bluuebunny/crossref_metadata_2025 huggingface dataset:
A Full Assistance System (FAS) for the Safe Use of the Tractor’s Foldable Rollover Protective Structure (FROPS)
Authors: Gattamelata Davide , Puri Daniele , Vita Leonardo , Fargnoli Mario
Published: January 2023

The use of agricultural tractors is a major concern in agriculture safety due to the high level of risk of loss of stability combined with the frequent absence of passive safety devices such as rollover protective structures (ROPSs). Indeed, although in most cases the ROPS is installed, when working in vineyards, orchards, or in other cases of limited crop height, the tractor is usually equipped with a foldable ROPS (FROPS), which is often misused because the effort needed for raising/lowering is excessive and the locking procedure is time-consuming. Thus, the goal of this research is to investigate the problem from the ergonomics point of view, developing a support system capable of facilitating FROPS operations. The research outcome consists of the development of a retrofitted full assistance system (FAS) for lowering/raising the FROPS by means of electric actuators. Additionally, an automatic locking device (ALD) was also developed to safely and automatically lock the FROPS. Both the FAS and ALD systems were implemented following a reverse-engineering approach, while their final validation was performed by means of a real prototype tested in a laboratory. The results achieved can contribute to expanding knowledge on human-centered research to improve safety in agriculture and thus social issues of sustainable agricultural systems.
A Novel Segmentation Recognition Algorithm of Agaricus bisporus Based on Morphology and Iterative Marker-Controlled Watershed Transform
Authors: Chen Chao , Yi Shanlin , Mao Jinyi , Wang Feng , Zhang Baofeng , Du Fuxin
Published: January 2023

Accurate recognition of Agaricus bisporus is a prerequisite for precise automatic harvesting in a factory environment. Aimed at segmenting mushrooms adhering together from the complex background, this paper proposes a watershed-based segmentation recognition algorithm for A. bisporus. First, the foreground of A. bisporus is extracted via Otsu threshold segmentation and morphological operations. Then, a preliminary segmentation algorithm and a novel iterative marker generation method are proposed to prepare watershed markers. On this basis, a marker-controlled watershed algorithm is adopted to segment and recognize A. bisporus individuals. All the algorithms are implemented based on OpenCV (Open Source Computer Vision) libraries. Tests on images of A. bisporus collected at the cultivation bed show that the average correct recognition rate of the proposed algorithm is 95.7%, the average diameter measurement error is 1.15%, and the average coordinate deviation rate is 1.43%. The average processing time is 705.7 ms per single image, satisfying the real-time constraints based on 1 image/s. The proposed algorithm performed better than the current Circle Hough Transform (OpenCV’s implementation). It is convenient and easy to operate, providing a sound basis for subsequent research on mechanized harvesting equipment for A. bisporus.
Acknowledgment to the Reviewers of Agronomy in 2022
Authors:   Agronomy Editorial Office
Published: January 2023

High-quality academic publishing is built on rigorous peer review [...]
Distribution Characteristics of Microbial Residues within Aggregates of Fluvo-Aquic Soil under Biochar Application
Authors: Cheng Yuyang , Zhang Shuai , Song Dali , Wu Hang , Wang Linxuan , Wang Xiubin
Published: January 2023

The use of biochar as a soil amendment has substantial potential to enhance soil quality and carbon sequestration. However, the responses to the addition of biochar based on soil microbial residues are not well understood, particularly at the aggregate level. Herein, a two-year field experiment investigated the characteristics of distribution of microbial residues in calcareous fluvo-aquic soil aggregates (SA) in Henan Province, China. Four treatments were established as follows: no fertilizer (CK), chemical fertilizer (NPK), biochar (BC), and biochar combined with chemical fertilizer (NPK + BC). The results showed that the effects of particle size substantially impacted the microbial residues with 2–0.25 mm SA having the largest contents of amino sugars and microbial residual carbon (MRC), followed by >2 mm SA. Compared with the CK, the NPK treatment markedly enhanced the levels of glucosamine (GluN), galactosamine (GalN), muramic acid (MurA), total amino sugar (TAS), and MRC in the 2–0.25 mm SA by 26.69%, 24.0%, 23.62%, 25.11%, and 24.82%, respectively. The NPK + BC treatment significantly increased the contents of GluN, GalN, TAS, and MRC in the bulk soil and 0.25–0.053 mm SA compared with the NPK treatment. Bacterial biomass and the activity of N-acetyl-glucosaminidase in the bulk soil and SA markedly and positively affected the content of carbon in the amino sugars and microbial residues. Overall, the 2–0.25 mm SA were microenvironments with the largest accumulation of soil microbial residues, and the combined application of NPK + BC was more effective at increasing the accumulation of microbial residues in the SA, which provides an ideal fertilization strategy to improve the soil microenvironment and enhance soil quality.
No Apparent Immediate Reproductive Costs of Overlapping Breeding and Moult in a Mediterranean Great Tit Population
Authors: Solís Iris , Álvarez Elena , Barba Emilio
Published: January 2023

Some phenological events in birds, such as breeding and moulting, are being affected by rising temperatures due to global warming, and many species have undergone temporary changes in these energetically demanding phases that are often separated in time. This has led to an increased overlap between breeding and moulting in some populations. This overlap causes conflicts in resource allocation and may impose fitness costs that could affect immediate reproductive performance. We tested whether this occurs in a great tit (Parus major) population in eastern Spain. In 71% of 390 pairs, in which both parents were captured during the period of overlap between moulting and breeding, at least one parent was moulting when feeding the chicks of its second brood. Later breeders were more likely to overlap breeding and moulting, and when both parents overlapped, clutch size was smaller, fewer eggs hatched and fewer fledglings in poorer body condition were produced. Some results were intermediate when only one parent moulted. However, all these differences between moulting and non-moulting pairs disappeared when the seasonal trend in reproductive parameters was taken into account, as moulting birds bred later and reproductive performance decreased seasonally. Therefore, the overlap of breeding and moulting does not impose additional reproductive costs in this population.
Ethyl Gallate Isolated from Castanopsis cuspidata var. sieboldii Branches Inhibits Melanogenesis and Promotes Autophagy in B16F10 Cells
Authors: Choi Moon-Hee , Yang Seung-Hwa , Kim Da-Song , Kim Nam-Doo , Shin Hyun-Jae
Published: January 2023

The Castanopsis cuspidata var. sieboldii (CCS) plant grows predominantly in temperate regions of Asian countries, such as South Korea. Research on CCS has so far concentrated on the nutritional analysis, antioxidant activity, and anti-inflammation properties of its branches. However, the isolation of compounds and structural elucidation of effective single molecules remain unexplored, necessitating further exploration of CCS branches. Therefore, this study demonstrates the antioxidant and antimelanogenic activity of a single substance of ethyl gallate (EG) isolated from CCS branch extracts. Notably, the antimelanogenic (whitening) activity of EG extracted from CCS branches remains unexplored. Tyrosinase inhibition, kinetic enzyme assays, and molecular docking studies were conducted using mushroom tyrosinase in order to examine the antioxidant mechanism and antimelanin activity of EG in B16F10 melanoma cells. Nontoxic EG concentrations were found to be below 5 µg/mL. While EG significantly reduced the levels of whitening-associated proteins, p-CREB, and p-PKA, it dose-dependently inhibited the expression of TYR, TRP-1, TRP-2, and transcription factor (MITF). In addition, EG downregulated melanogenetic gene expression and activated autophagy signals. Therefore, EG extracted from CCS branches could serve as a novel functional cosmetic material with antimelanogenic and autophagy-enhancing activity.
Methane Admixture Protects Liver Mitochondria and Improves Graft Function after Static Cold Storage and Reperfusion
Authors: Horváth Tamara , Sándor Lilla , Baráth Bálint , Donka Tibor , Baráth Bence , Mohácsi Árpád , Jász Kurszán Dávid , Hartmann Petra , Boros Mihály
Published: January 2023

Mitochondria are targets of cold ischemia-reperfusion (IR), the major cause of cell damage during static cold preservation of liver allografts. The bioactivity of methane (CH4) has recently been recognized in various hypoxic and IR conditions as having influence on many aspects of mitochondrial biology. We therefore hypothesized that cold storage of liver grafts in CH4-enriched preservation solution can provide an increased defence against organ dysfunction in a preclinical rat model of liver transplantation. Livers were preserved for 24 h in cold histidine–tryptophan–ketoglutarate (HTK) or CH4-enriched HTK solution (HTK-CH4) (n = 24 each); then, viability parameters were monitored for 60 min during normothermic isolated reperfusion and perfusate and liver tissue were collected. The oxidative phosphorylation capacity and extramitochondrial Ca2+ movement were measured by high resolution respirometry. Oxygen and glucose consumption increased significantly while hepatocellular damage was decreased in the HTK-CH4 grafts compared to the HTK group. Mitochondrial oxidative phosphorylation capacity was more preserved (128.8 ± 31.5 pmol/s/mL vs 201.3 ± 54.8 pmol/s/mL) and a significantly higher Ca2+ flux was detected in HTK-CH4 storage (2.9 ± 0.1 mV/s) compared to HTK (2.3 ± 0.09 mV/s). These results demonstrate the direct effect of CH4 on hepatic mitochondrial function and extramitochondrial Ca2+ fluxes, which may have contributed to improved graft functions and a preserved histomorphology after cold IR.
The Potential of Focusing Acoustic Retroreflectors for Architectural Surface Treatment
Authors: Cabrera Densil , Lu Shuai , Holmes Jonothan , Yadav Manuj
Published: January 2023

How much sound can a building surface reflect to a source, the location of which is not exactly known? This paper considers this question particularly for a planar surface acting as an array of retroreflectors, or of focusing retroreflectors. The question is investigated using finite-difference time-domain acoustic simulation, using ideal retroreflective patches achieved by space-reversal, and focusing achieved by delays. Extensive (7.2 × 7.2 m) and local (2.4 × 2.4 m) ideal planar reflector arrays were investigated at distances of 1.5 to 4 m from sources that were within a 2.4 × 2.4 m square plane. Patch sizes ranged from 0.3 m squares to the full reflector size. Physically realizable non-ideal focusing retroreflectors based on parabolic trihedra were also investigated. With sufficiently large patches, ideal focusing retroreflector arrays consistently outperform non-focusing retroreflector arrays. A large focusing retroreflector array has the potential to provide retroreflected energy levels (speech and A-weighted) from the first reflection to a source at 2 m distance comparable to the diffuse field energy level of acoustically supportive reverberant rooms. A small focusing retroreflector array returns less sound, but still much more than a single reflection from an equivalent specularly reflecting surface. Results from parabolic trihedra demonstrate that retroreflected energy levels similar to those from ideal surfaces can be achieved by architectural form. Challenges in translating these concepts to practical design solutions are discussed.
Image Scanning Microscopy to Investigate Polycomb Protein Colocalization onto Chromatin
Authors: Nepita Irene , Piazza Simonluca , Ruglioni Martina , Cristiani Sofia , Bosurgi Emanuele , Salvadori Tiziano , Vicidomini Giuseppe , Diaspro Alberto , Castello Marco , Bianchini Paolo , Storti Barbara , Bizzarri Ranieri
Published: January 2023

Super-resolution microscopy has been recently applied to understand the 3D topology of chromatin at an intermediated genomic scale (kilobases to a few megabases), as this corresponds to a sub-diffraction spatial scale crucial for the regulation of gene transcription. In this context, polycomb proteins are very renowned gene repressors that organize into the multiprotein complexes Polycomb Repressor Complex 1 (PRC1) and 2 (PRC2). PRC1 and PRC2 operate onto the chromatin according to a complex mechanism, which was recently recapitulated into a working model. Here, we present a functional colocalization study at 100–140 nm spatial resolution targeting PRC1 and PRC2 as well as the histone mark H3K27me3 by Image Scanning Microscopy (ISM). ISM offers a more flexible alternative to diffraction-unlimited SRMs such as STORM and STED, and it is perfectly suited to investigate the mesoscale of PRC assembly. Our data suggest a partially simultaneous effort of PRC1 and PRC2 in locally shaping the chromatin topology.
Electrochemical and Economic Analysis of No-Rinse, “True-Cr-Free” Surface Conversion Coatings for a Green, Cost-Saving, Corrosion Protection of 8079 Aluminium Alloy
Authors: Acquesta Annalisa , Sinagra Ciro , Monetta Tullio
Published: January 2023

Increasing the corrosion resistance of aluminium alloys using surface treatments while reducing the processes’ environmental impact and saving natural resources has become an urgent need. Some companies that typically use pollutant substances in their process lines have started to test low-environmental-impact products. This paper shows the results obtained using two commercial products for the conversion coating of AA8079 rolled-samples: the first, rinse, containing CrIII (the so-called “Cr-free” products), the second one, no-rinse, utterly free of Cr, based on hexafluorotitanate and dihydrogen hexafluorozirconate. The bare conversion-coated, and organic-coating-covered samples were compared with each other, evaluating their corrosion resistance when immersed in NaCl 3.5 wt.% aqueous solution. The experimental results showed that the completely Cr-free no-rinse conversion coatings demonstrate performance comparable to that of the so-called “Cr-free”. In addition, a comparison of the amount of water used in the “rinse” and the “no-rinse” industrial process is reported. Finally, an estimation of the economic balance for the process is presented, considering the waste reduction to be disposed of and the water quantity used. The aim of this paper was to demonstrate that some commercial conversion-coating products, completely free of Cr and no-rinse, are available nowadays, showing good protective properties and low environmental-impact, while guaranteeing an economic saving which is not negligible.
Collaborative Filtering Model of Graph Neural Network Based on Random Walk
Authors: Wang Jiahao , Mei Hongyan , Li Kai , Zhang Xing , Chen Xin
Published: January 2023

This paper proposes a novel graph neural network recommendation method to alleviate the user cold-start problem caused by too few relevant items in personalized recommendation collaborative filtering. A deep feedforward neural network is constructed to transform the bipartite graph of user–item interactions into the spectral domain, using a random wandering method to discover potential correlation information between users and items. Then, a finite-order polynomial is used to optimize the convolution process and accelerate the convergence of the convolutional network, so that deep connections between users and items in the spectral domain can be discovered quickly. We conducted experiments on the classic dataset MovieLens-1M. The recall and precision were improved, and the results show that the method can improve the accuracy of recommendation results, tap the association information between users and items more effectively, and significantly alleviate the user cold-start problem.
Westerly Variations in the Eastern Tibetan Plateau since the Last Interglacial Revealed by the Grain-Size Records of the Ganzi Loess
Authors: Yang Shengli , Zhou Jiantao , Chen Zixuan , Li Pushuang , Wen Chen , Xu Xuechao , Li Qiong
Published: January 2023

The westerlies play an important role in driving climate change in the Tibetan Plateau (TP). However, little is known about the history of the westerlies in the TP owing to limited observations and a lack of robust reconstructions. The widely distributed eolian loess in the eastern TP is one of the ideal materials to retrieve the intensity history for the westerlies. A detailed grain-size and endmember model analysis (EMMA) on the Ganzi loess sequence located in the eastern TP revealed that the EMMA decomposed the loess grain-size components into four endmembers: EM1 (modal size 1.42 μm) is related to pedogenesis, and EM2 (modal size 7.10 μm) is transported by the westerlies. Silt modes (EM3 and EM4) are transported by the TP winter monsoon or near-surface airflows. The mass accumulation rate (MAR) of EM2 indicated the westerly variations. Combined with the MAR, we reconstructed the history of westerly intensity since the last interglacial period from the Ganzi loess sequence. We found that the intensity of the westerlies showed typical glacial/interglacial variations since the last interglacial period in the eastern TP. The westerly intensity was strong with large fluctuations during the glacial period, whereas it was weak and stable during the Holocene and the last interglacial. The temperature gradient between high and low latitudes caused by changes in insolation and ice volume in the northern hemisphere were the dominant forcing mechanisms for the westerly intensity variations.
Aerosol Information Retrieval from GF-5B DPC Data over North China Using the Dark Dense Vegetation Algorithm
Authors: Zhang Ruijie , Zhou Wei , Chen Hui , Zhang Lianhua , Zhang Lijuan , Ma Pengfei , Zhao Shaohua , Wang Zhongting
Published: January 2023

A directional polarimetric camera (DPC) is a key payload on board China’s Gaofen 5B (hereafter denoted as GF-5B) satellite, a hyperspectral observation instrument for monitoring aerosols. On the basis of the dark dense vegetation (DDV) algorithm, this study applied DDV algorithm to DPC measurements. First, the reflectance of vegetation in three channels (0.443, 0.49, and 0.675 μm) was analyzed, and inversion channels were identified. Subsequently, the decrease in normalized difference vegetation index associated with various view angles was simulated, and the optimal view angle for extracting dark pixels was determined. Finally, the top-of-atmosphere reflectance at different view angles was simulated to determine the optimal view angle for aerosol inversion. The inversion experiments were conducted by using DPC data collected over North China from November 2021 to January 2022. The results revealed that DDV algorithm could monitor pollution from 30 December 2021 to 4 January 2022, and the inversion results were strongly correlated with Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol product and AERONET station data (R > 0.85).
Landscape Configuration Effects on Outdoor Thermal Comfort across Campus—A Case Study
Authors: Zhang Shaojie , Li Shanzhi , Shu Ling , Xiao Tieqiao , Shui Taotao
Published: January 2023

As a main place for student activities on campus, outdoor spaces have positive impacts on students’ physical and mental health. Namely, outdoor heat and comfort are of great significance to improve activity quality. Here, four unique outdoor spaces were studied to explore the varying effects on human thermal comfort during hot-summer and cold-winter periods. Distinct outdoor spaces (fully open, semi-open, semi-enclosed, and fully enclosed areas) from the southern campus of Anhui Jianzhu University were chosen. The PET was used as a metric for measuring thermal comfort and analyzing correlated spatiotemporal distributions. The results showed that outdoor thermal comfort was derived from multiple factors, including vegetation, underlying surface materials, building presence, and wind-heat environment. Notably, high correlations between Tmrt and thermal comfort were revealed, where such temperatures of places with trees or building shade were low; thus, PET was low. Further, Ws showed a significantly negative correlation with PET. Of the four outdoor space forms, the fully enclosed location had the lowest thermal comfort level, while the semi-enclosed spaces showed the highest level of body comfort. Therefore, semi-enclosed space (U-shaped) is recommended in campus planning and construction. Accordingly, an improved strategy was proposed based on experimental transformation for fully enclosed spaces. The thermal comfort after optimization was simulated to provide references for outdoor space thermal comfort improvement during seasonal extremes.
The Role of the Hydrogen Bond Network in Maintaining Heme Pocket Stability and Protein Function Specificity of C. diphtheriae Coproheme Decarboxylase
Authors: Sebastiani Federico , Baroni Chiara , Patil Gaurav , Dali Andrea , Becucci Maurizio , Hofbauer Stefan , Smulevich Giulietta
Published: January 2023

Monoderm bacteria accumulate heme b via the coproporphyrin-dependent biosynthesis pathway. In the final step, in the presence of two molecules of H2O2, the propionate groups of coproheme at positions 2 and 4 are decarboxylated to form vinyl groups by coproheme decarboxylase (ChdC), in a stepwise process. Decarboxylation of propionate 2 produces an intermediate that rotates by 90° inside the protein pocket, bringing propionate 4 near the catalytic tyrosine, to allow the second decarboxylation step. The active site of ChdCs is stabilized by an extensive H-bond network involving water molecules, specific amino acid residues, and the propionate groups of the porphyrin. To evaluate the role of these H-bonds in the pocket stability and enzyme functionality, we characterized, via resonance Raman and electronic absorption spectroscopies, single and double mutants of the actinobacterial pathogen Corynebacterium diphtheriae ChdC complexed with coproheme and heme b. The selective elimination of the H-bond interactions between propionates 2, 4, 6, and 7 and the polar residues of the pocket allowed us to establish the role of each H-bond in the catalytic reaction and to follow the changes in the interactions from the substrate to the product.
Application of Convolutional Neural Networks Using Action Potential Shape for In-Silico Proarrhythmic Risk Assessment
Authors: Jeong Da Un , Yoo Yedam , Marcellinus Aroli , Lim Ki Moo
Published: January 2023

This study proposes a convolutional neural network (CNN) model using action potential (AP) shapes as input for proarrhythmic risk assessment, considering the hypothesis that machine-learning features automatically extracted from AP shapes contain more meaningful information than do manually extracted indicators. We used 28 drugs listed in the comprehensive in vitro proarrhythmia assay (CiPA), consisting of eight high-risk, eleven intermediate-risk, and nine low-risk torsadogenic drugs. We performed drug simulations to generate AP shapes using experimental drug data, obtaining 2000 AP shapes per drug. The proposed CNN model was trained to classify the TdP risk into three levels, high-, intermediate-, and low-risk, based on in silico AP shapes generated using 12 drugs. We then evaluated the performance of the proposed model for 16 drugs. The classification accuracy of the proposed CNN model was excellent for high- and low-risk drugs, with AUCs of 0.914 and 0.951, respectively. The model performance for intermediate-risk drugs was good, at 0.814. Our proposed model can accurately assess the TdP risks of drugs from in silico AP shapes, reflecting the pharmacokinetics of ionic currents. We need to secure more drugs for future studies to improve the TdP-risk-assessment robustness.
Acknowledgment to the Reviewers of Behavioral Sciences in 2022
Authors:   Behavioral Sciences Editorial Office
Published: January 2023

High-quality academic publishing is built on rigorous peer review [...]
Galling-Free Fine Blanking of Titanium Plates Using Carbon-Supersaturated High-Speed Steel Punch
Authors: Aizawa Tatsuhiko , Fuchiwaki Kenji
Published: January 2023

A carbon-supersaturated (CS-) high-speed steel punch was prepared using low-temperature plasma carburizing for fine blanking of pure titanium plates. The bare high-speed steel punch was also prepared as a reference to describe the adhesion and abrasive galling in the fine blanking of the titanium plates, even in a single shot. The CS-punch was free from severe chemical galling, even after repeatedly fine-blanking the pure titanium plates. A microstructure analysis, element mapping and a chemical composition analysis demonstrated that titanium debris fragments slightly deposited at the CS-punch edges in the presence of agglomerated free-carbon film due to the CS-punch. This galling-free fine-blanking behavior came from the in situ formation of free carbon tribofilms. This in situ lubrication resulted in the completely burnished surfaces of pure titanium blanks.
Proteome-Wide Analysis Reveals TFEB Targets for Establishment of a Prognostic Signature to Predict Clinical Outcomes of Colorectal Cancer
Authors: Huang Zijia , Zhu Sheng , Han Ziqin , Li Chen , Liang Junze , Wang Yang , Zhang Shuixing , Zhang Jing
Published: January 2023

Dephosphorylation of transcription factor EB (TFEB) at Ser142 and Ser138 determines its nuclear localization and transcriptional activity. The link between TFEB-associated genes and colorectal cancer (CRC) progression and prognosis remains unclear. To systematically identify the targets of TFEB, we performed data-independent acquisition (DIA)-based quantitative proteomics to compare global protein changes in wild-type (WT) DLD1 cells and TFEBWT- or TFEBS142A/S138A (activated status)-expressing DLD1 cells. A total of 6048 proteins were identified and quantified in three independent experiments. The differentially expressed proteins in TFEBS142A/S138A versus TFEBWT and TFEBWT versus control groups were compared, and 60 proteins were identified as products of TFEB transcriptional regulation. These proteins were significantly associated with vesicular endocytic trafficking, the HIF-1 signaling pathway, and metabolic processes. Furthermore, we generated a TFEB-associated gene signature using a univariate and LASSO Cox regression model to screen robust prognostic markers. An eight-gene signature (PLSCR3, SERPINA1, ATP6V1C2, TIMP1, SORT1, MAP2, KDM4B, and DDAH2) was identified. According to the signature, patients were assigned to high-risk and low-risk groups. Higher risk scores meant worse overall survival and higher epithelial–mesenchymal transition (EMT) scores. Additionally, as per the clinicopathological parameters and gene signature, a nomogram was constructed that was utilized to enhance the quantification capacity in risk assessment for individual patients. This research shows that TFEB directly mediates network effects in CRC, and the identified TFEB gene signature-based model may provide important information for the clinical judgment of prognosis.
DRP1 Inhibition Enhances Venetoclax-Induced Mitochondrial Apoptosis in TP53-Mutated Acute Myeloid Leukemia Cells through BAX/BAK Activation
Authors: Jang Ji Eun , Hwang Doh Yu , Eom Ju-In , Cheong June-Won , Jeung Hoi-Kyung , Cho Hyunsoo , Chung Haerim , Kim Jin Seok , Min Yoo Hong
Published: January 2023

Although TP53 mutations in acute myeloid leukemia (AML) are associated with poor response to venetoclax, the underlying resistance mechanism remains unclear. Herein, we investigated the functional role of dynamin-related protein 1 (DRP1) in venetoclax sensitivity in AML cells with respect to TP53 mutation status. Effects of DRP1 inhibition on venetoclax-induced cell death were compared in TP53-mutated (THP-1 and Kasumi-1) and TP53 wild-type leukemia cell lines (MOLM-13 and MV4-11), as well as in primary AML cells obtained from patients. Venetoclax induced apoptosis in TP53 wild-type AML cells but had limited effects in TP53-mutated AML cells. DRP1 expression was downregulated in MOLM-13 cells after venetoclax treatment but was unaffected in THP-1 cells. Cotreatment of THP-1 cells with venetoclax and a TP53 activator NSC59984 downregulated DRP1 expression and increased apoptosis. Combination treatment with the DRP1 inhibitor Mdivi-1 and venetoclax significantly increased mitochondria-mediated apoptosis in TP53-mutated AML cells. The combination of Mdivi-1 and venetoclax resulted in noticeable downregulation of MCL-1 and BCL-xL, accompanied by the upregulation of NOXA, PUMA, BAK, and BAX. These findings suggest that DRP1 is functionally associated with venetoclax sensitivity in TP53-mutated AML cells. Targeting DRP1 may represent an effective therapeutic strategy for overcoming venetoclax resistance in TP53-mutated AML.
Novel Therapeutic Targets in Melanoma
Authors: Cerezo Michaël , Rocchi Stéphane
Published: January 2023

Melanoma is the most aggressive skin cancer type and ranks amongst the deadliest cancers due to its ability to develop resistance to current therapies [...]
Clinical Presentation, Management, and Evolution of Lymphomas in Patients with Inflammatory Bowel Disease: An ENEIDA Registry Study
Authors: Guerra Ivan , Bujanda Luis , Mañosa Miriam , Pérez-Martínez Isabel , Casanova María José , de la Peña Luisa , de Benito Marina , Rivero Montserrat , Varela Pilar , Bernal Lorena , Franco Ana Carolina , Ber Yolanda , Piqueras Marta , Tardillo Carlos , Ponferrada Ángel , Olivares Sonsoles , Lucendo Alfredo J. , Gilabert Pau , Sierra Ausín Mónica , Bellart María , Herrarte Amaia , Calafat Margalida , de Francisco Ruth , Gisbert Javier P. , Guardiola Jordi , Domènech Eugeni , Bermejo Fernando
Published: January 2023

An increased risk of lymphoma has been described in patients with inflammatory bowel disease (IBD). The aims of our study were to determine the clinical presentation, the previous exposure to immunosuppressive and biologic therapies, and the evolution of lymphomas in patients with IBD. IBD patients with diagnosis of lymphoma from October 2006 to June 2021 were identified from the prospectively maintained ENEIDA registry of GETECCU. We identified 52 patients (2.4 cases of lymphoma/1000 patients with IBD; 95% CI 1.8–3.1). Thirty-five were men (67%), 52% had ulcerative colitis, 60% received thiopurines, and 38% an anti-TNF drug before lymphoma diagnosis. Age at lymphoma was lower in those patients treated with thiopurines (53 ± 17 years old) and anti-TNF drugs (47 ± 17) than in those patients not treated with these drugs (63 ± 12; p < 0.05). Five cases had relapse of lymphoma (1.7 cases/100 patient-years). Nine patients (17%) died after 19 months (IQR 0–48 months). Relapse and mortality were not related with the type of IBD or lymphoma, nor with thiopurines or biologic therapies. In conclusion, most IBD patients had been treated with thiopurines and/or anti-TNF agents before lymphoma diagnosis, and these patients were younger at diagnosis of lymphoma than those not treated with these drugs. Relapse and mortality of lymphoma were not related with these therapies.
CAR-T Cell Therapy and the Gut Microbiota
Authors: Asokan Sahana , Cullin Nyssa , Stein-Thoeringer Christoph K. , Elinav Eran
Published: January 2023

Chimeric antigen receptor (CAR) - T cell cancer therapy has yielded promising results in treating hematologic malignancies in clinical studies, and a growing number of CAR-T regimens are approved for clinical usage. While the therapy is considered of great potential in expanding the cancer immunotherapy arsenal, more than half of patients receiving CAR-T infusions do not respond, while others develop significant adverse effects, collectively indicating a need for optimization of CAR-T treatment to the individual. The microbiota is increasingly suggested as a major modulator of immunotherapy responsiveness. Studying causal microbiota roles possibly contributing to CAR-T therapy efficacy, adverse effects reduction, and prediction of patient responsiveness constitutes an exciting area of active research. Herein, we discuss the latest developments implicating human microbiota involvement in CAR-T therapy, while highlighting challenges and promises in harnessing the microbiota as a predictor and modifier of CAR-T treatment towards optimized efficacy and minimization of treatment-related adverse effects.
Hyaluronan in the Cancer Cells Microenvironment
Authors: Karousou Evgenia , Parnigoni Arianna , Moretto Paola , Passi Alberto , Viola Manuela , Vigetti Davide
Published: January 2023

The presence of the glycosaminoglycan hyaluronan in the extracellular matrix of tissues is the result of the cooperative synthesis of several resident cells, that is, macrophages and tumor and stromal cells. Any change in hyaluronan concentration or dimension leads to a modification in stiffness and cellular response through receptors on the plasma membrane. Hyaluronan has an effect on all cancer cell behaviors, such as evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and metastasis. It is noteworthy that hyaluronan metabolism can be dramatically altered by growth factors and matrikines during inflammation, as well as by the metabolic homeostasis of cells. The regulation of HA deposition and its dimensions are pivotal for tumor progression and cancer patient prognosis. Nevertheless, because of all the factors involved, modulating hyaluronan metabolism could be tough. Several commercial drugs have already been described as potential or effective modulators; however, deeper investigations are needed to study their possible side effects. Moreover, other matrix molecules could be identified and targeted as upstream regulators of synthetic or degrading enzymes. Finally, co-cultures of cancer, fibroblasts, and immune cells could reveal potential new targets among secreted factors.
Inclusion of Metabolic Tumor Volume in Prognostic Models of Bone and Soft Tissue Sarcoma Increases the Prognostic Value
Authors: Pedersen Mette Abildgaard , Baad-Hansen Thomas , Gormsen Lars C. , Bærentzen Steen , Sandfeld-Paulsen Birgitte , Aggerholm-Pedersen Ninna , Vendelbo Mikkel Holm
Published: January 2023

Sarcomas are rare and have a high mortality rate. Further prognostic classification, with readily available parameters, is warranted, and several studies have examined circulating biomarkers and PET parameters separately. This single-site, retrospective study aimed to examine the prognostic values of several scoring systems in combination with PET parameters. We included 148 patients with sarcoma, who were treated and scanned at Aarhus University Hospital from 1 January 2016 to 31 December 2019. The Akaike information criterion and Harrell’s concordance index were used to evaluate whether the PET parameters added prognostic information to existing prognostic models using circulating biomarkers. Of the PET parameters, metabolic tumor volume (MTV) performed best, and when combined with the existing prognostic models, the prognostic value improved in all models. Backward stepwise selection was used to create a new model, SBSpib, which included albumin, lymphocytes, and one PET parameter, MTV. It has scores ranging from zero to three and increasing hazard ratios; HR = 4.83 (1.02–22.75) for group one, HR = 7.40 (1.6–33.42) for group two, and HR = 17.32 (3.45–86.93) for group three. Consequently, implementing PET parameters in prognostic models improved the prognostic value. SBSpib is a new prognostic model that includes both circulating biomarkers and PET parameters; however, validation in another sarcoma cohort is warranted.
The Omega-3 Docosahexaenoyl Ethanolamide Reduces CCL5 Secretion in Triple Negative Breast Cancer Cells Affecting Tumor Progression and Macrophage Recruitment
Authors: Augimeri Giuseppina , Fiorillo Marco , Morelli Catia , Panza Salvatore , Giordano Cinzia , Barone Ines , Catalano Stefania , Sisci Diego , Andò Sebastiano , Bonofiglio Daniela
Published: January 2023

Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype lacking effective targeted therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3 docosahexaenoic acid (DHA) in both tumor epithelial and stromal components of the breast cancer microenvironment. Particularly in breast cancer cells, DHA can be converted into its conjugate with ethanolamine, DHEA, leading to a more effective anti-oncogenic activity of the parent compound in estrogen receptor-positive breast cancer cells. Here, we investigated the ability of DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly, DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of DHEA in TNCB cells were mediated by reduced C-C motif chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients.
Radiomics-Based Inter-Lesion Relation Network to Describe [18F]FMCH PET/CT Imaging Phenotypes in Prostate Cancer
Authors: Cavinato Lara , Sollini Martina , Ragni Alessandra , Bartoli Francesco , Zanca Roberta , Pasqualetti Francesco , Marciano Andrea , Ieva Francesca , Erba Paola Anna
Published: January 2023

Advanced image analysis, including radiomics, has recently acquired recognition as a source of biomarkers, although there are some technical and methodological challenges to face for its application in the clinic. Among others, proper phenotyping of metastatic or systemic disease where multiple lesions coexist is an issue, since each lesion contributes to characterization of the disease. Therefore, the radiomic profile of each lesion should be modeled into a more complex architecture able to reproduce each “unit” (lesion) as a part of the “entire” (patient). This work aimed to characterize intra-tumor heterogeneity underpinning metastatic prostate cancer using an exhaustive innovative approach which consist of a i) feature transformation method to build an agnostic (i.e., irrespective of pre-existence knowledge, experience, and expertise) radiomic profile of lesions extracted from [18F]FMCH PET/CT, ii) qualitative assessment of intra-tumor heterogeneity of patients, iii) quantitative representation of the intra-tumor heterogeneity of patients in terms of the relationship between their lesions’ profiles, to be associated with prognostic factors. We confirmed that metastatic prostate cancer patients encompassed lesions with different radiomic profiles that exhibited intra-tumor radiomic heterogeneity and that the presence of many radiomic profiles within the same patient impacted the outcome.
Characterization of Estrogen Receptors in Pancreatic Adenocarcinoma with Tertiary Lymphoid Structures
Authors: Zou Xuan , Liu Yu , Lin Xuan , Wang Ruijie , Dai Zhengjie , Chen Yusheng , Ma Mingjian , Tasiheng Yesiboli , Yan Yu , Wang Xu , Yu Xianjun , Cheng He , Liu Chen
Published: January 2023

The role of estrogen signaling in antitumor immunology remains unknown for non-traditional sex-biased cancer types such as pancreatic adenocarcinoma (PAAD). Tertiary lymphoid structures (TLS) are active zones composed of multiple types of immune cells, whose presence indicates anti-tumor immune responses. In this study, we employed a 12-chemokine signature to characterize potential gene categories associated with TLS development and identified seventeen major gene categories including estrogen receptors (ERs). Immunohistochemistry staining revealed the expression patterns of three ERs (ERα, ERβ, and GPER) in 174 PAAD samples, and their correlation with clinicopathological characteristics, immune cell infiltration levels, and intratumoral TLS presence was analyzed. The results indicated that ERα (+) and ERβ (+) were correlated with high tumor grade, and ERβ (+) and GPER (+) were correlated with lower TNM stage, and both ERα (+) and GPER (+) displayed a beneficial effect on prognosis in this cohort. Interestingly, positive staining of all three ERs was significantly correlated with the presence of intratumoral TLSs and infiltration of more active immune cells into the microenvironment. Moreover, the chemotaxis of CD8+T-cells to PAAD cells was significantly increased in vitro with upregulated expression of ERα or ERβ on PAAD cells. To conclude, our study showed a novel correlation between ER expression and TLS development, suggesting that ERs may play a protective role by enhancing anti-tumor immune responses in PAAD.
Inhibition of Checkpoint Kinase 1 (CHK1) Upregulates Interferon Regulatory Factor 1 (IRF1) to Promote Apoptosis and Activate Anti-Tumor Immunity via MICA in Hepatocellular Carcinoma (HCC)
Authors: Li Xicai , Huang Jingquan , Wu Qiulin , Du Qiang , Wang Yingyu , Huang Yubin , Cai Xiaoyong , Geller David A. , Yan Yihe
Published: January 2023

Background: CHK1 is considered a key cell cycle checkpoint kinase in DNA damage response (DDR) pathway to communicate with several signaling pathways involved in the tumor microenvironment (TME) in numerous cancers. However, the mechanism of CHK1 signaling regulating TME in hepatocellular carcinoma (HCC) remains unclear. Methods: CHK1 expression in HCC tissue was determined by IHC staining assay. DNA damage and apoptosis in HCC cells induced by cisplatin or CHK1 inhibition were detected by WB and flow cytometry. The interaction of CHK1 and IRF1 was analyzed by single-cell RNA-sequence, WB, and immunoprecipitation assay. The mechanism of IRF1 regulating MICA was investigated by ChIP-qPCR. Results: CHK1 expression is upregulated in human HCC tumors compared to the background liver. High CHK1 mRNA level predicts advanced tumor stage and worse prognosis. Cisplatin and CHK1 inhibition augment cellular DNA damage and apoptosis. Overexpressed CHK1 suppresses IRF1 expression through proteolysis. Furthermore, single-cell RNA-sequence analyses confirmed that MICA expression positively correlated with IRF1 in HCC cells. Immunoprecipitation assay showed the binding between CHK1 and IRF1. Cisplatin and CHK1 inhibition upregulate MICA expression through IRF1-mediated transcriptional effects. A novel specific cis-acting IRF response element was identified at -1756 bp in the MICA promoter region that bound IRF1 to induce MICA gene transcription. MICA may increase NK cell and CD8+T cell infiltration in HCC. Conclusions: DNA damage regulates the interaction of CHK1 and IRF1 to activate anti-tumor immunity via the IRF1-MICA pathway in HCC.
ATX-LPA-Dependent Nuclear Translocation of Endonuclease G in Respiratory Epithelial Cells: A New Mode Action for DNA Damage Induced by Crystalline Silica Particles
Authors: Zheng Huiyuan , Stenius Ulla , Högberg Johan
Published: January 2023

Crystalline silica particles (CSi) are an established human carcinogen, but it is not clear how these particles cause necessary mutations. A well-established scenario includes inflammation caused by retained particles in the bronchioles, activated macrophages, and reactive oxygen species (ROS) that cause DNA damage. In previous studies, we showed that CSi in contact with the plasma membrane of human bronchial epithelium induced double strand breaks within minutes. A signaling pathway implicating the ATX-LPA axis, Rac1, NLRP3, and mitochondrial depolarization upstream of DSB formation was delineated. In this paper, we provide in vitro and in vivo evidence that this signaling pathway triggers endonuclease G (EndoG) translocation from the mitochondria to the nucleus. The DNA damage is documented as γH2AX and p53BP1 nuclear foci, strand breaks in the Comet assay, and as micronuclei. In addition, the DNA damage is induced by low doses of CSi that do not induce apoptosis. By inhibiting the ATX-LPA axis or by EndoG knockdown, we prevent EndoG translocation and DSB formation. Our data indicate that CSi in low doses induces DSBs by sub-apoptotic activation of EndoG, adding CSi to a list of carcinogens that may induce mutations via sub-apoptotic and “minority MOMP” effects. This is the first report linking the ATX-LPA axis to this type of carcinogenic effect.
Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities
Authors: Pandey Himani , Tang Daryl W. T. , Wong Sunny H. , Lal Devi
Published: January 2023

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications.
In-Depth Kinetic Modeling and Chemical Analysis for the Epoxidation of Vegetable Oils in a Liquid–Liquid–Solid System
Authors: Meng Yudong , Kebir Nasreddine , Cai Xiaoshuang , Leveneur Sebastien
Published: January 2023

A heterogeneous catalyst for producing epoxidized vegetable oils, an important intermediate in the production of non-isocyanate polyurethanes, is essential for product separation and for decreasing the side-reaction, i.e., ring-opening reaction, via the Prileschajew method. The development of reliable kinetic models considering key variables for both phases and the mass transfer phenomena is missing in the literature. The reaction pathway for the ring-opening reaction is also under debate. Therefore, we studied the kinetics of epoxidation of cottonseed oil by perpropionic acid over the solid acid catalyst amberlite IR-120. An in-depth kinetic model was developed by using Bayesian inference. The reaction pathway for the ring opening was investigated. Propionic acid, a weak acid, allows for a decrease in the oxirane ring-opening side reaction.