bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Study of Ocular Pharmacokinetics of Topical 0.3% Gatifloxacin Eye Gel and Solution in Rabbits
Authors: Liu Manli , Zhao Xin , Yang Yao , Yang Qiang , Zeng Jieting , Li Yujie , Lin Xiaofeng , Duan Fang
Published: April 2022

Few articles have reported drug concentrations of different ophthalmic dosage forms in the ocular tissues. This study aimed to determine the ocular pharmacokinetics of gatifloxacin 0.3% eye gel (GTX-Gel) and gatifloxacin 0.3% eye solution (GTX-Sol) at different time intervals after topical instillation in rabbits. A total of 126 healthy New Zealand rabbits were included, of which six rabbits did not receive antibiotics (control group). The remaining rabbits were randomly divided into four groups. GTX-Gel and GTX-Sol (50 μL) were topically instilled every hour in groups A1 and B1, respectively, and every two hours in groups A2 and B2, respectively, for 12 h. Ocular tissues were collected 2, 4, 8, 12, and 24 h after administration. Gatifloxacin concentration was measured using high-performance liquid chromatography coupled with tandem mass spectrometry. The drug reached peak concentrations (Cmax) in all tissues at 8–12 h. With the same administration frequency, the Cmax was higher with GTX-Gel than with GTX-Sol (p < 0.05). Except for the iris-ciliary body, other ocular tissues did not show significant difference (p > 0.05) in gatifloxacin concentration between either pair of groups. Gatifloxacin ophthalmic gel was found to attain significantly higher concentrations than the ophthalmic solution in ocular tissues.
TEM,CTX-M,SHV Genes in ESBL-Producing Escherichia coli and Klebsiella pneumoniae Isolated from Clinical Samples in a County Clinical Emergency Hospital Romania-Predominance of CTX-M-15
Authors: Ghenea Alice Elena , Zlatian Ovidiu Mircea , Cristea Oana Mariana , Ungureanu Anca , Mititelu Radu Razvan , Balasoiu Andrei Theodor , Vasile Corina Maria , Salan Alex-Ioan , Iliuta Daniel , Popescu Mihaela , Udriștoiu Anca-Loredana , Balasoiu Maria
Published: April 2022

Background: CTX-M betalactamases have shown a rapid spread in the recent years among Enterobacteriaceae and have become the most prevalent Extended Spectrum Beta-Lactamases (ESBLs) in many parts of the world. The introduction and dissemination of antibiotic-resistant genes limits options for treatment, increases mortality and morbidity in patients, and leads to longer hospitalization and expensive costs. We aimed to identify the beta-lactamases circulating encoded by the genes blaCTX-M-15, blaSHV-1 and blaTEM-1 in Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) strains. Furthermore, we established the associated resistance phenotypes among patients hospitalized in the Intensive Care Unit (ICU) from County Clinical Emergency Hospital of Craiova, Romania. Methods: A total of 46 non-duplicated bacterial strains (14 strains of E. coli and 32 strains of K. pneumoniae), which were resistant to ceftazidime (CAZ) and cefotaxime (CTX) by Kirby–Bauer disk diffusion method, were identified using the automated VITEK2 system. Detection of ESBL-encoding genes and other resistance genes was carried out by PCR. Results. E. coli strains were resistant to 3rd generation cephalosporins and moderately resistant to quinolones, whereas K. pneumoniae strains were resistant to penicillins, cephalosporins, and sulfamides, and moderately resistant to quinolones and carbapenems. Most E. coli strains harbored blaCTX-M-15 gene (13/14 strains), a single strain had the blaSHV-1 gene, but 11 strains harbored blaTEM-1 gene. The mcr-1 gene was not detected. We detected tet(A) gene in six strains and tet(B) in one strain. In K. pneumoniae strains we detected blaCTX-M-15 in 23 strains, blaSHV-1 in all strains and blaTEM-1 in 14 strains. The colistin resistance gene mcr-1 was not detected. The tetracycline gene tet(A) was detected in 11 strains, but the gene tet(B) was not detected in any strains. Conclusions. The development in antibiotic resistance highlights the importance of establishing policies to reduce antibiotic use and improving the national resistance surveillance system in order to create local antibiotic therapy guidelines.
Impact of Bioactive Compounds of Plant Leaf Powders in White Chocolate Production: Changes in Antioxidant Properties during the Technological Processes
Authors: Poliński Szymon , Topka Patrycja , Tańska Małgorzata , Kowalska Sylwia , Czaplicki Sylwester , Szydłowska-Czerniak Aleksandra
Published: April 2022

Bioactive compounds present in the powdered leaves of matcha green tea (Camellia sinensis L.) (MGTP) and moringa (Moringa oleifera) (MOLP) seem to be related to health benefits due to their antioxidant properties. The growing accessibility of these powders has led to their being more widely used in food production. The aim of this study was to evaluate the total phenolic content (TPC) and antioxidant capacity (AC) of white chocolate (WCh) supplemented with MGTP and MOLP. AC was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric ion-reducing antioxidant capacity (CUPRAC), and ferric-reducing antioxidant power (FRAP) assays, whereas TPC was determined by the Folin–Ciocalteu (FC) method. Both additives were incorporated at four levels (1, 2, 3 and 4%) in two chocolate processing steps (conching and tempering). Additionally, the amounts of phenolic acids, tocopherols, and carotenoids in WCh samples enriched by MGTP and MOLP were determined to explain their influence on AC. The results showed that the chocolates supplemented with MGTP were characterized by higher antioxidant properties than those with MOLP. In turn, MOLP significantly increased the content of lipophilic antioxidants in chocolates, tocopherols and carotenoids, which also exhibit pro-health effects. Furthermore, the incorporation of these additives during the tempering process was more relevant to the improvement of the antioxidant properties of WCh.
Protective Effect of a Cocoa-Enriched Diet on Oxidative Stress Induced by Intensive Acute Exercise in Rats
Authors: Ruiz-Iglesias Patricia , Massot-Cladera Malén , Rodríguez-Lagunas Maria J. , Franch Àngels , Camps-Bossacoma Mariona , Pérez-Cano Francisco J. , Castell Margarida
Published: April 2022

Intensive acute exercise can induce oxidative stress, leading to muscle damage and immune function impairment. Cocoa diet could prevent this oxidative stress and its consequences on immunity. Our aim was to assess the effect of a cocoa-enriched diet on the reactive oxygen species (ROS) production by peritoneal macrophages, blood immunoglobulin (Ig) levels, leukocyte counts, and the physical performance of rats submitted to an intensive acute exercise, as well as to elucidate the involvement of cocoa fiber in such effects. For this purpose, Wistar rats were fed either a standard diet, i.e., a diet containing 10% cocoa (C10), or a diet containing 5% cocoa fiber (CF) for 25 days. Then, half of the rats of each diet ran on a treadmill until exhaustion, and 16 h later, the samples were obtained. Both C10 and CF diets significantly prevented the increase in ROS production. However, neither the cocoa diet or the cocoa fiber-enriched diet prevented the decrease in serum IgG induced by acute exercise. Therefore, although the cocoa-enriched diet was able to prevent the excessive oxidative stress induced by intensive exercise, this was not enough to avoid the immune function impairment due to exercise.
Medical Gas Plasma—A Potent ROS-Generating Technology for Managing Intraoperative Bleeding Complications
Authors: Miebach Lea , Poschkamp Broder , van der Linde Julia , Bekeschus Sander
Published: April 2022

Cold medical gas plasmas are under pre-clinical investigation concerning their hemostatic activity and could be applied for intra-operative bleeding control in the future. The technological leap innovation was their generation at body temperature, thereby causing no thermal harm to the tissue and ensuring tissue integrity. This directly contrasts with current techniques such as electrocautery, which induces hemostasis by carbonizing the tissue using a heated electrode. However, the necrotized tissue is prone to fall, raising the risk of post-operative complications such as secondary bleedings or infection. In recent years, various studies have reported on the ability of medical gas plasmas to induce blood coagulation, including several suggestions concerning their mode of action. As non-invasive and gentle hemostatic agents, medical gas plasmas could be particularly eligible for vulnerable tissues, e.g., colorectal surgery and neurosurgery. Further, their usage could be beneficial regarding the prevention of post-operative bleedings due to the absence or sloughing of eschar. However, no clinical trials or individual healing attempts for medical gas plasmas have been reported to pave the way for clinical approvement until now, despite promising results in experimental animal models. In this light, the present mini-review aims to emphasize the potential of medical gas plasmas to serve as a hemostatic agent in clinical procedures. Providing a detailed overview of the current state of knowledge, feasible application fields are discussed, and possible obstacles are addressed.
Anterior Incisal Onlay—A Minimally Invasive Non-Surgical Approach to Correct an Esthetic Complication of an Implant Supported Crown in the Anterior Zone
Authors: Zabrovsky Asher , Bar-on Hilit , Beyth Nurit , Smidt Ami , Ben-Gal Gilad
Published: April 2022

The growing demand for re-treatment of existing implant supported restorations in the anterior area due to esthetic complications poses a clinical challenge. One-piece implant supported restoration adds to the clinical complexity. Single implant crown restorations appear short as a result of expected cranio-facial changes. In the presented clinical case, a minimally invasive approach is offered as a solution for such an esthetic difficulty. The clinical old crown was prepared to receive an anterior incisal onlay (AIO) made from lithium disilicate and felspathic porcelain. The manufactured addition was adhesively cemented, presenting a simple prosthetic solution for an esthetic complaint, with no need for surgical procedure, while not challenging the one-piece implant body. As the variety of materials and methods for predictable adhesion increases, non-surgical and non-invasive treatment options will receive high priority. When correctly diagnosed and meticulously performed, the presented solution will meet the patient expectations and provide a satisfying result.
Study on the Law of Influence of Seepage Field Anomalies on Displacement Field Induced by Leakage of Enclosure Structure
Authors: Chen Bingbing , Liu Ming , Deng Shenggui , Li Yao , Zhang Xuhai , Liu Tao
Published: April 2022

The leakage of an enclosure structure will cause abnormal changes in the seepage flow field, which in turn can lead to the deformation of the enclosure structure and affect the surrounding geotechnical body. In this paper, a fiber-optic temperature measurement system is used to detect the location of the seepage points in a station of the Qingdao subway during open pit excavation, and the abnormal variation of the seepage field caused by the seepage points is obtained by numerical calculation and field measurement. Then, numerical simulation is performed to analyze the effects of seepage field anomalies on the deformation of the enclosure structure and surface settlement. It is found that the seepage flow caused by the leakage point has a significant influence on the surface settlement and the deformation of the enclosure structure. With the increase of excavation depth, the deformation of the enclosure structure increases and the maximum deformation position shifts downward. The deformation of the enclosure structure decreases when the leakage point exists. The surface volume also increases gradually with the excavation, and the maximum surface settlement position shifts outward significantly. The settlement range becomes larger when the leakage point exists.
Research on Identification Technology of Field Pests with Protective Color Characteristics
Authors: Hu Zhengfang , Xiang Yang , Li Yajun , Long Zhenhuan , Liu Anwen , Dai Xiufeng , Lei Xiangming , Tang Zhenhui
Published: April 2022

Accurate identification of field pests has crucial decision-making significance for integrated pest control. Most current research focuses on the identification of pests on the sticky card or the case of great differences between the target and the background. There is little research on field pest identification with protective color characteristics. Aiming at the problem that it is difficult to identify pests with protective color characteristics in the complex field environment, a field pest identification method based on near-infrared imaging technology and YOLOv5 is proposed in this paper. Firstly, an appropriate infrared filter and ring light source have been selected to build an image acquisition system according to the wavelength with the largest spectral reflectance difference between the spectral curves of the pest (Pieris rapae) and its host plants (cabbage), which are formed by specific spectral characteristics. Then, field pest images have been collected to construct a data set, which has been trained and tested through YOLOv5. Experimental results demonstrate that the average time required to detect one pest image is 0.56 s, and the mAP reaches 99.7%.
A Probabilistic Framework for Robustness Quantification of Precast Concrete Frames under Seismic Loading
Authors: Zeng Yihua , Huang Yan , Sun Zeyang
Published: April 2022

Structural robustness is the property of a structure to resist accidental events such as explosions, impacts and earthquakes. In the design field of structural engineering, structural robustness has attained unprecedented significance in the present design environment. This paper presents a probabilistic framework for the robustness quantification of precast concrete frames under seismic loading. After the essences of structural robustness and the philosophy of robustness quantification are examined, the probabilistic framework is developed by investigating the relationship between the failure of structural components and the failure of structural systems. Its process consists of the identification of the relationship, the uncertainty characterization, the reliability and the robustness indices formulations. The proposed probabilistic framework is demonstrated to be feasible and effective in quantifying the robustness of precast concrete frame structures by employing an example illustration.
Mesoscale Observational Analysis of Isolated Convection Associated with the Interaction of the Sea Breeze Front and the Gust Front in the Context of the Urban Heat Humid Island Effect
Authors: Zhang Nan , Wang Yan , Lin Xiaomeng
Published: April 2022

An isolated convection was unexpectedly initiated in the evening of 1 August 2019 around the Tianjin urban region (TUR), which happened at some distance from the shear line at lower level and the preexisting convection to the South, analyzed by using ERA5 reanalysis data and observations from surface weather stations, and a S-band radar. The results show that, 42 min before the initiation of the convection, the atmospheric thermodynamic conditions around TUR were favorable for the initiation of the isolated convection, although the southerly and vertical shear of the horizontal wind at the lower level was weak. A sea-breeze front approached the TUR and continued to move West, leading to the triggering of the isolated convection in the context of the urban humid heat island (UHHI) effect. Subsequently, the gust front, which was formed between the cold pool away from the TUR and the warm and humid air of the UHHI, moved northward, approached the convection, and collided with sea breeze front, resulting in five reflectivity centers of isolated convection being merged and the convection’s development. Finally, the isolated convection split into two convections that moved away from the TUR and disappeared at 20:36 Beijing Time. The isolated convection was initiated and developed by the interaction of the sea breeze front and gust front in the context of the UHHI effect. The sea breeze front triggered the isolated convection around TUR in the context of the UHHI effect, and the gust front produced by the early convective storms to the south played a vital role in the development of the isolated convection.
WRF Model Sensitivity to Spatial Resolution in Singapore: Analysis for a Heavy Rain Event and General Suitability
Authors: Huva Robert , Song Guiting
Published: April 2022

Granularity of the grid (both horizontally and vertically) is a key consideration when conducting localised Numerical Weather Prediction (NWP) modelling. Generally speaking, an NWP model with a finer grid can explicitly resolve more processes and require less parameterisation. However, a finer grid also requires more computation and it is not always clear that a finer grid will produce a more accurate forecast. In this study, we explore the sensitivity of rainfall prediction over Singapore to grid resolution. We use the Weather and Research Forecasting model (WRF) to forecast rainfall over Singapore and explore the performance of horizontal resolutions ranging from 1 km to 12 km. We test the performance on a set of dates from across the years 2020–2021 against both ground observations and radar-derived rain rates. When compared to ground observations, we show that, overall, the higher resolution produces the highest Critical Success Index (CSI) for rain rates in excess of 0.5 mm/h. When compared against radar-derived rain rates, the 1 km domain produces superior CSI values for all rain rates. The daily-average hourly Fractional Skill Score (FSS) was then calculated for some dates and showed agreement with the CSI results with the exception of a north-east monsoon day where, for heavier rain rates, the 3 km domain has superior FSS. We also investigate a particularly heavy rain event on 10 January 2021 and show that the 3 km grid has highest CSI for rain rates of 4 mm/h and 16 mm/h (based on both ground-based and radar-derived rain rates), however, the 1 km has superior FSS for this event.
Cell Culture Media, Unlike the Presence of Insulin, Affect α-Synuclein Aggregation in Dopaminergic Neurons
Authors: Hlushchuk Irena , Barut Justyna , Airavaara Mikko , Luk Kelvin , Domanskyi Andrii , Chmielarz Piotr
Published: April 2022

There are several links between insulin resistance and neurodegenerative disorders such as Parkinson’s disease. However, the direct influence of insulin signaling on abnormal α-synuclein accumulation—a hallmark of Parkinson’s disease—remains poorly explored. To our best knowledge, this work is the first attempt to investigate the direct effects of insulin signaling on pathological α-synuclein accumulation induced by the addition of α-synuclein preformed fibrils in primary dopaminergic neurons. We found that modifying insulin signaling through (1) insulin receptor inhibitor GSK1904529A, (2) SHIP2 inhibitor AS1949490 or (3) PTEN inhibitor VO-OHpic failed to significantly affect α-synuclein aggregation in dopaminergic neurons, in contrast to the aggregation-reducing effects observed after the addition of glial cell line-derived neurotrophic factor. Subsequently, we tested different media formulations, with and without insulin. Again, removal of insulin from cell culturing media showed no effect on α-synuclein accumulation. We observed, however, a reduced α-synuclein aggregation in neurons cultured in neurobasal medium with a B27 supplement, regardless of the presence of insulin, in contrast to DMEM/F12 medium with an N2 supplement. The effects of culture conditions were present only in dopaminergic but not in primary cortical or hippocampal cells, indicating the unique sensitivity of the former. Altogether, our data contravene the direct involvement of insulin signaling in the modulation of α-synuclein aggregation in dopamine neurons. Moreover, we show that the choice of culturing media can significantly affect preformed fibril-induced α-synuclein phosphorylation in a primary dopaminergic cell culture.
Hypertension of Developmental Origins: Consideration of Gut Microbiome in Animal Models
Authors: Tain You-Lin , Hsu Chien-Ning
Published: April 2022

Hypertension is the leading cause of global disease burden. Hypertension can arise from early life. Animal models are valuable for giving cogent evidence of a causal relationship between various environmental insults in early life and the hypertension of developmental origins in later life. These insults consist of maternal malnutrition, maternal medical conditions, medication use, and exposure to environmental chemicals/toxins. There is a burgeoning body of evidence on maternal insults can shift gut microbiota, resulting in adverse offspring outcomes later in life. Emerging evidence suggests that gut microbiota dysbiosis is involved in hypertension of developmental origins, while gut microbiota-targeted therapy, if applied early, is able to help prevent hypertension in later life. This review discusses the innovative use of animal models in addressing the mechanisms behind hypertension of developmental origins. We will also highlight the application of animal models to elucidate how the gut microbiota connects with other core mechanisms, and the potential of gut microbiota-targeted therapy as a novel preventive strategy to prevent hypertension of developmental origins. These animal models have certainly enhanced our understanding of hypertension of developmental origins, closing the knowledge gap between animal models and future clinical translation.
Aptamer-Based Fluorescence Detection and Selective Disinfection of Salmonella Typhimurium by Using Hollow Carbon Nitride Nanosphere
Authors: Liu Xinyi , Xu Jing , Lou Yang , Pan Chengsi , Zhang Yin , Wang Zhouping
Published: April 2022

Hollow carbon nitride nanosphere (HCNS) was synthesized via the hard template method to improve the fluorescence characteristics, drug delivery ability, and photocatalytic activity. Blue fluorescent HCNS was utilized as a quenching agent and an internal reference to combine with Cy5-labelled aptamer (Cy5-Apt), resulting in an off-on fluorescence aptasensing method for the detection of Salmonella typhimurium (S. typhimurium). Under optimum conditions, this fluorescence assay presented a linear range from 30 to 3 × 104 CFU mL−1 with a detection limit of 13 CFU mL−1. In addition, HCNS was also used as a drug carrier to load chloramphenicol (Cap) molecules. The Cap-loading amount of HCNS could reach 550 μg mg−1 within 24 h, whereas the corresponding Cap-release amount is 302.5 μg mg−1 under acidic and irradiation conditions. The integration of photocatalyst with antibiotic could endow HCNS-Cap with better disinfection performance. The bactericidal efficiency of HCNS-Cap (95.0%) against S. typhimurium within 12 h was better than those of HCNS (85.1%) and Cap (72.9%). In addition, selective disinfection of S. typhimurium was further realized by decorating aptamer. Within 4 h, almost all S. Typhimurium were inactivated by HCNS-Cap-Apt, whereas only 13.3% and 48.2% of Staphylococcus aureus and Escherichia coli cells were killed, respectively. Therefore, HCNS is a promising bio-platform for aptamer-based fluorescence detection and selective disinfection of S. typhimurium.
Validation of the Application of Solid Contact Ion-Selective Electrode for Off-Body Sweat Ion Monitoring
Authors: Liu Huixin , Gu Zhen , Liu Yuan , Xiao Xinxin , Xiu Guangli
Published: April 2022

The solid contact ion-selective electrode (ISE) is a promising skin-interfaced monitoring system for sweat ions. Despite a growing number of on-body usages of ISE with fancy new materials and device fabrications, there are very few reports attempting to validate ISE results with a gold standard technique. For this purpose, this work uses inductively coupled plasma-optical emission spectrometry (ICP-OES) as a reference technique to conduct a direct evaluation of the sweat sodium and potassium ion levels obtained by ISE in an off-body approach. Eight healthy male subjects were recruited to collect exercise-induced sweat. It was found that sweat sodium and potassium ions present a rather wide concentration range. The sweat sodium concentration did not vary greatly in an exercise period of half an hour, while the sweat potassium concentration typically decreased with exercise. Mineral drink intake had no clear impact on the sweat sodium level, but increased the sweat potassium level. A paired t-test and mean absolute relative difference (MARD) analysis, a method typically used for evaluating the performance of glucometers, was employed to compare the results of ISE and ICP-OES. The statistical analysis validated the feasibility of ISE for measuring sweat ions, although better accuracy is required. Our data suggests that overweight subjects are likely to possess a higher sweat sodium level.
Predicting Employer and Worker Responsibilities in Accidents That Involve Falls in Building Construction Sites
Authors: Akcay Emre Caner , Arditi David
Published: April 2022

Fall-related accidents have received more attention in building construction than in civil construction as fall-from-heights is more common in building construction. In addition to social costs, construction companies face a significant financial burden when fall-related accidents occur. The major portion of the direct cost of accidents that involve falls includes the compensation paid by the employer to the worker. The employer and the worker try to reach an agreement on the size of the compensation, however, most of the time the process is contentious. The objective of this study is to predict the parties’ responsibilities for a fall-related accident by modeling the relationship between the employer and the worker using a multi-agent system. The research pursued a three-step method, including collection of data, development of a multi-agent model, and testing of the model. The model provides satisfactory results and can be used to quantify the employer’s and the worker’s responsibilities in construction fall accidents, hence avoiding any escalation to pursue arbitration or litigation.
Definition of High-Risk Early Hormone-Positive HER2−Negative Breast Cancer: A Consensus Review
Authors: Garutti Mattia , Griguolo Gaia , Botticelli Andrea , Buzzatti Giulia , De Angelis Carmine , Gerratana Lorenzo , Molinelli Chiara , Adamo Vincenzo , Bianchini Giampaolo , Biganzoli Laura , Curigliano Giuseppe , De Laurentiis Michelino , Fabi Alessandra , Frassoldati Antonio , Gennari Alessandra , Marchiò Caterina , Perrone Francesco , Viale Giuseppe , Zamagni Claudio , Zambelli Alberto , Del Mastro Lucia , De Placido Sabino , Guarneri Valentina , Marchetti Paolo , Puglisi Fabio
Published: April 2022

Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone receptor-positive/HER2−negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and endocrine treatment. However, estimating the risk of relapse of breast cancer on an individual basis is still challenging. The IRIDE (hIGh Risk DEfinition in breast cancer) working group was established with the aim of reviewing evidence from the literature to synthesize the current relevant features that predict hormone-positive/HER2−negative early breast cancer relapse. A panel of experts in breast cancer was involved in identifying clinical, pathological, morphological, and genetic factors. A RAND consensus method was used to define the relevance of each risk factor. Among the 21 features included, 12 were considered relevant risk factors for relapse. For each of these, we provided a consensus statement and relevant comments on the supporting scientific evidence. This work may guide clinicians in the practical management of hormone-positive/HER2−negative early breast cancers.
Analysis of the Correlation between the Radioactive Iodine Activity and Neutrophil-to-Lymphocyte Ratio in Patients with Differentiated Thyroid Cancer
Authors: Stanciu Adina Elena , Verzia Andreea , Stanciu Marcel Marian , Zamfirescu Anca , Gheorghe Dan Cristian
Published: April 2022

Publications investigating the effect of radioactive iodine (131I) therapy on the circulating peripheral blood cells in patients with differentiated thyroid cancer (DTC) are limited to blood samples collected more than 92 h after 131I. Studies conducted on blood samples collected up to 92 h are rare due to the radioactive contamination risk. This research aimed to assess the relationship between the prescribed 131I activity, human whole blood activity, and peripheral blood cells at many time points (6, 22, 46, 69, and 92 h after 131I). The study enrolled 50 female patients with DTC who received a 131I median activity of 90.54 mCi (3.35 GBq). The neutrophil-to-lymphocyte ratio (NLR) was measured as an inflammatory marker. 131I uptake in the residual thyroid tissue peaked after 46 h. Blood activity decreased in the first 46 h and increased 69 h after the 131I intake. Blood activity was associated with the absolute lymphocyte count and the NLR at 69 h (r = −0.49 and r = 0.52, p < 0.001). Our results demonstrate that the time interval between 46 and 69 h should be associated with the release of hematological inflammatory mediators, such as neutrophils and lymphocytes, to eradicate tumor cells in response to 131I therapy.
Outcomes and Toxicities of Modern Combined Modality Therapy with Atezolizumab Plus Bevacizumab and Radiation Therapy for Hepatocellular Carcinoma
Authors: Manzar Gohar Shahwar , De Brian Sandeep , Abana Chike Osita , Lee Sunyoung S. , Javle Milind , Kaseb Ahmed O. , Vauthey Jean-Nicolas , Tran Cao Hop Sanderson , Koong Albert C. , Smith Grace Li , Taniguchi Cullen M. , Holliday Emma Brey , Das Prajnan , Koay Eugene Jon , Ludmir Ethan Bernard
Published: April 2022

Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we matched the analysis to a previously cohort of RT-treated HCC patients who did not receive atezolizumab/bevacizumab. Survival and time-to-liver-failure were analyzed using Kaplan–Meier. Results: Of 21 patients, with a median follow-up of 9.5 months, the median OS was 16.1 months. Post-RT, all patients had reduced tumors or treatment response. There were no ≥Grade 3 RT-related toxicities. Autoimmune complications occurred in two patients (9.5%), and GI bleeding in three patients (14.3%). Liver function remained stable post-RT. There was a marked decrease in ALCs immediately post-RT (post-RT/pre-RT ratio 47.3%, p < 0.0001), restored by 1 month to pre-treatment baseline (1-month post-RT/pre-RT ratio 95.1%, n.s.). Compared to HCC patients treated with RT alone, post-RT ALC recovery was faster with atezolizumab/bevacizumab (p = 0.009). Conclusion: In this first reported experience of RT with modern systemic therapy for HCC, combination therapy is safe and well-tolerated. As a favorable prognosticator, there appears to be faster recovery of ALC among patients who received RT with atezolizumab/bevacizumab.
Metabolic Vulnerabilities in Multiple Myeloma
Authors: Lim Julia S. L. , Chong Phyllis S. Y. , Chng Wee-Joo
Published: April 2022

Multiple myeloma (MM) remains an incurable malignancy with eventual emergence of refractory disease. Metabolic shifts, which ensure the availability of sufficient energy to support hyperproliferation of malignant cells, are a hallmark of cancer. Deregulated metabolic pathways have implications for the tumor microenvironment, immune cell function, prognostic significance in MM and anti-myeloma drug resistance. Herein, we summarize recent findings on metabolic abnormalities in MM and clinical implications driven by metabolism that may consequently inspire novel therapeutic interventions. We highlight some future perspectives on metabolism in MM and propose potential targets that might revolutionize the field.
Ontologies and Knowledge Graphs in Oncology Research
Authors: Silva Marta Contreiras , Eugénio Patrícia , Faria Daniel , Pesquita Catia
Published: April 2022

The complexity of cancer research stems from leaning on several biomedical disciplines for relevant sources of data, many of which are complex in their own right. A holistic view of cancer—which is critical for precision medicine approaches—hinges on integrating a variety of heterogeneous data sources under a cohesive knowledge model, a role which biomedical ontologies can fill. This study reviews the application of ontologies and knowledge graphs in cancer research. In total, our review encompasses 141 published works, which we categorized under 14 hierarchical categories according to their usage of ontologies and knowledge graphs. We also review the most commonly used ontologies and newly developed ones. Our review highlights the growing traction of ontologies in biomedical research in general, and cancer research in particular. Ontologies enable data accessibility, interoperability and integration, support data analysis, facilitate data interpretation and data mining, and more recently, with the emergence of the knowledge graph paradigm, support the application of Artificial Intelligence methods to unlock new knowledge from a holistic view of the available large volumes of heterogeneous data.
Evaluation of Temozolomide Treatment for Glioblastoma Using Amide Proton Transfer Imaging and Diffusion MRI
Authors: Onishi Ryutarou , Sawaya Reika , Tsuji Keiho , Arihara Narumi , Ohki Akiko , Ueda Junpei , Hata Junichi , Saito Shigeyoshi
Published: April 2022

This study aimed to evaluate tumor changes due to chemotherapy with temozolomide (TMZ) in terms of quantitative values measured by APT imaging and NODDI. We performed TMZ treatment (administered orally by gavage to the TMZ-40 mg and TMZ-60 mg groups) on 7-week-old male Wistar rats with rat glioma C6 implanted in the right brain. T2WI, APT imaging, diffusion tensor imaging (DTI), and NODDI were performed on days 7 and 14 after implantation using 7T-MRI, and the calculated quantitative values were statistically compared. Then, HE staining was performed on brain tissue at day 7 and day 14 for each group to compare the results with the MR images. TMZ treatment inhibited tumor growth and necrotic area formation. The necrotic areas observed upon hematoxylin and eosin (HE) staining were consistent with the MTR low-signal areas observed upon APT imaging. The intracellular volume fraction (ICVF) map of the NODDI could best show the microstructure of the tumor, and its value could significantly highlight the difference in treatment effects at different TMZ doses. APT imaging and NODDI can be used to detect the microstructural changes caused by TMZ-induced tumor growth inhibition. The ICVF may be useful as a parameter for determining the effect of TMZ.
Establishment of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models for Receptor Peptide-Targeted Therapy
Authors: Tran Catherine G. , Borbon Luis C. , Mudd Jacqueline L. , Abusada Ellen , AghaAmiri Solmaz , Ghosh Sukhen C. , Vargas Servando Hernandez , Li Guiying , Beyer Gabriella V. , McDonough Mary , Li Rachel , Chan Carlos H.F. , Walsh Susan A. , Wadas Thaddeus J. , O’Dorisio Thomas , O’Dorisio M Sue , Govindan Ramaswamy , Cliften Paul F. , Azhdarinia Ali , Bellizzi Andrew M. , Fields Ryan C. , Howe James R. , Ear Po Hien
Published: April 2022

Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for studying GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of six mice developed tumors (NEC913 and NEC1452). Over 80% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2), whereas NEC1452 PDX tumors did not express SSTR2. Exome sequencing revealed loss of TP53 and RB1 in both NEC tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and the fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as a valuable resource for GEP NEN therapy testing.
Targeting Wnt/β-Catenin Pathways in Primary Liver Tumours: From Microenvironment Signaling to Therapeutic Agents
Authors: Selvaggi Federico , Catalano Teresa , Cotellese Roberto , Aceto Gitana Maria
Published: April 2022

Primary liver cancers (PLCs) are steadily increasing in incidence and mortality in the world. They have a poor prognosis due to their silent nature, late discovery and resistance to common chemotherapy. At present, there are limited treatment alternatives, and the understanding of PLC molecular aspects is essential to develop more efficient drugs and therapeutic surgical and loco-regional strategies. A clear causal link with liver damage, inflammation, and regeneration has been found in the occurrence of PLC over the last few decades. Physiologically, Wingless/It (Wnt)-β-catenin signaling plays a key role in liver development, metabolic zonation and regeneration. Loss of functional homeostasis of this pathway appears to be a major driver of carcinogenesis in the liver parenchyma. In the hepatic microenvironment, molecular deregulations that exceed the Wnt signaling biological capacity can induce tumor initiation and progression. Indeed, somatic mutations are identified in key components of canonical and non-canonical Wnt signaling and in PLCs and precancerous lesions. In this review, the altered functions of Wnt/β-catenin signaling are considered in human PLCs, with emphasis on hepatocellular carcinomas (HCC), cholangiocarcinomas (CCA) and hepatoblastomas (HB). Based on recent literature, we also focused on liver cancerogenesis through Wnt deregulation. An overview of preclinical and clinical studies on approved and experimental drugs, targeting the Wnt/β-catenin cascade in PLCs, is proposed. In addition, the clinical implication of molecule inhibitors that have been shown to possess activity against the Wnt pathway in association with conventional surgical and loco-regional therapies are reviewed.
The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy
Authors: Gudd Cathrin L. C. , Possamai Lucia A.
Published: April 2022

Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in the field of oncology. This is an important complication to consider as more immune oncological targets are being identified to show promising results in clinical trials. The application of these therapeutics may be complicated by the development of immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation of cancer therapy. Hepatoxicity presents one of the most frequently encountered irAEs and a better understanding of the underlying mechanism is crucial for the development of alternative therapeutic interventions. As a novel drug side effect, the immunopathogenesis of the condition is not completely understood. In the liver, myeloid cells play a central role in the maintenance of homeostasis and promotion of inflammation. Recent research has identified myeloid cells to be associated with hepatic adverse events of various immune modulatory monoclonal antibodies. In this review article, we provide an overview of the role of myeloid cells in the immune pathogenesis during hepatoxicity related to cancer immunotherapies and highlight potential treatment options.
Diagnostic Value of Radiolabelled Somatostatin Analogues for Neuroendocrine Tumour Diagnosis: The Benefits and Drawbacks of [64Cu]Cu-DOTA-TOC
Authors: Vahidfar Nasim , Farzanehfar Saeed , Abbasi Mehrshad , Mirzaei Siroos , Delpassand Ebrahim S. , Abbaspour Farzad , Salehi Yalda , Biersack Hans Jürgen , Ahmadzadehfar Hojjat
Published: April 2022

Neuroendocrine tumours (NETs) arise from secondary epithelial cell lines in the gastrointestinal or respiratory system organs. The rate of development of these tumours varies from an indolent to an aggressive course, typically being initially asymptomatic. The identification of these tumours is difficult, particularly because the primary tumour is often small and undetectable by conventional anatomical imaging. Consequently, diagnosis of NETs is complicated and has been a significant challenge until recently. In the last 30 years, the advent of novel nuclear medicine diagnostic procedures has led to a substantial increase in NET detection. Great varieties of exclusive single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals for detecting NETs are being applied successfully in clinical settings, including [111In]In-pentetreotide, [99mTc]Tc-HYNIC-TOC/TATE, [68Ga]Ga-DOTA-TATE, and [64Cu]Cu-DOTA-TOC/TATE. Among these tracers for functional imaging, PET radiopharmaceuticals are clearly and substantially superior to planar or SPECT imaging radiopharmaceuticals. The main advantages include higher resolution, better sensitivity and increased lesion-to-background uptake. An advantage of diagnosis with a radiopharmaceutical is the capacity of theranostics to provide concomitant diagnosis and treatment with particulate radionuclides, such as beta and alpha emitters including Lutetium-177 (177Lu) and Actinium-225 (225Ac). Due to these unique challenges involved with diagnosing NETs, various PET tracers have been developed. This review compares the clinical characteristics of radiolabelled somatostatin analogues for NET diagnosis, focusing on the most recently FDA-approved [64Cu]Cu-DOTA-TATE as a state-of-the art NET-PET/CT radiopharmaceutical.
Sustainable Synthesis of a Highly Stable and Coke-Free Ni@CeO2 Catalyst for the Efficient Carbon Dioxide Reforming of Methane
Authors: Kim Seung Bo , Eissa Ahmed Al-Shahat , Kim Min-Jae , Goda Emad S. , Youn Jae-Rang , Lee Kyubock
Published: April 2022

A facile and green synthetic strategy is developed in this paper for the construction of an efficient catalyst for the industrially important carbon dioxide reforming of methane, which is also named the dry reforming of methane (DRM). Through controlling the synthetic strategy and Ni content, a high-performance Ni@CeO2 catalyst was successfully fabricated. The catalyst showed superb efficiency for producing the syngas with high and stable conversions at prolonged operating conditions. Incorporating Ni during the ceria (CeO2) crystallization resulted in a more stable structure and smaller nanoparticle (NP) size with a more robust interaction with the support than loading Ni on CeO2 supports by the conventional impregnation method. The H2/CO ratio was almost 1.0, indicating the promising applicability of utilizing the obtained syngas for the Fischer–Tropsch process to produce worthy chemicals. No carbon deposits were observed over the as-synthesized catalyst after operating the DRM reaction for 50.0 h, even at a more coke-favoring temperature (700 °C). Owing to the superb resistance to coke and sintering, control of the size of the Ni-NPs, uniform dispersion of the active phase, and potent metal interaction with the support, the synthesized catalyst achieved a magnificent catalytic activity and durability during serving for the DRM reaction for extended operating periods.
Discovery of Resistance Genes in Rye by Targeted Long-Read Sequencing and Association Genetics
Authors: Vendelbo Nikolaj M. , Mahmood Khalid , Steuernagel Burkhard , Wulff Brande B. H. , Sarup Pernille , Hovmøller Mogens S. , Justesen Annemarie Fejer , Kristensen Peter S. , Orabi Jihad , Jahoor Ahmed
Published: April 2022

The majority of released rye cultivars are susceptible to leaf rust because of a low level of resistance in the predominant hybrid rye-breeding gene pools Petkus and Carsten. To discover new sources of leaf rust resistance, we phenotyped a diverse panel of inbred lines from the less prevalent Gülzow germplasm using six distinct isolates of Puccinia recondita f. sp. secalis and found that 55 out of 92 lines were resistant to all isolates. By performing a genome-wide association study using 261,406 informative SNP markers, we identified five resistance-associated QTLs on chromosome arms 1RS, 1RL, 2RL, 5RL and 7RS. To identify candidate Puccinia recondita (Pr) resistance genes in these QTLs, we sequenced the rye nucleotide-binding leucine-rich repeat (NLR) intracellular immune receptor complement using a Triticeae NLR bait-library and PacBio® long-read single-molecule high-fidelity (HiFi) sequencing. Trait-genotype correlations across 10 resistant and 10 susceptible lines identified four candidate NLR-encoding Pr genes. One of these physically co-localized with molecular markers delimiting Pr3 on chromosome arm 1RS and the top-most resistance-associated QTL in the panel.
Live-Cell Imaging of the Contractile Velocity and Transient Intracellular Ca2+ Fluctuations in Human Stem Cell-Derived Cardiomyocytes
Authors: Acharya Aviseka , Nemade Harshal , Rajendra Prasad Krishna , Khan Khadija , Hescheler Jürgen , Blackburn Nick , Hemmersbach Ruth , Papadopoulos Symeon , Sachinidis Agapios
Published: April 2022

Live-cell imaging techniques are essential for acquiring vital physiological and pathophysiological knowledge to understand and treat heart disease. For live-cell imaging of transient alterations of [Ca2+]i in human cardiomyocytes, we engineered human-induced pluripotent stem cells carrying a genetically-encoded Ca2+-indicator (GECI). To monitor sarcomere shortening and relaxation in cardiomyocytes in real-time, we generated a α-cardiac actinin (ACTN2)-copepod (cop) green fluorescent protein (GFP+)-human-induced pluripotent stem cell line by using the CRISPR-Cas9 and a homology directed recombination approach. The engineered human-induced pluripotent stem cells were differentiated in transgenic GECI-enhanced GFP+-cardiomyocytes and ACTN2-copGFP+-cardiomyocytes, allowing real-time imaging of [Ca2+]i transients and live recordings of the sarcomere shortening velocity of ACTN2-copGFP+-cardiomyocytes. We developed a video analysis software tool to quantify various parameters of sarcoplasmic Ca2+ fluctuations recorded during contraction of cardiomyocytes and to calculate the contraction velocity of cardiomyocytes in the presence and absence of different drugs affecting cardiac function. Our cellular and software tool not only proved the positive and negative inotropic and lusitropic effects of the tested cardioactive drugs but also quantified the expected effects precisely. Our platform will offer a human-relevant in vitro alternative for high-throughput drug screenings, as well as a model to explore the underlying mechanisms of cardiac diseases.