bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycosaminoglycans: From Vascular Physiology to Tissue Engineering Applications
Authors: Lepedda Antonio Junior , Nieddu Gabriele , Formato Marilena , Baker Matthew Brandon , Fernández-Pérez Julia , Moroni Lorenzo
Published: May 2021

Cardiovascular diseases represent the number one cause of death globally, with atherosclerosis a major contributor. Despite the clinical need for functional arterial substitutes, success has been limited to arterial replacements of large-caliber vessels (diameter > 6 mm), leaving the bulk of demand unmet. In this respect, one of the most challenging goals in tissue engineering is to design a “bioactive” resorbable scaffold, analogous to the natural extracellular matrix (ECM), able to guide the process of vascular tissue regeneration. Besides adequate mechanical properties to sustain the hemodynamic flow forces, scaffold’s properties should include biocompatibility, controlled biodegradability with non-toxic products, low inflammatory/thrombotic potential, porosity, and a specific combination of molecular signals allowing vascular cells to attach, proliferate and synthesize their own ECM. Different fabrication methods, such as phase separation, self-assembly and electrospinning are currently used to obtain nanofibrous scaffolds with a well-organized architecture and mechanical properties suitable for vascular tissue regeneration. However, several studies have shown that naked scaffolds, although fabricated with biocompatible polymers, represent a poor substrate to be populated by vascular cells. In this respect, surface functionalization with bioactive natural molecules, such as collagen, elastin, fibrinogen, silk fibroin, alginate, chitosan, dextran, glycosaminoglycans (GAGs), and growth factors has proven to be effective. GAGs are complex anionic unbranched heteropolysaccharides that represent major structural and functional ECM components of connective tissues. GAGs are very heterogeneous in terms of type of repeating disaccharide unit, relative molecular mass, charge density, degree and pattern of sulfation, degree of epimerization and physicochemical properties. These molecules participate in a number of vascular events such as the regulation of vascular permeability, lipid metabolism, hemostasis, and thrombosis, but also interact with vascular cells, growth factors, and cytokines to modulate cell adhesion, migration, and proliferation. The primary goal of this review is to perform a critical analysis of the last twenty-years of literature in which GAGs have been used as molecular cues, able to guide the processes leading to correct endothelialization and neo-artery formation, as well as to provide readers with an overall picture of their potential as functional molecules for small-diameter vascular regeneration.
Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins
Authors: London Shira , De Franco Elisa , Elias-Assad Ghadir , Barhoum Marie Noufi , Felszer Clari , Paniakov Marina , Weiner Scott A. , Tenenbaum-Rakover Yardena
Published: May 2021

Background

Mutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in β-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys.

Cases

We describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development. Sequence analysis of GLIS3 identified a novel homozygous nonsense mutation, c.2392C>T, p.Gln798Ter (p.Q798*), which results in an early stop codon. The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring. Fluctuating blood glucose and intermittent hypoglycemia were observed on follow-up.

Conclusions

This report highlights the importance of early molecular diagnosis for appropriate management of NDM. We describe a novel nonsense mutation of GLIS3 causing NDM, extend the phenotype, and discuss the challenges in clinical management. Our findings provide new areas for further investigation into the roles of GLIS3 in the pathophysiology of diabetes mellitus.
Comprehensive Benefit/Cost Analysis of Utilizing PEV Parking Lots as Virtual Energy Storage for the Energy Supply Sustainability of Future Distribution Systems
Authors: Zeng Bo , Sun Bo , Mu Hongwei , Wang Yuqing , Wei Xuan , Wang Libin
Published: May 2021

The proliferation of plug-in electric vehicles has led to increased public charging infrastructure in cities worldwide. Grid-connected parking lot spaces are the most common charging option due to their technological readiness and convenience of adoption. Since the batteries aggregated by parking lots can be regarded as virtual energy storage, grid-connected parking lots are expected to provide many benefits to the urban distribution grid. This paper proposes a comprehensive methodological framework to evaluate the potential benefits and costs of utilizing grid-connected parking lot infrastructures to promote energy supply sustainability in future power distribution grids. Capacity-value-based and cost-effectiveness indexes are developed, which quantify the potential contribution of parking lots to power supply reliability and the associated economic implications. To realistically describe the available generation capacity of parking lot resources, a comprehensive model is presented, which explicitly considers the impact of external stimuli (incentive rates) on the behavioral patterns of lot users. Vehicle user responsiveness to incentive grades is derived from social field surveys. To conduct the evaluation, a hybrid algorithm based on Monte Carlo simulations is employed. The proposed methodology is illustrated on a real distribution grid in Beijing. The results confirm the effectiveness of our proposed approach and support practical policy suggestions.
Seroprevalence Surveys for Anti-SARS-CoV-2 Antibody in Different Populations in Taiwan With Low Incidence of COVID-19 in 2020 and Severe Outbreaks of SARS in 2003
Authors: Tseng Wen-Pin , Wu Jhong-Lin , Wu Chen-Chi , Kuo Kuan-Ting , Lin Chien-Hao , Chung Ming-Yi , Lee Ya-Fan , Yang Bey-Jing , Huang Chien-Hua , Chen Shey-Ying , Yu Chong-Jen , Chen Shyr-Chyr , Hsueh Po-Ren
Published: May 2021

Accurate detection of anti-SARS-CoV-2 antibodies provides a more accurate estimation of incident cases, epidemic dynamics, and risk of community transmission. We conducted a cross-sectional seroprevalence study specifically targeting different populations to examine the performance of pandemic control in Taiwan: symptomatic patients with epidemiological risk and negative qRT-PCR test (Group P), frontline healthcare workers (Group H), healthy adult citizens (Group C), and participants with prior virologically-confirmed severe acute respiratory syndrome (SARS) infection in 2003 (Group S). The presence of anti−SARS−CoV−2 total and IgG antibodies in all participants were determined by Roche Elecsys® Anti−SARS−CoV−2 test and Abbott SARS-CoV-2 IgG assay, respectively. Sera that showed positive results by the two chemiluminescent immunoassays were further tested by three anti-SARS-CoV-2 lateral flow immunoassays and line immunoassay (MIKROGEN recomLine SARS-CoV-2 IgG). Between June 29 and July 25, 2020, sera of 2,115 participates, including 499 Group P participants, 464 Group H participants, 1,142 Group C participants, and 10 Group S participants, were tested. After excluding six false-positive samples, SARS-CoV-2 seroprevalence were 0.4, 0, and 0% in Groups P, H, and C, respectively. Cross-reactivity with SARS-CoV-2 antibodies was observed in 80.0% of recovered SARS participants. Our study showed that rigorous exclusion of false-positive testing results is imperative for an accurate estimate of seroprevalence in countries with previous SARS outbreak and low COVID-19 prevalence. The overall SARS-CoV-2 seroprevalence was extremely low among populations of different exposure risk of contracting SARS-CoV-2 in Taiwan, supporting the importance of integrated countermeasures in containing the spread of SARS-CoV-2 before effective COVID-19 vaccines available.
Artificial Neural Network Architecture for Prediction of Contact Mechanical Response
Authors: Kalliorinne Kalle , Larsson Roland , Pérez-Ràfols Francesc , Liwicki Marcus , Almqvist Andreas
Published: May 2021

Predicting the contact mechanical response for various types of surfaces is and has long been a subject, where many researchers have made valuable contributions. This is because the surface topography has a tremendous impact on the tribological performance of many applications. The contact mechanics problem can be solved in many ways, with less accurate but fast asperity-based models on one end to highly accurate but not as fast rigorous numerical methods on the other. A mathematical model as fast as an asperity-based, yet as accurate as a rigorous numerical method is, of course, preferred. Artificial neural network (ANN)–based models are fast and can be trained to interpret how in- and output of processes are correlated. Herein, 1,536 surface topographies are generated with different properties, corresponding to three height probability density and two power spectrum functions, for which, the areal roughness parameters are calculated. A numerical contact mechanics approach was employed to obtain the response for each of the 1,536 surface topographies, and this was done using four different values of the hardness per surface and for a range of loads. From the results, 14 in situ areal roughness parameters and six contact mechanical parameters were calculated. The load, the hardness, and the areal roughness parameters for the original surfaces were assembled as input to a training set, and the in situ areal roughness parameters and the contact mechanical parameters were used as output. A suitable architecture for the ANN was developed and the training set was used to optimize its parameters. The prediction accuracy of the ANN was validated on a test set containing specimens not seen during training. The result is a quickly executing ANN, that given a surface topography represented by areal roughness parameters, can predict the contact mechanical response with reasonable accuracy. The most important contact mechanical parameters, that is, the real area of contact, the average interfacial separation, and the contact stiffness can in fact be predicted with high accuracy. As the model is only trained on six different combinations of height probability density and power spectrum functions, one can say that an output should only be trusted if the input surface can be represented with one of these.
Cryo-EM Map–Based Model Validation Using the False Discovery Rate Approach
Authors: Olek Mateusz , Joseph Agnel Praveen
Published: May 2021

Significant technological developments and increasing scientific interest in cryogenic electron microscopy (cryo-EM) has resulted in a rapid increase in the amount of data generated by these experiments and the derived atomic models. Robust measures for the validation of 3D reconstructions and atomic models are essential for appropriate interpretation of the data. The resolution of data and availability of software tools that work across a range of resolutions often limit the quality of derived models. Hence, the final atomic model is often incomplete or contains regions where atomic positions are less reliable or incorrectly built. Extensive manual pruning and local adjustments or rebuilding are usually required to address these issues. The presented research introduces a software tool for the validation of the backbone trace of atomic models built in the cryo-EM density maps. In this study, we use the false discovery rate analysis, which can be used to segregate molecular signals from the background. Each atomic position in the model can be associated with an FDR backbone validation score, which can be used to identify potential mistraced residues. We demonstrate that the proposed validation score is complementary to existing validation metrics and is useful especially in cases where the model is built in the maps having varying local resolution. We also discuss the application of the score for automated pruning of atomic models built ab-initio during the iterative model building process in Buccaneer. We have implemented this score in the CCP-EM software suite.
Upregulation of lncRNA147410.3 in the Brain of Mice With Chronic Toxoplasma Infection Promoted Microglia Apoptosis by Regulating Hoxb3
Authors: Wang Yongliang , Han Ruxia , Xu Zhejun , Sun Xiahui , Zhou Chunxue , Han Bing , He Shenyi , Cong Hua
Published: May 2021

Toxoplasma gondii is neurotropic and affects the function of nerve cells, while the mechanism is unclear. LncRNAs are abundantly enriched in the brain and participated in the delicate regulation of the central nervous system (CNS) development. However, whether these lncRNAs are involved in the regulation of microglia activation during the process of T. gondii infection is largely unknown. In this study, the upregulation of a novel lncRNA147410.3 (ENSMUST00000147410.3) was identified as a key factor to influence this process. The target gene of lncRNA147410.3 was predicted and identified as Hoxb3. The localization of lncRNA147410.3 in the brain and cells was proved in the nucleus of neuroglia through FISH assay. Furthermore, the function of lncRNA147410.3 on neuronal cell was confirmed that lncRNA147410.3 could affect proliferation, differentiation, and apoptosis of mouse microglia by positively regulating Hoxb3. Thus, our study explored the modulatory action of lncRNA147410.3 in T. gondii infected mouse brain, providing a scientific basis for using lncRNA147410.3 as a therapeutic target to treat neurological disorder induced by T. gondii.
Development of an Aerobic Glycolysis Index for Predicting the Sorafenib Sensitivity and Prognosis of Hepatocellular Carcinoma
Authors: Pan Yu , Hu Geng-yuan , Jiang Shi , Xia Shun-jie , Maher Hendi , Lin Zhong-jie , Mao Qi-jiang , Zhao Jie , Cai Liu-xin , Xu Ying-hua , Xu Jun-jie , Cai Xiu-jun
Published: May 2021

Hepatocellular carcinoma (HCC) is a deadly tumor with high heterogeneity. Aerobic glycolysis is a common indicator of tumor growth and plays a key role in tumorigenesis. Heterogeneity in distinct metabolic pathways can be used to stratify HCC into clinically relevant subgroups, but these have not yet been well-established. In this study, we constructed a model called aerobic glycolysis index (AGI) as a marker of aerobic glycolysis using genomic data of hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) project. Our results showed that this parameter inferred enhanced aerobic glycolysis activity in tumor tissues. Furthermore, high AGI is associated with poor tumor differentiation and advanced stages and could predict poor prognosis including reduced overall survival and disease-free survival. More importantly, the AGI could accurately predict tumor sensitivity to Sorafenib therapy. Therefore, the AGI may be a promising biomarker that can accurately stratify patients and improve their treatment efficacy.
Association Between Diet Quality and Risk of Ovarian and Endometrial Cancers: A Systematic Review of Epidemiological Studies
Authors: Zhang Yu-Hua , Li Zhuo , Tan Ming-Zi
Published: May 2021

Objectives

The relationship between diet quality indices and risk of ovarian and endometrial cancers were unclear. We aimed at conducting a systematic review to evaluate the epidemiological evidence.

Methods

Embase, PubMed, Web of Science and Scopus databases were searched for eligible studies up to December 2020. Epidemiological studies reported the association of the diet quality with risk of ovarian and endometrial cancers were evaluated.

Results

Eleven eligible studies were identified, of which six studies were case-control studies, four were cohort studies, and one was case-cohort study. All studies were considered as high-quality with low risk of bias. Seven studies evaluated the association of diet quality with risk of ovarian cancer. Four studies reported null association for diet quality indices such as Healthy Eating Index (HEI)-2005, HEI-2010, Mediterranean Diet Score (MDS) and Recommended Foods Score (RFS). Two studies reported significantly inverse association for Alternate Healthy Eating Index (AHEI)-2010 and Healthy Diet Score (HDS) indices. One study reported significantly increased risk of ovarian cancer associated with higher level of Dietary Guidelines for Americans Index. Dose-response analysis showed pooled relative risks of 0.98 (95%Cl: 0.95, 1.01) and 0.94 (95%Cl: 0.77, 1.13) for each 10 points increase in the HEI-2005 and AHEI-2010 indices. Seven studies evaluated the association of diet quality with risk of endometrial cancer. Three studies reported significantly inverse association of diet quality as assessed by the MDS and Diet Score Quintiles with risk of endometrial cancer. Four studies reported null association for other diet quality indices including HEI-2005, HEI-2010, RFS and HDS. Dose-response analysis showed a pooled relative risk of 0.87 (95%CI: 0.81, 0.93) for one unit increment of the MDS.

Conclusion

This study suggests little evidence on the association between diet quality and risk of ovarian cancer. Adherence to high quality diet, as assessed by MDS, might be associated with lower the risk of endometrial cancer.
Discovery and Characterization of the Biflavones From Ginkgo biloba as Highly Specific and Potent Inhibitors Against Human Carboxylesterase 2
Authors: Song Yun-Qing , He Rong-Jing , Pu Dan , Guan Xiao-Qing , Shi Jin-Hui , Li Yao-Guang , Hou Jie , Jia Shou-Ning , Qin Wei-Wei , Fang Sheng-Quan , Ge Guang-Bo
Published: May 2021

Human carboxylesterase 2 (CES2), one of the most abundant hydrolases distributed in the small intestine, has been validated as a key therapeutic target to ameliorate the intestinal toxicity caused by irinotecan. This study aims to discover efficacious CES2 inhibitors from natural products and to characterize the inhibition potentials and inhibitory mechanisms of the newly identified CES2 inhibitors. Following high-throughput screening and evaluation of the inhibition potency of more than 100 natural products against CES2, it was found that the biflavones isolated from Ginkgo biloba displayed extremely potent CES2 inhibition activities and high specificity over CES1 (>1000-fold). Further investigation showed that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed hydrolysis of various substrates, including the CES2 substrate-drug irinotecan. Notably, the inhibition potentials of four biflavones against CES2 were more potent than that of loperamide, a marketed anti-diarrhea agent used for alleviating irinotecan-induced intestinal toxicity. Inhibition kinetic analyses demonstrated that ginkgetin, bilobetin, sciadopitysin and isoginkgetin potently inhibited CES2-catalyzed fluorescein diacetate hydrolysis via a reversible and mixed inhibition manner, with Ki values of less than 100 nM. Ensemble docking and molecular dynamics revealed that these biflavones could tightly and stably bind on the catalytic cavity of CES2 via hydrogen bonding and π-π stacking interactions, while the interactions with CES1 were awfully poor. Collectively, this study reports that the biflavones isolated from Ginkgo biloba are potent and highly specific CES2 inhibitors, which offers several promising lead compounds for developing novel anti-diarrhea agent to alleviate irinotecan-induced diarrhea.
The Heterogenous Effect of COVID-19 on Liver Transplantation Activity and Waitlist Mortality in the United States
Authors: Yuan Qing , Haque Omar , Coe Taylor M. , Markmann James F.
Published: May 2021

Background: The COVID-19 pandemic curtailed the practice of liver transplantation (LT), which lacks a temporizing life-saving measure for candidates on the waitlist.

Aims/Objectives: The objective of this research was to (1) determine the effect of decreased LT activity on waitlist mortality in the United States and (2) assess if this effect was homogenous across the country.

Methods: We conducted a retrospective, cross-sectional analysis utilizing United Network for Organ Sharing (UNOS) data assessing 3,600 liver transplants from January 1, 2020 to June 2, 2020. COVID-19 incidence data was taken directly from the New York Times case count.

Results: During weeks 10 to 15 of 2020, there was a 38% reduction in the number of LTs performed nationally, which was temporally associated with a transient 97% increase in waitlist mortality. When stratified by UNOS region, waitlist mortality was inversely correlated with the number of LTs performed in all 11 regions. However, the range of the association strength (r) was large (Pearson correlation coefficient range: −0.73 to −0.01).

Conclusion: Interruptions in LT activity due to COVID-19 were associated with rapid increases in waitlist mortality, and these effects were unevenly distributed among candidates across the United States. The transplant community can utilize these results to mitigate inequalities in transplant allocation between UNOS regions and advocate for the uninterrupted practice of LT should another pandemic surge or COVID-19 variant arise.
The Semiclassical Limit of the Gailitis Formula Applied to Electron Impact Broadening of Spectral Lines of Ionized Atoms
Authors: Sahal-Bréchot Sylvie
Published: May 2021

The present paper revisits the determination of the semi-classical limit of the Feshbach resonances which play a role in electron impact broadening (the so-called “Stark“ broadening) of isolated spectral lines of ionized atoms. The Gailitis approximation will be used. A few examples of results will be provided, showing the importance of the role of the Feshbach resonances.
Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents
Authors: Zhou Dong , Chen Huaping , Mpoy Cedric , Afrin Sadia , Rogers Buck E. , Garbow Joel R. , Katzenellenbogen John A. , Xu Jinbin
Published: May 2021

Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [18F]talazoparib and its in vitro and in vivo evaluation. Talazoparib (3a″) and its bromo- or iodo-derivatives were synthesized as racemic mixtures (3a, 3b and 3c), and these compounds exhibit high affinity to PARP-1 (Ki for talazoparib (3a″): 0.65 ± 0.07 nM; 3a: 2.37 ± 0.56 nM; 3b: 1.92 ± 0.41 nM; 3c: 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [3H]WC-DZ for screening. [18F]Talazoparib (3a″) was radiosynthesized via a multiple-step procedure with good radiochemical and chiral purities (98%) and high molar activity (28 GBq/μmol). The preliminary biodistribution studies in the murine PC-3 tumor model showed that [18F]talazoparib had a good level of tumor uptake that persisted for over 8 h (3.78 ± 0.55 %ID/gram at 4 h and 4.52 ± 0.32 %ID/gram at 8 h). These studies show the potential for the bromo- and iodo- derivatives for PARP-1 targeted radiotherapy studies using therapeutic radionuclides.
Predict Score: A New Biological and Clinical Tool to Help Predict Risk of Intensive Care Transfer for COVID-19 Patients
Authors: Gette Mickael , Fernandes Sara , Marlinge Marion , Duranjou Marine , Adi Wijayanto , Dambo Maelle , Simeone Pierre , Michelet Pierre , Bruder Nicolas , Guieu Regis , Fromonot Julien
Published: May 2021

Background: The COVID-19 crisis has strained world health care systems. This study aimed to develop an innovative prediction score using clinical and biological parameters (PREDICT score) to anticipate the need of intensive care of COVID-19 patients already hospitalized in standard medical units. Methods: PREDICT score was based on a training cohort and a validation cohort retrospectively recruited in 2020 in the Marseille University Hospital. Multivariate analyses were performed, including clinical, and biological parameters, comparing a baseline group composed of COVID-19 patients exclusively treated in standard medical units to COVID-19 patients that needed intensive care during their hospitalization. Results: Independent variables included in the PREDICT score were: age, Body Mass Index, Respiratory Rate, oxygen saturation, C-reactive protein, neutrophil–lymphocyte ratio and lactate dehydrogenase. The PREDICT score was able to correctly identify more than 83% of patients that needed intensive care after at least 1 day of standard medical hospitalization. Conclusions: The PREDICT score is a powerful tool for anticipating the intensive care need for COVID-19 patients already hospitalized in a standard medical unit. It shows limitations for patients who immediately need intensive care, but it draws attention to patients who have an important risk of needing intensive care after at least one day of hospitalization.
Cellular Senescence in Human Aldosterone-Producing Adrenocortical Cells and Related Disorders
Authors: Pieroni Jacopo , Yamazaki Yuto , Gao Xin , Tezuka Yuta , Ogata Hiroko , Omata Kei , Ono Yoshikiyo , Morimoto Ryo , Nakamura Yasuhiro , Satoh Fumitoshi , Sasano Hironobu
Published: May 2021

In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in KCNJ5-mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex.
Imaging of Functional Brain Circuits during Acquisition and Memory Retrieval in an Aversive Feedback Learning Task: Single Photon Emission Computed Tomography of Regional Cerebral Blood Flow in Freely Behaving Rats
Authors: Braun Katharina , Mannewitz Anja , Bock Joerg , Kreitz Silke , Hess Andreas , Scheich Henning , Goldschmidt Jürgen
Published: May 2021

Active avoidance learning is a complex form of aversive feedback learning that in humans and other animals is essential for actively coping with unpleasant, aversive, or dangerous situations. Since the functional circuits involved in two-way avoidance (TWA) learning have not yet been entirely identified, the aim of this study was to obtain an overall picture of the brain circuits that are involved in active avoidance learning. In order to obtain a longitudinal assessment of activation patterns in the brain of freely behaving rats during different stages of learning, we applied single-photon emission computed tomography (SPECT). We were able to identify distinct prefrontal cortical, sensory, and limbic circuits that were specifically recruited during the acquisition and retrieval phases of the two-way avoidance learning task.
Familial Occurrence of Adult Granulosa Cell Tumors: Analysis of Whole-Genome Germline Variants
Authors: Roze Joline F. , Kutzera Joachim , Koole Wouter , Ausems Margreet G. E. M. , Engelstad Kristi , Piek Jurgen M. J. , de Kroon Cor D. , Verheijen René H. M. , van Haaften Gijs , Zweemer Ronald P. , Monroe Glen R.
Published: May 2021

Adult granulosa cell tumor (AGCT) is a rare ovarian cancer subtype, with a peak incidence around 50–55 years. Although AGCT can occur in specific syndromes, a genetic predisposition for AGCT has not been identified. The aim of this study is to identify a genetic variant in families with AGCT patients, potentially contributing to tumor evolution. We identified four families, each including two women diagnosed with AGCT. Whole-genome sequencing was performed to identify overlapping germline variants or affected genes. Familial relationship was evaluated using genealogy and genomic analyses. Patient characteristics, medical (family) history, and pedigrees were collected. Findings were compared to a reference group of 33 unrelated AGCT patients. Mean age at diagnosis was 38 years (range from 17 to 60) versus 51 years in the reference group, and seven of eight patients were premenopausal. In two families, three first degree relatives were diagnosed with breast cancer. Furthermore, polycystic ovary syndrome (PCOS) and subfertility was reported in three families. Predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were identified. In conclusion, AGCTs occur in families and could potentially be hereditary. In these families, the age of AGCT diagnosis is lower and cases of breast cancer, PCOS, and subfertility are present. We could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for AGCT.
Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups
Authors: Mueller-Schoell Anna , Michelet Robin , Klopp-Schulze Lena , van Dyk Madelé , Mürdter Thomas E. , Schwab Matthias , Joerger Markus , Huisinga Wilhelm , Mikus Gerd , Kloft Charlotte
Published: May 2021

Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (CSS,min ENDX) >5.97 ng/mL have been associated with favorable outcome. Endoxifen formation is mediated by the enzyme CYP2D6, and impaired CYP2D6 function has been associated with lower CSS,min ENDX. In the Women’s Healthy Eating and Living (WHEL) study proposing the target concentration, 20% of patients showed subtarget CSS,min ENDX at tamoxifen standard dosing. CYP2D6 allele frequencies vary largely between populations, and as 87% of the patients in the WHEL study were White, little is known about the risk for subtarget CSS,min ENDX in other populations. Applying pharmacokinetic simulations, this study investigated the risk for subtarget CSS,min ENDX at tamoxifen standard dosing and the need for dose individualization in nine different biogeographical groups with distinct CYP2D6 allele frequencies. The high variability in CYP2D6 allele frequencies amongst the biogeographical groups resulted in an up to three-fold difference in the percentages of patients with subtarget CSS,min ENDX. Based on their CYP2D6 allele frequencies, East Asian breast cancer patients were identified as the population for which personalized, model-informed precision dosing would be most beneficial (28% of patients with subtarget CSS,min ENDX).
Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors
Authors: Caliò Anna , Brunelli Matteo , Gobbo Stefano , Argani Pedram , Munari Enrico , Netto George , Martignoni Guido
Published: May 2021

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.
Identification of Lifestyle Behaviors Associated with Recurrence and Survival in Colorectal Cancer Patients Using Random Survival Forests
Authors: van Zutphen Moniek , van Duijnhoven Fränzel J. B. , Wesselink Evertine , Schrauwen Ruud W. M. , Kouwenhoven Ewout A. , van Halteren Henk K. , de Wilt Johannes H. W. , Winkels Renate M. , Kok Dieuwertje E. , Boshuizen Hendriek C.
Published: May 2021

Current lifestyle recommendations for cancer survivors are the same as those for the general public to decrease their risk of cancer. However, it is unclear which lifestyle behaviors are most important for prognosis. We aimed to identify which lifestyle behaviors were most important regarding colorectal cancer (CRC) recurrence and all-cause mortality with a data-driven method. The study consisted of 1180 newly diagnosed stage I–III CRC patients from a prospective cohort study. Lifestyle behaviors included in the current recommendations, as well as additional lifestyle behaviors related to diet, physical activity, adiposity, alcohol use, and smoking were assessed six months after diagnosis. These behaviors were simultaneously analyzed as potential predictors of recurrence or all-cause mortality with Random Survival Forests (RSFs). We observed 148 recurrences during 2.6-year median follow-up and 152 deaths during 4.8-year median follow-up. Higher intakes of sugary drinks were associated with increased recurrence risk. For all-cause mortality, fruit and vegetable, liquid fat and oil, and animal protein intake were identified as the most important lifestyle behaviors. These behaviors showed non-linear associations with all-cause mortality. Our exploratory RSF findings give new ideas on potential associations between certain lifestyle behaviors and CRC prognosis that still need to be confirmed in other cohorts of CRC survivors.
Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity
Authors: Kanaki Zoi , Voutsina Alexandra , Markou Athina , Pateras Ioannis S. , Potaris Konstantinos , Avgeris Margaritis , Makrythanasis Periklis , Athanasiadis Emmanouil I. , Vamvakaris Ioannis , Patsea Eleni , Vachlas Konstantinos , Lianidou Evi , Georgoulias Vassilis , Kotsakis Athanasios , Klinakis Apostolos
Published: May 2021

Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients’ peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice.
MRI-Based Radiomics Analysis for the Pretreatment Prediction of Pathologic Complete Tumor Response to Neoadjuvant Systemic Therapy in Breast Cancer Patients: A Multicenter Study
Authors: Granzier Renée W. Y. , Ibrahim Abdalla , Primakov Sergey P. , Samiei Sanaz , van Nijnatten Thiemo J. A. , de Boer Maaike , Heuts Esther M. , Hulsmans Frans-Jan , Chatterjee Avishek , Lambin Philippe , Lobbes Marc B. I. , Woodruff Henry C. , Smidt Marjolein L.
Published: May 2021

This retrospective study investigated the value of pretreatment contrast-enhanced Magnetic Resonance Imaging (MRI)-based radiomics for the prediction of pathologic complete tumor response to neoadjuvant systemic therapy in breast cancer patients. A total of 292 breast cancer patients, with 320 tumors, who were treated with neo-adjuvant systemic therapy and underwent a pretreatment MRI exam were enrolled. As the data were collected in two different hospitals with five different MRI scanners and varying acquisition protocols, three different strategies to split training and validation datasets were used. Radiomics, clinical, and combined models were developed using random forest classifiers in each strategy. The analysis of radiomics features had no added value in predicting pathologic complete tumor response to neoadjuvant systemic therapy in breast cancer patients compared with the clinical models, nor did the combined models perform significantly better than the clinical models. Further, the radiomics features selected for the models and their performance differed with and within the different strategies. Due to previous and current work, we tentatively attribute the lack of improvement in clinical models following the addition of radiomics to the effects of variations in acquisition and reconstruction parameters. The lack of reproducibility data (i.e., test-retest or similar) meant that this effect could not be analyzed. These results indicate the need for reproducibility studies to preselect reproducible features in order to properly assess the potential of radiomics.
In Vitro Glioblastoma Models: A Journey into the Third Dimension
Authors: Paolillo Mayra , Comincini Sergio , Schinelli Sergio
Published: May 2021

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.
Oxidative Stress-Dependent Synergistic Antiproliferation, Apoptosis, and DNA Damage of Ultraviolet-C and Coral-Derived Sinularin Combined Treatment for Oral Cancer Cells
Authors: Peng Sheng-Yao , Tang Jen-Yang , Li Ruei-Nian , Huang Hurng-Wern , Wu Chang-Yi , Chiu Chien-Chih , Chang Fang-Rong , Zhang Hong-Wei , Lee Yun-Jou , Sheu Jyh-Horng , Chang Hsueh-Wei
Published: May 2021

Combined treatment is increasingly used to improve cancer therapy. Non-ionizing radiation ultraviolet-C (UVC) and sinularin, a coral Sinularia flexibilis-derived cembranolide, were separately reported to provide an antiproliferation function to some kinds of cancer cells. However, an antiproliferation function using the combined treatment of UVC/sinularin has not been investigated as yet. This study aimed to examine the combined antiproliferation function and explore the combination of UVC/sinularin in oral cancer cells compared to normal oral cells. Regarding cell viability, UVC/sinularin displays the synergistic and selective killing of two oral cancer cell lines, but remains non-effective for normal oral cell lines compared to treatments in terms of MTS and ATP assays. In tests using the flow cytometry, luminescence, and Western blotting methods, UVC/sinularin-treated oral cancer cells exhibited higher reactive oxygen species production, mitochondrial superoxide generation, mitochondrial membrane potential destruction, annexin V, pan-caspase, caspase 3/7, and cleaved-poly (ADP-ribose) polymerase expressions than that in normal oral cells. Accordingly, oxidative stress and apoptosis are highly induced in a combined UVC/sinularin treatment. Moreover, UVC/sinularin treatment provides higher G2/M arrest and γH2AX/8-hydroxyl-2′deoxyguanosine-detected DNA damages in oral cancer cells than in the separate treatments. A pretreatment can revert all of these changes of UVC/sinularin treatment with the antioxidant N-acetylcysteine. Taken together, UVC/sinularin acting upon oral cancer cells exhibits a synergistic and selective antiproliferation ability involving oxidative stress-dependent apoptosis and cellular DNA damage with low toxic side effects on normal oral cells.
Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response
Authors: Liu Chun-Shan , Toth Reka , Bakr Ali , Goyal Ashish , Islam Md Saiful , Breuer Kersten , Mayakonda Anand , Lin Yu-Yu , Stepper Peter , Jurkowski Tomasz P. , Veldwijk Marlon R. , Sperk Elena , Herskind Carsten , Lutsik Pavlo , Weichenhan Dieter , Plass Christoph , Schmezer Peter , Popanda Odilia
Published: May 2021

Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis.
The Proportion Cured of Patients with Resected Stage II–III Cutaneous Melanoma in Sweden
Authors: Eriksson Hanna , Utjés Deborah , Olofsson Bagge Roger , Gillgren Peter , Isaksson Karolin , Lapins Jan , Schultz Inkeri Leonardsson , Lyth Johan , Andersson Therese M.-L.
Published: May 2021

Background: Cure proportion represents the proportion of patients who experience the same mortality rate as the general population and can be estimated together with the survival of the proportion experiencing excess mortality (the uncured). The aim was to estimate the cure proportions and survival among uncured stage II–III cutaneous melanoma (CM) patients. Methods: 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II–III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005–2013 with a follow-up through 2018. Results: Stages IIB and IIC showed significant differences in standardized cure proportions vs. stage IIA CM (0.80 (95% CI 0.77–0.83) stage IIA; 0.62 (95% CI 0.59–0.66) stage IIB; 0.42 (95% CI 0.37–0.46) for stage IIC). Significant differences in standardized cure proportions were found for stages IIIB and IIIC-D CM vs. stage IIIA (0.76 (95% CI 0.68–0.84) stage IIIA; 0.52 (95% CI 0.45–0.59) stage IIIB; 0.35 (95% CI 0.30–0.39) for stage IIIC–D). Conclusions: The results are emphasizing the poor prognosis with low proportions cured by surgery only for sub-groups of stage II–III CM, specifically within stages IIB–C CM.