bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of lumbar brucella spondylitis with negative pressure wound therapy via extreme lateral approach: A case report
Authors: Cui Haocheng , Chang Zhengqi , Yu Xiuchun
Published: October 2022

Brucella spondylitis (BS) is a specific spinal infection. Surgical treatment is required for Brucella spondylitis that has caused neurological symptoms in the lower extremities and developed an intraspinal abscess. The main purpose of surgery is to remove the lesion and restore the stability of the spine. However, both the anterior approach and the posterior approach cannot completely remove the lesions, resulting in a low cure rate and a certain recurrence rate. Although anterior or posterior debridement is more thorough, it is unbearable for some patients with poor general condition. In this study, for the first time, a negative pressure wound therapy (NPWT) device was introduced into the intervertebral space through the extreme lateral approach to treat a patient with Brucella spondylitis. We summarize the treatment process, and discuss the feasibility and effectiveness of this surgical approach through 1-year follow-up.
Methods of quantifying interactions among populations using Lotka-Volterra models
Authors: Davis Jacob D. , Olivença Daniel V. , Brown Sam P. , Voit Eberhard O.
Published: October 2022

The Lotka-Volterra (LV) model was introduced in the early 20th Century to describe predator-prey systems. Since then, the model has been expanded to capture the dynamics of numerous types of interacting populations and to include the effects of external factors from the environment. Despite many simplifying assumptions, the LV approach has proven to be a very valuable tool for gaining insights into the dynamics of diverse biological interaction systems. In particular, recognizing the critical importance of microbiomes for human and environmental heath, LV systems have become effective tools of analysis and, indeed, the default for quantitatively assessing interactions within these large microbial communities. Here we present an overview of parameter inference methods for LV systems, specifically addressing individuals entering the field of biomathematical modeling, who have a modest background in linear algebra and calculus. The methods include traditional local and global strategies, as well as a recently developed inference method based strictly on linear algebra. We compare the different strategies using both lab-acquired and synthetic time series data. We also address a recent debate within the scientific community of whether it is legitimate to compose large models from information inferred for the dynamics of subpopulations. In addition to parameter estimation methods, the overview includes preparatory aspects of the inference process, including data cleaning, smoothing, and the choice of an adequate loss function. Our comparisons demonstrate that traditional fitting strategies, such as gradient descent optimization and differential evolution, tend to yield low residuals but sometimes overfit noisy data and incur high computation costs. The linear-algebra-based method produces a satisfactory solution much faster, generally without overfitting, but requires the user to estimate slopes from the time series, which can introduce undue error. The results also suggest that composing large models from information regarding sub-models can be problematic. Overall, there is no clear “always-best method” for inferring parameters from data, and prudent combinations may be the best strategy.
R400: A novel gene signature for dose prediction in radiation exposure studies in humans
Authors: St. Peter Frederick , Vadrev Srinivas Mukund , Soufan Othman
Published: October 2022

Radiation’s harmful effects on biological organisms have long been studied through mainly evaluating pathological changes in cells, tissues, or organs. Recently, there have been more accessible gene expression datasets relating to radiation exposure studies. This provides an opportunity to analyze responses at the molecular level toward revealing phenotypic differences. Biomarkers in toxicogenomics have been suggested as indicators of radiation exposure and seem to react differently to various dosages of radiation. This study proposes a predictive gene signature specific to radiation exposure and can be used in automatically diagnosing the exposure dose. In searching for a reliable gene set that will correctly identify the exposure dose, consideration needs to be given to the size of the set. For this reason, we experimented with the number of genes used for training and testing. Gene set sizes of 28, 100, 200, 300, 400, 500, 600, 700, 800, 900 and 1,000 were tested to find the size that provided the best accuracy across three datasets. Models were then trained and tested using multiple datasets in various ways, including an external validation. The dissimilarities between these datasets provide an analogy to real-world conditions where data from multiple sources are likely to have variances in format, settings, time parameters, participants, processes, and machine tolerances, so a robust training dataset from many heterogeneous samples should provide better predictability. All three datasets showed positive results with the correct classification of the radiation exposure dose. The average accuracy of all three models was 88% for gene sets of both 400 and 1,000 genes. R400 provided the best results when testing the three datasets used in this study. A literature validation of top selected genes shows high relevance of perturbations to adverse effects reported during cancer radiotherapy.
ITRAQ-based quantitative proteomics analysis of forest musk deer with pneumonia
Authors: Tang Jie , Suo Lijuan , Li Feiran , Yang Chao , Bian Kun , Wang Yan
Published: October 2022

Pneumonia can seriously threaten the life of forest musk deer (FMD, an endangered species). To gain a comprehensive understanding of pneumonia pathogenesis in FMD, iTRAQ-based proteomics analysis was performed in diseased (Pne group) lung tissues of FMD that died of pneumonia and normal lung tissues (Ctrl group) of FMD that died from fighting against each other. Results showed that 355 proteins were differentially expressed (fold change ≥ 1.2 and adjusted P-value < 0.05) in Pne vs. Ctrl. GO/KEGG annotation and enrichment analyses showed that dysregulated proteins might play vital roles in bacterial infection and immunity. Given the close association between bacterial infection and pneumonia, 32 dysregulated proteins related to Staphylococcus aureus infection, bacterial invasion of epithelial cells, and pathogenic Escherichia coli infection were screened out. Among these 32 proteins, 13 proteins were mapped to the bovine genome. Given the close phylogenetic relationships of FMD and bovine, the protein-protein interaction networks of the above-mentioned 13 proteins were constructed by the String database. Based on the node degree analysis, 5 potential key proteins related to pneumonia-related bacterial infection in FMD were filtered out. Moreover, 85 dysregulated proteins related to the immune system process were identified given the tight connection between immune dysregulation and pneumonia pathogenesis. Additionally, 12 proteins that might function as crucial players in pneumonia-related immune response in FMD were screened out using the same experimental strategies described above. In conclusion, some vital proteins, biological processes, and pathways in pneumonia development were identified in FMD.
Effect of methionine hydroxy analog feed supplements: Significant alteration and enrichment of rumen microbiota and metabolome in Hu sheep
Authors: Li Shujie , Zeng Hanfang , Wang Changjian , Han Zhaoyu
Published: October 2022

Methionine hydroxy analogs (MHA) are widely used as the main sources of methionine in ruminant feed production. The purpose of this study was to explore the effect of using MHA supplements such as MHA as a salt of calcium (MHA-Ca) and 2-hydroxy-4-(methylthio)-butanoic acid isopropyl ester (HMBi) as sources of methionine on the rumen microbiota and metabolome in Hu sheep. Seventy-two healthy Hu sheep were randomly assigned to three dietary treatment groups: control, MHA-Ca, and HMBi groups. The results showed that the concentrations of total volatile fatty acids, acetate, and propionate were higher in the HMBi group than in the control group. The HMBi and MHA-Ca groups had higher alpha diversity values than those in control group. We compared the rumen microbiota by using 16S rRNA gene sequencing. At the phylum level, the HMBi group had a higher relative abundance of Firmicutes and a lower relative abundance of Synergistetes than did the control group. At the genus level, the control group had a higher relative abundance of Treponema_2 than did the HBMi group and a higher relative abundance of Prevotellaceae_UCG_004 than did the MHA-Ca group. Metabolomic analyses revealed that fatty acids, amino acids, lipids, organic acids, sugars, amines, and nucleosides were significantly altered in both MHA-Ca and HMBi groups. Metabolites with significant differences were enriched in amino acid and carbohydrate metabolisms, such as phenylalanine metabolism, biosynthesis of amino acids, tryptophan metabolism, galactose metabolism, and tyrosine metabolism. Above all, the findings presented in this study indicate that MHA alter the rumen microbiota and metabolites and that different forms of MHA have different impacts. The results of our study contribute to a better understanding of the effects of MHA.
Analyzing Meta-Heuristic Algorithms for Task Scheduling in a Fog-Based IoT Application
Authors: Rahbari Dadmehr
Published: October 2022

In recent years, the increasing use of the Internet of Things (IoT) has generated excessive amounts of data. It is difficult to manage and control the volume of data used in cloud computing, and since cloud computing has problems with latency, lack of mobility, and location knowledge, it is not suitable for IoT applications such as healthcare or vehicle systems. To overcome these problems, fog computing (FC) has been used; it consists of a set of fog devices (FDs) with heterogeneous and distributed resources that are located between the user layer and the cloud on the edge of the network. An application in FC is divided into several modules. The allocation of processing elements (PEs) to modules is a scheduling problem. In this paper, some heuristic and meta-heuristic algorithms are analyzed, and a Hyper-Heuristic Scheduling (HHS) algorithm is presented to find the best allocation with respect to low latency and energy consumption. HHS allocates PEs to modules by low-level heuristics in the training and testing phases of the input workflow. Based on simulation results and comparison of HHS with traditional, heuristic, and meta-heuristic algorithms, the proposed method has improvements in energy consumption, total execution cost, latency, and total execution time.
Evaluation of the Clinical Outcome and Cost Analysis of Antibiotics in the Treatment of Acute Respiratory Tract Infections in the Emergency Department in Saudi Arabia
Authors: Alanazi Menyfah Q. , AlQahtani Hajar , Almangour Thamer A. , Aleanizy Fadilah Sfouq , Alqahtani Fulwah Yahya
Published: October 2022

This study aims to assess the prevalence and antibiotic-treatment patterns of respiratory tract infections (RTIs), prevalence and types of antibiotic-prescribing errors, and the cost of inappropriate antibiotic use among emergency department (ED) patients. A cross-sectional study was conducted at the ED in King Abdulaziz Medical City, Riyadh, Saudi Arabia. Patient characteristics (age, sex, weight, allergies, diagnostic tests (CX-Ray), cultures, microorganism types, and prescription characteristics) were studied. During the study, 3185 cases were diagnosed with RTIs: adults (>15 years) 55% and pediatrics (<15 years) 44%. The overall prevalence of RTIs was 21%, differentiated by upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI) (URTI 13.4%; LRTI 8.4%), of total visits. Three main antibiotics (ATB) categories were prescribed in both age groups: penicillin (pediatrics 43%; adults 26%), cephalosporin (pediatrics 29%; adults 19%), and macrolide (pediatrics 26%; adults 38%). The prevalence of inappropriate ATB prescriptions was 53% (pediatrics 35%; adults 67%). Errors in ATB included selection (3.3%), dosage (22%), frequency (3%), and duration (32%). There is a compelling need to create antimicrobial stewardship (AMS) programs to improve antibiotic use due to the high number of prescriptions in the ED deemed as inappropriate. This will help to prevent unwanted consequences on the patients and the community associated with antibiotic use.
Low-Dose Dioxin Reduced Glucose Uptake in C2C12 Myocytes: The Role of Mitochondrial Oxidative Stress and Insulin-Dependent Calcium Mobilization
Authors: Im Suyeol , Kang Sora , Kim Ji Hwan , Oh Seung Jun , Pak Youngmi Kim
Published: October 2022

Chronic exposure to some environmental polluting chemicals (EPCs) is strongly associated with metabolic syndrome, and insulin resistance is a major biochemical abnormality in the skeletal muscle in patients with metabolic syndrome. However, the causal relationship is inconsistent and little is known about how EPCs affect the insulin signaling cascade in skeletal muscle. Here, we investigated whether exposure to 100 pM of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) as a low dose of dioxin induces insulin resistance in C2C12 myocytes. The treatment with TCDD inhibited the insulin-stimulated glucose uptake and translocation of glucose transporter 4 (GLUT4). The low-dose TCDD reduced the expression of insulin receptor β (IRβ) and insulin receptor substrate (IRS)-1 without affecting the phosphorylation of Akt. The TCDD impaired mitochondrial activities, leading to reactive oxygen species (ROS) production and the blockage of insulin-induced Ca2+ release. All TCDD-mediated effects related to insulin resistance were still observed in aryl hydrocarbon receptor (AhR)-deficient myocytes and prevented by MitoTEMPO, a mitochondria-targeting ROS scavenger. These results suggest that low-dose TCDD stress may induce muscle insulin resistance AhR-independently and that mitochondrial oxidative stress is a novel therapeutic target for dioxin-induced insulin resistance.
Treatment of Human HeLa Cells with Black Raspberry Extracts Enhances the Removal of DNA Lesions by the Nucleotide Excision Repair Mechanism
Authors: Sales Ana H. , Kolbanovskiy Marina , Geacintov Nicholas E. , Chen Kun-Ming , Sun Yuan-Wan , El-Bayoumy Karam
Published: October 2022

As demonstrated by us earlier and by other researchers, a diet containing freeze-dried black raspberries (BRB) inhibits DNA damage and carcinogenesis in animal models. We tested the hypothesis that the inhibition of DNA damage by BRB is due, in part, to the enhancement of DNA repair capacity evaluated in the human HeLa cell extract system, an established in vitro system for the assessment of cellular DNA repair activity. The pre-treatment of intact HeLa cells with BRB extracts (BRBE) enhances the nucleotide excision repair (NER) of a bulky deoxyguanosine adduct derived from the polycyclic aromatic carcinogen benzo[a]pyrene (BP-dG) by ~24%. The NER activity of an oxidatively-derived non-bulky DNA lesion, guanidinohydantoin (Gh), is also enhanced by ~24%, while its base excision repair activity is enhanced by only ~6%. Western Blot experiments indicate that the expression of selected, NER factors is also increased by BRBE treatment by ~73% (XPA), ~55% (XPB), while its effects on XPD was modest (<14%). These results demonstrate that BRBE significantly enhances the NER yields of a bulky and a non-bulky DNA lesion, and that this effect is correlated with an enhancement of expression of the critically important NER factor XPA and the helicase XPB, but not the helicase XPD.
Markers of Endothelial Dysfunction Are Attenuated by Resveratrol in Preeclampsia
Authors: Bueno-Pereira Thaina Omia , Bertozzi-Matheus Mariana , Zampieri Gabriela Morelli , Abbade Joelcio Francisco , Cavalli Ricardo C. , Nunes Priscila Rezeck , Sandrim Valeria Cristina
Published: October 2022

Preeclampsia (PE) is characterized by great endothelial dysfunction, decreased nitric oxide (NO) bioavailability, and higher levels of arginase activity. In the present study, we investigated the potential modulatory effects of trans-resveratrol (RSV) on arginase and endothelial dysfunction biomarkers in endothelial cells exposed to plasma from patients with PE and healthy pregnant (HP) women, and umbilical arteries from patients with PE. Human umbilical vein endothelial cells (HUVECs) were incubated with pooled plasma from 10 HP or 10 PE pregnant women and RSV; umbilical arteries from patients with PE were incubated with RSV; intracellular NO and total reactive oxygen species (ROS) levels were assessed using a probe that interacted with these radicals; total arginase activity was evaluated measuring the urea produced; total antioxidant capacity was measured using the ferric reduction ability power (FRAP) assay; and endothelial dysfunction biomarkers were assessed using qPCR in endothelial cells and umbilical arteries. RSV increased NO levels and decreased total arginase activity in endothelial cells incubated with plasma from patients with PE. In addition, RSV increased total antioxidant capacity and downregulated endothelial dysfunction biomarkers, such as intercellular adhesion molecule-1 (ICAM-1), von Willebrand factor (vWF), and Caspase-3, (CASP-3), in endothelial cells and umbilical arteries from PE patients. RSV treatment positively modulated the L-arginine–NO pathway, decreased arginase activity, and increased antioxidant capacity, in addition to downregulating endothelial dysfunction biomarkers.
A Randomized Controlled Trial on Pleurotus eryngii Mushrooms with Antioxidant Compounds and Vitamin D2 in Managing Metabolic Disorders
Authors: Kleftaki Stamatia-Angeliki , Amerikanou Charalampia , Gioxari Aristea , Lantzouraki Dimitra Z. , Sotiroudis George , Tsiantas Konstantinos , Tsiaka Thalia , Tagkouli Dimitra , Tzavara Chara , Lachouvaris Lefteris , Zervakis Georgios I. , Kalogeropoulos Nick , Zoumpoulakis Panagiotis , Kaliora Andriana C.
Published: October 2022

This study examined the effects of a Pleurotus eryngii mushroom snack on metabolically unhealthy patients. After harvest, mushrooms were baked and subjected to UV-B irradiation to enhance vitamin D2 content. A randomized controlled trial was conducted for three months with two arms. Both groups received conventional nutritional counseling for metabolic disorders, while the intervention group had to consume the snack daily as well. We collected blood samples at the beginning and the end of the study to determine biochemical measurements and serum 25(OH)D2 and to evaluate inflammation and oxidative stress. One hundred patients consented and were randomized. Comparatively to the control group, snack consumption regulated glucose levels and reduced body weight, fat, waist and hip circumferences. In addition, 25(OH)D2 increased significantly in the intervention group. The levels of LDL and SGOT were lower only in the intervention group. Levels of IL-6 and ox-LDL decreased in the mushroom group, while the overall physical health increased. These findings suggest potential antidiabetic, antiobesity, anti-inflammatory and antioxidant health benefits of the snack to metabolically unhealthy individuals.
Research on Seismic Wave Quality Factor of Marble Jointed Rock Mass under SHPB Impact
Authors: Sun Changkun , Li Changhong , Wei Xiaoming
Published: October 2022

In order to quantitatively describe the energy dissipation law of jointed rock mass, we obtained the jointed cores in laboratory conditions using marble from the roof and floor of Jinchanghe Lead–zinc mine in Baoshan. The dissipative degree of stress wave in marble jointed rock mass is measured by introducing quality factor Qs parameter. Based on the experimental principle of Split Hopkinson Pressure rod loading device (SHPB), we proposed a three-wave energy method of incident wave, reflected wave and projected wave for calculating jointed rock samples’ quality factor Qs based on stress wave energy. Using the SHPB test system for multiple specimens taken from the same piece of rock mass shock compression experiment, the three groups of specimens under different loading conditions gained incident wave and reflected wave and transmission wave experimental data, using the method of stress wave energy to deal with stress wave data, and calculate the joint sample maximum storage energy, dissipation energy and Qs quality factors. The results show that: ① The non-destructive breaking time–history strain of Dali rock mass under impact load is obtained by SHPB dynamic test system; combined with the deformation energy and dissipation energy calculation principle of quality factor, six groups of Qs experimental values are obtained. Although the Qs experimental values are discrete, the overall deviation is small with an average of 43.07. ② AUTODYN-Code was used to simulate the damage and fracture characteristics of rock mass with different quality factors under explosive dynamic load. The results showed that the radius of rock mass compression shear damage area gradually increased with the increase in porosity, but it was not obvious.
Atmospheric CO2 Concentrations in Caves Protected as Nature Reserves and Related Gas Hazard
Authors: Madonia Paolo , Cangemi Marianna , Casamento Giulia , Di Maggio Cipriano , Di Pietro Rosario , Interlandi Marco , Barraco Gianfranco , D’Aleo Roberto , Di Trapani Francesco
Published: October 2022

Atmospheric CO2 concentrations can reach high levels inside natural caves, representing a hazardous condition for both humans frequenting the underground environment and its safeguard due to the corrosion of speleothems induced by the acidification of atmospheric moisture. These issues are particularly critical for the eco-sustainable management of caves protected as nature reserves and undergoing touristic exploitation. In this paper we present the results of the C6 project, which was activated in 1999 for the monitoring of air quality inside three caves protected as nature reserves in Sicily (Italy). Near-real-time and spot measurements of air temperature and CO2 concentration have been carried out since the year 2000, giving the opportunity of evaluating the gas hazard for visitors and its potential impact on the protected underground environments, as well as the influence of meteorological and hydrological conditions in driving carbon dioxide accumulations. The analysis of data acquired in the hypogeal atmosphere, and their comparison with analogous epigeal measures, indicates that carbon dioxide accumulation is controlled by a complex interaction among cave topography, meteorological dynamics, gaseous exchanges between groundwaters and the atmosphere, and human fruition. This last factor, under particular conditions, can surprisingly diminishing underground CO2 concentrations.
Bioaerosol Concentration in a Cattle Feedlot in Neuquén, Argentina
Authors: Cogliati Marisa Gloria , Paez Paula Andrea , Pianciola Luis Alfredo , Caputo Marcelo Alejandro , Mut Paula Natalia
Published: October 2022

There is a global trend toward intensive livestock breeding, which tends to increase the microbial load in the environment as well as the presence of volatile compounds and dust that can cause health issues. Cattle is the major producer of Escherichiacoli (E. coli), a group of foodborne bacteria associated with severe human diseases, and Neuquén province in Argentina has one of the highest rates of uremic hemolytic syndrome incidence in the world. This paper presents the results of two sampling events of E. coli bacteria at 39 sites in La Paisana ranch (LPR), in Añelo (Neuquén), considering locations inside the pens, upwind, and downwind of the feedlot with different time steps, using a Microflow α equipment. The ranch has approximately 600 heads and clean and controlled installations. The field experiment included sampling airborne aerosol deposition and concentration using passive and active methods. Concentrations were also estimated using an atmospheric dispersion model. During the field experiment, counts of up to 2970 CFU/m3 were obtained in the cattle stockyards and up to 111 CFU/m3 at a distance of 100 m.
Comprehensive Validation and Calibration of MODIS PWV over Mainland China
Authors: Zhao Yanyan , Zhao Hongwei , Li Junqiang , Xiao Gongwei
Published: October 2022

Although ground-based precipitable water vapor (PWV) can be obtained with a high temporal resolution and spatial resolution of tens of kilometers in an urban area using Global Navigation Satellite System (GNSS) observation, it remains fairly sparse in the vast regions over Mainland China. Satellite-derived PWV has a high spatial resolution, thereby enabling the accurate investigation of regional climate change. However, understanding the quality of satellite-derived PWV products is a prerequisite before use, which has become the focus of this study. PWV products, namely, MOD05_L2 and MYD05_L2, over the entirety of Mainland China derived from MODerate Resolution Imaging Spectroradiometer (MODIS) onboard Terra and Aqua satellites are validated over the period 2000–2017 using multiple sources, including GNSS, radiosonde, AErosol RObotic NETwork (AERONET), and European Center for Medium-Range Weather Forecasts ERA-Interim (ECMWF). The accuracy of MODIS PWV products is less than 4.3 mm over the entirety of Mainland China; however, it varies in four areas of South China (SC), North China (NC), Northwest China (NWC), and Tibetan Plateau (TP), separately with values ranging from 3 mm to 6 mm. A linear fit model is applied to calibrate the MODIS PWV products, and the accuracies of the corrected PWV from MODIS infrared (IR) and near-infrared (NIR) products have been improved by approximately 7.5% and 50.6%, respectively. The MODIS PWV is compared and calibrated in the four areas, and the improved accuracies vary widely. The root mean square error (RMSE) of IR PWV is approximately less than 4 mm over China except for the SC area with a value of approximately 5.3 mm after calibration, whereas the values of NIR PWV are approximately 2 mm over the entirety of Mainland China, except for the TP area, with a value of approximately 2.6 mm. The MODIS NIR PWV performs better than that of IR PWV data in most areas of Mainland China regardless of whether with calibration. The validation and calibration of MODIS water vapor products over Mainland China also indicate their capability to investigate the seasonal and annual variations as well as long-term trend changes in water vapor in China.
Real-Time PM2.5 Monitoring in a Diesel Generator Workshop Using Low-Cost Sensors
Authors: Feng Zikang , Zheng Lina , Liu Lingyu , Zhang Wenli
Published: October 2022

Particulates from diesel generator operation are a known air pollutant with adverse health effects. In this study, we used low-cost particulate matter (PM) sensors to monitor PM2.5 in a diesel generator plant. We compared the measurement results from a PM sensor and a reference instrument (DustTrak), and we found a high correlation between them. The data overestimation or underestimation of PM sensors implied the need for data calibration. Hence, we proposed a data calibration algorithm based on a nonlinear support vector machines(SVM )model, and we investigated the effect of three calibration factors on the model: humidity, temperature, and total volatile organic compounds (TVOC). It was found that the TVOC correction coefficient has great influence on the model, which should be considered when calibrating the low-cost PM sensor in diesel generator operation sites. A monitoring network with six low-cost sensors was installed in the diesel generator plant to monitor PM2.5 concentration. It was found that normal diesel generator work, diesel generator set handling work, and human activity are the most dominant ways of producing particulate matter at the site, and dispersion is the main cause of increased PM2.5 concentrations in nonworking areas. In this study, PM2.5 emissions from two different diesel generators were tested, and PM2.5 concentrations at monitoring points reached 220 μg/m3 and 120 μg/m3, respectively. This further confirms that diesel generators produce many respirable particles when working.
Central Serotonin/Noradrenaline Transporter Availability and Treatment Success in Patients with Obesity
Authors: Griebsch Nora-Isabell , Kern Johanna , Hansen Jonas , Rullmann Michael , Luthardt Julia , Helfmeyer Stephanie , Dekorsy Franziska J. , Soeder Marvin , Hankir Mohammed K. , Zientek Franziska , Becker Georg-Alexander , Patt Marianne , Meyer Philipp M. , Dietrich Arne , Blüher Matthias , Ding Yu-Shin , Hilbert Anja , Sabri Osama , Hesse Swen
Published: October 2022

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.
A Multi-Center Clinical Study to Harvest and Characterize Circulating Tumor Cells from Patients with Metastatic Breast Cancer Using the Parsortix® PC1 System
Authors: Cohen Evan N. , Jayachandran Gitanjali , Moore Richard G. , Cristofanilli Massimo , Lang Julie E. , Khoury Joseph D. , Press Michael F. , Kim Kyu Kwang , Khazan Negar , Zhang Qiang , Zhang Youbin , Kaur Pushpinder , Guzman Roberta , Miller Michael C. , Reuben James M. , Ueno Naoto T.
Published: October 2022

Circulating tumor cells (CTCs) captured from the blood of cancer patients may serve as a surrogate source of tumor material that can be obtained via a venipuncture (also known as a liquid biopsy) and used to better understand tumor characteristics. However, the only FDA-cleared CTC assay has been limited to the enumeration of surface marker–defined cells and not further characterization of the CTCs. In this study, we tested the ability of a semi-automated device capable of capturing and harvesting CTCs from peripheral blood based on cell size and deformability, agnostic of cell-surface markers (the Parsortix® PC1 System), to yield CTCs for evaluation by downstream techniques commonly available in clinical laboratories. The data generated from this study were used to support a De Novo request (DEN200062) for the classification of this device, which the FDA recently granted. As part of a multicenter clinical trial, peripheral blood samples from 216 patients with metastatic breast cancer (MBC) and 205 healthy volunteers were subjected to CTC enrichment. A board-certified pathologist enumerated the CTCs from each participant by cytologic evaluation of Wright-Giemsa-stained slides. As proof of principle, cells harvested from a concurrent parallel sample provided by each participant were evaluated using one of three additional evaluation techniques: molecular profiling by qRT-PCR, RNA sequencing, or cytogenetic analysis of HER2 amplification by FISH. The study demonstrated that the Parsortix® PC1 System can effectively capture and harvest CTCs from the peripheral blood of MBC patients and that the harvested cells can be evaluated using orthogonal methodologies such as gene expression and/or Fluorescence In Situ Hybridization (FISH).
TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status
Authors: Ben Khaled Najib , Hammer Katharina , Ye Liangtao , Alnatsha Ahmed , Widholz Sebastian A. , Piseddu Ignazio , Sirtl Simon , Schneider Julia , Munker Stefan , Mahajan Ujjwal Mukund , Montero Juan José , Griger Joscha , Mayerle Julia , Reiter Florian P. , De Toni Enrico N.
Published: October 2022

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.
Novel BH4-BCL-2 Domain Antagonists Induce BCL-2-Mediated Apoptosis in Triple-Negative Breast Cancer
Authors: Kanakaveti Vishnupriya , Ramasamy Sakthivel , Kanumuri Rahul , Balasubramanian Vaishnavi , Saravanan Roshni , Ezhil Inemai , Pitani Ravishankar , Venkatraman Ganesh , Rayala Suresh Kumar , Gromiha M. Michael
Published: October 2022

Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer.
Molecular Engines, Therapeutic Targets, and Challenges in Pediatric Brain Tumors: A Special Emphasis on Hydrogen Sulfide and RNA-Based Nano-Delivery
Authors: Fahmy Sherif Ashraf , Dawoud Alyaa , Zeinelabdeen Yousra Ahmed , Kiriacos Caroline Joseph , Daniel Kerolos Ashraf , Eltahtawy Omar , Abdelhalim Miriam Mokhtar , Braoudaki Maria , Youness Rana A.
Published: October 2022

Pediatric primary brain tumors represent a real challenge in the oncology arena. Besides the psychosocial burden, brain tumors are considered one of the most difficult-to-treat malignancies due to their sophisticated cellular and molecular pathophysiology. Notwithstanding the advances in research and the substantial efforts to develop a suitable therapy, a full understanding of the molecular pathways involved in primary brain tumors is still demanded. On the other hand, the physiological nature of the blood–brain barrier (BBB) limits the efficiency of many available treatments, including molecular therapeutic approaches. Hydrogen Sulfide (H2S), as a member of the gasotransmitters family, and its synthesizing machinery have represented promising molecular targets for plentiful cancer types. However, its role in primary brain tumors, generally, and pediatric types, particularly, is barely investigated. In this review, the authors shed the light on the novel role of hydrogen sulfide (H2S) as a prominent player in pediatric brain tumor pathophysiology and its potential as a therapeutic avenue for brain tumors. In addition, the review also focuses on the challenges and opportunities of several molecular targeting approaches and proposes promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumor patients.
Visceral Obesity Is a More Important Factor for Colorectal Adenomas than Skeletal Muscle or Body Fat
Authors: Seo Ji Yeon , Han Yoo Min , Chung Su Jin , Lim Seon Hee , Bae Jung Ho , Chung Goh Eun
Published: October 2022

Objective: Although the incidence of colorectal adenomas increases with obesity, the role of various body compositions is still unknown. We aimed to determine which body composition best reflects the risk of colorectal adenomas. Methods: Patients aged 50–75 years who underwent colonoscopy and a bioelectrical impedance analysis (BIA) for a health check-up from 2017 to 2019 were retrospectively enrolled. The skeletal muscle index (SMI), fat mass index (FMI), and visceral fat index (VFI) were obtained using BIA. The muscle-to-fat ratio (MFR) and the skeletal muscle mass to visceral fat area ratio (SVR) were calculated. Results: Among 15,102 patients, 6605 (43.7%) had adenomas. SMI, FMI, MFR, VFI, and SVR were all associated with the risk of adenomas and high-risk adenomas in the age- and sex-adjusted model. When further adjusted for metabolic and lifestyle factors, VFI was the only factor significantly associated with the risk of colorectal adenomas and high-risk adenomas (adenomas: odds ratio (OR) 1.40, 95% confidence interval (CI) 1.22–1.61; high-risk adenomas: OR 1.47, 95% CI 1.16–1.87, for the highest quartile). Conclusion: Among the various body indices, VFI was the most important index associated with the development of colorectal adenoma. More attention should be paid to visceral fat when predicting the risk of colorectal adenomas.
DGKα, Bridging Membrane Shape Changes with Specific Molecular Species of DAG/PA: Implications in Cancer and Immunosurveillance
Authors: Bozelli José Carlos , Epand Richard M.
Published: October 2022

Cancer immunotherapy has revolutionized the oncology field. Despite the success, new molecular targets are needed to increase the percentage of patients that benefits from this therapy. Diacylglycerol kinase α (DGKα) has gathered great attention as a potential molecular target in immunotherapy because of its role in cancer proliferation and immunosuppression. DGKα catalyzes the ATP-dependent phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid (PA). Since both lipids are potent signaling messengers, DGKα acts as a switch between different signaling pathways. Its role in cancer and immunosuppression has long been ascribed to the regulation of DAG/PA levels. However, this paradigm has been challenged with the identification of DGKα substrate acyl chain specificity, which suggests its role in signaling could be specific to DAG/PA molecular species. In several biological processes where DGKα plays a role, large membrane morphological changes take place. DGKα substrate specificity depends on the shape of the membrane that the enzyme binds to. Hence, DGKα can act as a bridge between large membrane morphological changes and the regulation of specific molecular species of DAG/PA. Bearing in mind the potential therapeutic benefits of targeting DGKα, here, the role of DGKα in cancer and T cell biology with a focus on the modulation of its enzymatic properties by membrane shape is reviewed. The goal is to contribute to a global understanding of the molecular mechanisms governing DGKα biology. This will pave the way for future experimentation and, consequently, the design of better, more potent therapeutic strategies aiming at improving the health outcomes of cancer patients.
Experiences of Relatedness during Enforced Remote Work among Employees in Higher Education
Authors: Tapani Annukka , Sinkkonen Merja , Sjöblom Kirsi , Vangrieken Katrien , Mäkikangas Anne
Published: October 2022

The aim of this study was to investigate experiences of relatedness among higher education staff during enforced remote work caused by the COVID-19 pandemic. Experiences were investigated both at the earliest stages of enforced remote work (April 2020) and in November/December 2021. Remote work experiences were analysed through the lens of Deci and Ryan’s self-determination theory, especially through the concept of relatedness. Within this framework, relatedness is described as one of three basic psychological needs affecting health, well-being, and productivity. The main research focus includes ascertaining which factors affect experiences of relatedness among employees in higher education at work at the beginning of enforced remote work and at the end of it. The study uses qualitative data collected from Finnish university employees, analysed using theory-driven content analysis. The analysis of the two datasets enabled us to identify three categories of relatedness: (1) interaction among co-workers, (2) feelings of care and (3) experiences of connectedness. The results showed that the experience of relatedness was severely challenged during the enforced work period. In the future, the need for relatedness needs to be addressed more deliberately in multi-locational work conditions because remote work is especially affecting the experiences of relatedness. Positive experiences of relatedness can be achieved even in remote work conditions with deliberate and thought-out actions, for example by developing good remote interaction practices within the team and remote leadership practices that convey care for the employees.
Anticipatory Awareness and Actual Handwriting Performance Measures among Adolescents with Deficient Executive Functions
Authors: Fogel Yael , Rosenblum Sara
Published: October 2022

This secondary analysis explores differences and correlations between handwriting anticipatory awareness (time estimation, expected performance, and expected difficulty) before a paragraph copying task and actual performance time and legibility among adolescents with executive function deficits (EFD) versus neurotypical adolescents. Eighty-one adolescents (10–18 years old; 41 with EFD and daily functioning difficulties as per parent reports) estimated their time, expected performance, and expected difficulty before the paragraph copying task using the Self-Awareness of Performance Questionnaire (SAP-Q). Time duration was assessed using the Computerized Penmanship Evaluation Tool (ComPET) software, and legibility was scored using the Handwriting Legibility Scale (HLS). Significant between-group differences were found in actual time duration (ComPET), HLS total score and legibility components, and three SAP-Q questions. Both groups estimated significantly more performance time than their actual performance duration. The adolescents with EFD underestimated their performance before the handwriting task. Significant correlations were found between actual performance, anticipatory awareness, and Executive Function (EF) in both groups. Their performance predictions were significantly correlated with their EF and product’s legibility. The results highlight the potential relationships between anticipatory awareness and actual handwriting performance (time duration and legibility) of adolescents with and without EFD. Further studies may analyze the benefits of focusing on both EF and anticipatory awareness for handwriting improvement among populations with EF deficits.
Bi0.5Na0.5TiO3-Bi3.25La0.75Ti3O12 Lead-Free Thin Films for Energy Storage Applications through Nanodomain Design
Authors: Yue Wenfeng , Jia Tingting , Chen Yanrong , Dai Wenbin , Yu Liang , Cai Yali , Li Ting , Liu Lixia , Guo Quansheng , Yu Shuhui
Published: October 2022

Dielectric capacitors have received increasing attention due to their high power density. The Bi-based Aurivillius phase compound Bi3.25La0.75Ti3O12 (BLT) is considered a potential material in the field of energy storage due to its excellent ferroelectric properties and good fatigue resistance, and temperature stability. In this paper, 0.4Bi0.5Na0.5TiO3-0.6Bi3.25La0.75Ti3O12 (0.4NBT4BNT-0.6BLT)-thin films were prepared on Pt/Ti/SiO2/Si substrates with the sol-gel method. The addition of BNT destroys the long-range ferroelectric order of BLT and forms nanodomains. By increasing the BNT content, the BLT is transformed from a ferroelectric state to a relaxed state, and its application in the field of energy storage is realized. The recoverable energy density is 42.41 J/cm3, and the recoverable energy storage density is relatively stable in the range of 25–200 °C with good thermal stability. The energy storage efficiency is 75.32% at ~2663 kV/cm. The leakage current density at 300 kV/cm is 1.06 × 10−9 A/cm2.