HPV+ group. Kaplan–Meier analysis showed that both OS and DFS were significantly better in HPV- patients with lower NRS 2002 scores. However, this relationship was not observed in the HPV+ group. Conclusions: Regardless of HPV status, patients with OPC can develop malnutrition during RT/CRT. Therefore, nutritional support during RT/CRT is required in patients with HPV- and HPV+ OPC.
Genome-Scale Metabolic Model Analysis of Metabolic Differences between Lauren Diffuse and Intestinal Subtypes in Gastric Cancer
Authors: Nam Seungyoon , Lee Yongmin
Published: May 2022

Gastric cancer (GC) is one of the most lethal cancers worldwide; it has a high mortality rate, particularly in East Asia. Recently, genetic events (e.g., mutations and copy number alterations) and molecular signaling associated with histologically different GC subtypes (diffuse and intestinal) have been elucidated. However, metabolic differences among the histological GC subtypes have not been studied systematically. In this study, we utilized transcriptome-based genome-scale metabolic models (GEMs) to identify differential metabolic pathways between Lauren diffuse and intestinal subtypes. We found that diverse metabolic pathways, including cholesterol homeostasis, xenobiotic metabolism, fatty acid metabolism, the MTORC1 pathway, and glycolysis, were dysregulated between the diffuse and intestinal subtypes. Our study provides an overview of the metabolic differences between the two subtypes, possibly leading to an understanding of metabolism in GC heterogeneity.
P-glycoprotein Mediates Resistance to the Anaplastic Lymphoma Kinase Inhibitor Ensartinib in Cancer Cells
Authors: Wu Chung-Pu , Hung Cheng-Yu , Murakami Megumi , Wu Yu-Shan , Lin Chun-Ling , Huang Yang-Hui , Hung Tai-Ho , Yu Jau-Song , Ambudkar Suresh
Published: May 2022

Ensartinib (X-396) is a promising second-generation small-molecule inhibitor of anaplastic lymphoma kinase (ALK) that was developed for the treatment of ALK-positive non-small-cell lung cancer. Preclinical and clinical trial results for ensartinib showed superior efficacy and a favorable safety profile compared to the first-generation ALK inhibitors that have been approved by the U.S. Food and Drug Administration. Although the potential mechanisms of acquired resistance to ensartinib have not been reported, the inevitable emergence of resistance to ensartinib may limit its therapeutic application in cancer. In this work, we investigated the interaction of ensartinib with P-glycoprotein (P-gp) and ABCG2, two ATP-binding cassette (ABC) multidrug efflux transporters that are commonly associated with the development of multidrug resistance in cancer cells. Our results revealed that P-gp overexpression, but not expression of ABCG2, was associated with reduced cancer cell susceptibility to ensartinib. P-gp directly decreased the intracellular accumulation of ensartinib, and consequently reduced apoptosis and cytotoxicity induced by this drug. The cytotoxicity of ensartinib could be significantly reversed by treatment with the P-gp inhibitor tariquidar. In conclusion, we report that ensartinib is a substrate of P-gp, and provide evidence that this transporter plays a role in the development of ensartinib resistance. Further investigation is needed.
Lung Cancer Screening: New Perspective and Challenges in Europe
Authors: Van Meerbeeck Jan P. , O’Dowd Emma , Ward Brian , Van Schil Paul , Snoeckx Annemiek
Published: May 2022

Randomized-controlled trials have shown clear evidence that lung cancer screening with low-dose CT in a high-risk population of current or former smokers can significantly reduce lung-cancer-specific mortality by an inversion of stage distribution at diagnosis. This paper will review areas in which there is good or emerging evidence and areas which still require investment, research or represent implementation challenges. The implementation of population-based lung cancer screening in Europe is variable and fragmented. A number of European countries seem be on the verge of implementing lung cancer screening, mainly through the implementation of studies or trials. The cost and capacity of CT scanners and radiologists are considered to be the main hurdles for future implementation. Actions by the European Commission, related to its published Europe’s Beating Cancer Plan and the proposal to update recommendations on cancer screening, could be an incentive to help speed up its implementation.
The Multiple Myeloma Landscape: Epigenetics and Non-Coding RNAs
Authors: Coira Isabel F. , Rincón Rafael , Cuendet Muriel
Published: May 2022

Despite advances in available treatments, multiple myeloma (MM) remains an incurable disease and represents a challenge in oncohematology. New insights into epigenetic factors contributing to MM development and progression have improved the knowledge surrounding its molecular basis. Beyond classical epigenetic factors, including methylation and acetylation, recent genome analyses have unveiled the importance of non-coding RNAs in MM pathogenesis. Non-coding RNAs have become of interest, as their dysregulation opens the door to new therapeutic approaches. The discovery, in the past years, of molecular techniques, such as CRISPR-Cas, has led to innovative therapies with potential benefits to achieve a better outcome for MM patients. This review summarizes the current knowledge on epigenetics and non-coding RNAs in MM pathogenesis.
Whole-Genome Sequencing Identifies PPARGC1A as a Putative Modifier of Cancer Risk in BRCA1/2 Mutation Carriers
Authors: Zhu Qianqian , Wang Jie , Yu Han , Hu Qiang , Bateman Nicholas W. , Long Mark , Rosario Spencer , Schultz Emily , Dalgard Clifton L. , Wilkerson Matthew D. , Sukumar Gauthaman , Huang Ruea-Yea , Kaur Jasmine , Lele Shashikant B. , Zsiros Emese , Villella Jeannine , Lugade Amit , Moysich Kirsten , Conrads Thomas P. , Maxwell George L. , Odunsi Kunle
Published: May 2022

While BRCA1 and BRCA2 mutations are known to confer the largest risk of breast cancer and ovarian cancer, the incomplete penetrance of the mutations and the substantial variability in age at cancer onset among carriers suggest additional factors modifying the risk of cancer in BRCA1/2 mutation carriers. To identify genetic modifiers of BRCA1/2, we carried out a whole-genome sequencing study of 66 ovarian cancer patients that were enriched with BRCA carriers, followed by validation using data from the Pan-Cancer Analysis of Whole Genomes Consortium. We found PPARGC1A, a master regulator of mitochondrial biogenesis and function, to be highly mutated in BRCA carriers, and patients with both PPARGC1A and BRCA1/2 mutations were diagnosed with breast or ovarian cancer at significantly younger ages, while the mutation status of each gene alone did not significantly associate with age of onset. Our study suggests PPARGC1A as a possible BRCA modifier gene. Upon further validation, this finding can help improve cancer risk prediction and provide personalized preventive care for BRCA carriers.
Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma
Authors: Jee ByulA , Seo Eunjeong , Park Kyunghee , Kim Yi Rang , Byeon Sun-ju , Lee Sang Min , Chung Jae Hoon , Song Wan , Sung Hyun Hwan , Jeon Hwang Gyun , Jeong Byong Chang , Seo Seong Il , Jeon Seong Soo , Lee Hyun Moo , Park Se Hoon , Park Woong-Yang , Kang Minyong
Published: May 2022

Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in PBRM1, a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of PBRM1 mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing (n = 60) and whole transcriptomic sequencing (WTS) (n = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of PBRM1 mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of PBRM1 mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of PBRM1 mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that GATM (glycine amidinotransferase), as a novel gene associated with PBRM1 mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene GATM can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs.
Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer
Authors: Bauman Julie E. , Julian Ricklie , Saba Nabil F. , Wise-Draper Trisha M. , Adkins Douglas R. , O’Brien Paul , Fidler Mary Jo , Gibson Michael K. , Duvvuri Umamaheswar , Heath-Chiozzi Margo , Alvarado Diego , Gedrich Richard , Golden Philip , Cohen Roger B.
Published: May 2022

In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8–22.1). Median PFS and OS were 2.2 (95% CI: 1.3–3.6) and 6.6 months (95% CI: 2.7–7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30–44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0–19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.
Promotional Effect of Pt-Doping on the Catalytic Performance of Pt−CeO2 Catalyst for CO Oxidation
Authors: Jiang Angran , Ren Zhibo , Qu Yaqi , Zhang Yanjun , Li Jianwei
Published: May 2022

Growing interest in the development of a hydrogen economy means that CO oxidation is increasingly important for upgrading H2-rich fuel gas streams for fuel cells. CeO2-supported catalysts are the most promising candidates for the catalytic oxidation of CO because of their high activity. In the present work, DFT+U calculations were performed to investigate the stability and CO oxidation reactivity of Ptn (n = 1−4) clusters supported on CeO2(111) (Pt/CeO2) and Pt-doped CeO2(111) (Pt/(Pt−Ce)O2) surfaces. The Pt clusters showed similar nucleation behavior on both CeO2 and (Pt−Ce)O2 surfaces. Further, the formation of oxygen vacancies (Ov) was facilitated because of surface charge depletion caused by the dopant Pt. Our DFT results suggest that the interfacial OV plays an important role in the CO oxidation reaction cycle, and the calculated energy barrier for the CO oxidation reaction on the Pt/(Pt−Ce)O2 surface is approximately 0.43 eV lower than that on the surface of the undoped catalyst, suggesting enhanced CO oxidation reactivity. Therefore, the chemical modification of the CeO2 support via doping is an effective strategy for improving the catalytic performance of Pt/CeO2.
The Role of Non-Coding RNAs in the Human Placenta
Authors: Žarković Milena , Hufsky Franziska , Markert Udo R. , Marz Manja
Published: May 2022

Non-coding RNAs (ncRNAs) play a central and regulatory role in almost all cells, organs, and species, which has been broadly recognized since the human ENCODE project and several other genome projects. Nevertheless, a small fraction of ncRNAs have been identified, and in the placenta they have been investigated very marginally. To date, most examples of ncRNAs which have been identified to be specific for fetal tissues, including placenta, are members of the group of microRNAs (miRNAs). Due to their quantity, it can be expected that the fairly larger group of other ncRNAs exerts far stronger effects than miRNAs. The syncytiotrophoblast of fetal origin forms the interface between fetus and mother, and releases permanently extracellular vesicles (EVs) into the maternal circulation which contain fetal proteins and RNA, including ncRNA, for communication with neighboring and distant maternal cells. Disorders of ncRNA in placental tissue, especially in trophoblast cells, and in EVs seem to be involved in pregnancy disorders, potentially as a cause or consequence. This review summarizes the current knowledge on placental ncRNA, their transport in EVs, and their involvement and pregnancy pathologies, as well as their potential for novel diagnostic tools.