bluuebunny/crossref_metadata_2025 huggingface dataset:
BIM Approach to Modeling a Sports Pavilion for University Use
Authors: Nuñez Muñoz Juan , Villena Manzanares Francisco , Marçal Gonçalves Marta
Published: December 2020

New developments in software projects for the construction sector are a technological revolution and provide new methods of infrastructure design and modeling, highlighting the Building Information Modeling (BIM). BIM is a technology and methodology used in the most developed countries and little by little this technology is being implemented in other countries where its use is increasing. This new work methodology makes it easier to manage and plan new projects, saving time and minimizing costs. The advantages of using BIM stand out in large projects thanks to the better handling of large volumes of information. This article will address, with the example of using BIM technology, the design project of a fictitious university sports pavilion located in Seville (Spain). Using the BIM Edificius® software, the 3D modeling of this building will be carried out in order to calculate and design the building’s facilities with CYPECAD MEP® software, making use of the IFC (Industry Foundation Classes) format to exchange the building design between both programs.
Geoengineering: Impact of Marine Cloud Brightening Control on the Extreme Temperature Change over East Asia
Authors: Kim Do-Hyun , Shin Ho-Jeong , Chung Il-Ung
Published: December 2020

We investigated the effect of artificial marine cloud brightening on extreme temperatures over East Asia. We used simulation data from five global climate models which have conducted the GeoMIP G4cdnc experiment. G4cdnc was designed to simulate an increase in the cloud droplet number concentration of the global marine lower clouds by 50% under the greenhouse gas forcing of the RCP4.5 scenario. G4cdnc decreased the net radiative forcing in the top of the atmosphere more over the ocean, alleviating the rise in mean temperature under RCP4.5 forcing. For extreme temperatures, G4cdnc reduced both the monthly minimum of daily minimum temperature (TNn) and monthly maximum of daily maximum temperature (TXx). The response of TNn was higher than that of TXx, especially in the winter, over the Sea of Okhotsk and the interior of the continent. This spatial heterogeneity and seasonality of the response were associated with sea ice–albedo and snow–albedo feedbacks. We also calculated the efficacy of warming mitigation as a measure of the relative effect of geoengineering. The efficacy for TXx was higher than that for TNn, opposite to the absolute effect. After the termination of geoengineering, both TNn and TXx tended to rapidly revert to their trend under the RCP4.5 forcing.
Study on Riparian Shading Envelope for Wetlands to Create Desirable Urban Bioclimates
Authors: Shahjahan Abu Taib Mohammed , Ahmed Khandaker Shabbir , Said Ismail Bin
Published: December 2020

Climate change and rapid urbanization are adversely affecting the urban environment by exacerbating the widely reported urban heat island effect in Dhaka, Bangladesh. Two wetland areas with variable riparian shadings in the warm-humid conditions of urban Dhaka were investigated through field campaigns on microclimatic parameters for their cooling potential on the surrounding urban fabric. It was observed that an inversion layer of fully saturated air develops over the water surface of wetland, suppressing evaporation from the wetland water surface layer, which was effectively reducing the heat exchange between the water surface and the air layer above it through its action as an insulating vapor blanket. Due to this effect, the wetland was unable to render as a source of coolth for the surrounding overheated urban area. This effect of the inversion layer was more pronounced in the urban wetland without riparian shading either by the urban form or tree canopy. A multiphysics simulation study conducted on the selected urban wetlands indicates the effect of differential shading pattern on the relation between fetch and inversion layer thickness. This research hypothesizes that the wetland can act as an urban adaption measure against the urban heat island effect by potentially transforming them into an urban cooling island (UCI) towards a favorable urban bioclimate.
Role of BamHI-A Rightward Frame 1 in Epstein–Barr Virus-Associated Epithelial Malignancies
Authors: Blanco Rancés , Aguayo Francisco
Published: December 2020

Epstein–Barr virus (EBV) infection is associated with a subset of both lymphoid and epithelial malignancies. During the EBV latency program, some viral products involved in the malignant transformation of infected cells are expressed. Among them, the BamHI-A rightward frame 1 (BARF1) is consistently detected in nasopharyngeal carcinomas (NPC) and EBV-associated gastric carcinomas (EBVaGCs) but is practically undetectable in B-cells and lymphomas. Although BARF1 is an early lytic gene, it is expressed during epithelial EBV latency, mainly as a secreted protein (sBARF1). The capacity of sBARF1 to disrupt both innate and adaptive host antiviral immune responses contributes to the immune escape of infected cells. Additionally, BARF1 increases cell proliferation, shows anti-apoptotic effects, and promotes an increased hTERT activity and tumor formation in nude mice cooperating with other host proteins such as c-Myc and H-ras. These facts allow for the consideration of BARF1 as a key protein for promoting EBV-associated epithelial tumors. In this review, we focus on structural and functional aspects of BARF1, such as mechanisms involved in epithelial carcinogenesis and its capacity to modulate the host immune response.
The Influence of Physical Activity on the Bioactive Lipids Metabolism in Obesity-Induced Muscle Insulin Resistance
Authors: Imierska Monika , Kurianiuk Adam , Błachnio-Zabielska Agnieszka
Published: December 2020

High-fat diet consumption and lack of physical activity are important risk factors for metabolic disorders such as insulin resistance and cardiovascular diseases. Insulin resistance is a state of a weakened response of tissues such as skeletal muscle, adipose tissue, and liver to insulin, which causes an increase in blood glucose levels. This condition is the result of inhibition of the intracellular insulin signaling pathway. Skeletal muscle is an important insulin-sensitive tissue that accounts for about 80% of insulin-dependent glucose uptake. Although the exact mechanism by which insulin resistance is induced has not been thoroughly understood, it is known that insulin resistance is most commonly associated with obesity. Therefore, it is believed that lipids may play an important role in inducing insulin resistance. Among lipids, researchers’ attention is mainly focused on biologically active lipids: diacylglycerols (DAG) and ceramides. These lipids are able to regulate the activity of intracellular enzymes, including those involved in insulin signaling. Available data indicate that physical activity affects lipid metabolism and has a positive effect on insulin sensitivity in skeletal muscles. In this review, we have presented the current state of knowledge about the impact of physical activity on insulin resistance and metabolism of biologically active lipids.
Misincorporation of Galactose by Chondroitin Synthase of Escherichia coli K4: From Traces to Synthesis of Chondbiuronan, a Novel Chondroitin-Like Polysaccharide
Authors: Leroux Mélanie , Michaud Julie , Bayma Eric , Armand Sylvie , Drouillard Sophie , Priem Bernard
Published: December 2020

Chondroitin synthase KfoC is a bifunctional enzyme which polymerizes the capsular chondroitin backbone of Escherichia coli K4, composed of repeated β3N-acetylgalactosamine (GalNAc)-β4-glucuronic acid (GlcA) units. Sugar donors UDP-GalNAc and UDP-GlcA are the natural precursors of bacterial chondroitin synthesis. We have expressed KfoC in a recombinant strain of Escherichia coli deprived of 4-epimerase activity, thus incapable of supplying UDP-GalNAc in the bacterial cytoplasm. The strain was also co-expressing mammal galactose β-glucuronyltransferase, providing glucuronyl-lactose from exogenously added lactose, serving as a primer of polymerization. We show by the mean of NMR analyses that in those conditions, KfoC incorporates galactose, forming a chondroitin-like polymer composed of the repeated β3-galactose (Gal)-β4-glucuronic acid units. We also show that when UDP-GlcNAc 4-epimerase KfoA, encoded by the K4-operon, was co-expressed and produced UDP-GalNAc, a small proportion of galactose was still incorporated into the growing chain of chondroitin.
Development of Biomimetic Alginate/Gelatin/Elastin Sponges with Recognition Properties toward Bioactive Peptides for Cardiac Tissue Engineering
Authors: Rosellini Elisabetta , Madeddu Denise , Barbani Niccoletta , Frati Caterina , Graiani Gallia , Falco Angela , Lagrasta Costanza , Quaini Federico , Cascone Maria Grazia
Published: December 2020

In recent years, there has been an increasing interest toward the covalent binding of bioactive peptides from extracellular matrix proteins on scaffolds as a promising functionalization strategy in the development of biomimetic matrices for tissue engineering. A totally new approach for scaffold functionalization with peptides is based on Molecular Imprinting technology. In this work, imprinted particles with recognition properties toward laminin and fibronectin bioactive moieties were synthetized and used for the functionalization of biomimetic sponges, which were based on a blend of alginate, gelatin, and elastin. Functionalized sponges underwent a complete morphological, physicochemical, mechanical, functional, and biological characterization. Micrographs of functionalized sponges showed a highly porous structure and a quite homogeneous distribution of imprinted particles on their surface. Infrared and thermal analyses pointed out the presence of interactions between blend components. Biodegradation and mechanical properties appeared adequate for the aimed application. The results of recognition tests showed that the deposition on sponges did not alter the specific recognition and binding behavior of imprinted particles. In vitro biological characterization with cardiac progenitor cells showed that early cell adherence was promoted. In vivo analysis showed that developed scaffolds improved cardiac progenitor cell adhesion and differentiation toward myocardial phenotypes.
Repeat Sequence Mapping Shows Different W Chromosome Evolutionary Pathways in Two Caprimulgiformes Families
Authors: de Souza Marcelo Santos , Kretschmer Rafael , Barcellos Suziane Alves , Costa Alice Lemos , Cioffi Marcelo de Bello , de Oliveira Edivaldo Herculano Corrêa , Garnero Analía Del Valle , Gunski Ricardo José
Published: December 2020

Although birds belonging to order Caprimulgiformes show extensive karyotype variation, data concerning their genomic organization is still scarce, as most studies have presented only results obtained from conventional staining analyses. Nevertheless, some interesting findings have been observed, such as the W chromosome of the Common Potoo, Nyctibius griseus (2n = 86), which has the same morphology and size of the Z chromosome, a rare feature in Neognathae birds. Hence, we aimed to investigate the process by which the W chromosome of this species was enlarged. For that, we analyzed comparatively the chromosome organization of the Common Potoo and the Scissor-tailed Nightjar, Hydropsalis torquata (2n = 74), which presents the regular differentiated sex chromosomes, by applying C-banding, G-banding and mapping of repetitive DNAs (microsatellite repeats and 18S rDNA). Our results showed an accumulation of constitutive heterochromatin in the W chromosome of both species. However, 9 out of 11 microsatellite sequences hybridized in the large W chromosome in the Common Potoo, while none of them hybridized in the W chromosome of the Scissor-tailed Nightjar. Therefore, we can conclude that the accumulation of microsatellite sequences, and consequent increase in constitutive heterochromatin, was responsible for the enlargement of the W chromosome in the Common Potoo. Based on these results, we conclude that even though these two species belong to the same order, their W chromosomes have gone through different evolutionary histories, with an extra step of accumulation of repetitive sequences in the Common Potoo.
Thalamic Deep Brain Stimulation in Essential Tremor Plus Is as Effective as in Essential Tremor
Authors: Steffen Julia K. , Jergas Hannah , Petry-Schmelzer Jan N. , Dembek Till A. , Thies Tabea , Jost Stefanie T. , Dafsari Haidar S. , Kessler Josef , Wirths Jochen , Fink Gereon R. , Visser-Vandewalle Veerle , Barbe Michael T.
Published: December 2020

The new essential tremor (ET) classification defined ET-plus (ET-p) as an ET subgroup with additional neurological signs besides action tremor. While deep brain stimulation (DBS) is effective in ET, there are no studies specifically addressing DBS effects in ET-p. 44 patients with medication-refractory ET and thalamic/subthalamic DBS implanted at our center were postoperatively classified into ET and ET-p according to preoperative documentation. Tremor suppression with DBS (stimulation ON vs. preoperative baseline and vs. stimulation OFF), measured via the Fahn–Tolosa–Marin tremor rating scale (TRS), stimulation parameters, and the location of active contacts were compared between patients classified as ET and ET-p. TRS scores at baseline were higher in ET-p. ET-p patients showed comparable tremor reduction as patients with ET, albeit higher stimulation parameters were needed in ET-p. Active electrode contacts were located more dorsally in ET-p of uncertain reason. Our data show that DBS is similarly effective in ET-p compared to ET. TRS scores were higher in ET-p preoperatively, and higher stimulation parameters were needed for tremor reduction compared to ET. The latter may be related to a more dorsal location of active electrode contacts in the ET-p group of this cohort. Prospective studies are warranted to investigate DBS in ET-p further.
Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression
Authors: Słupski Jakub , Cubała Wiesław Jerzy , Górska Natalia , Słupska Anita , Gałuszko-Węgielnik Maria
Published: December 2020

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery–Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.
Trigeminocardiac Reflex Induced by Maxillary Nerve Stimulation during Sphenopalatine Ganglion Implantation: A Case Series
Authors: Hammad Yousef , Mootz Allison , Klein Kevin , Zuniga John R.
Published: December 2020

Background: The trigeminocardiac reflex (TCR) is a brainstem reflex following stimulation of the trigeminal nerve, resulting in bradycardia, asystole and hypotension. It has been described in maxillofacial and craniofacial surgeries. This case series highlights TCR events occurring during sphenopalatine ganglion (SPJ) neurostimulator implantation as part of the Pathway CH-2 clinical trial “Sphenopalatine ganglion Stimulation for Treatment of Chronic Cluster Headache”. Methods: This is a case series discussing sphenopalatine ganglion neurostimulator implantation in the pterygopalatine fossa as treatment for intractable cluster headaches. Eight cases are discussed with three demonstrating TCR events. All cases received remifentanil and desflurane for anesthetic maintenance. Results: Each patient with a TCR event experienced severe bradycardia. In two cases, TCR resolved with removal of the introducer, while the third case’s TCR event resolved with both anticholinergic treatment and surgical stimulation cessation. Conclusion: Each TCR event occurred before stimulation of the fixed introducer device, suggesting the cause for the TCR events was mechanical in origin. Due to heightened concern for further TCR events, all subsequent cases had pre-anesthesia external pacing pads placed. Resolution can occur with cessation of surgical manipulation and/or anticholinergic treatment. Management of TCR events requires communication between surgical teams and anesthesia providers, especially during sphenopalatine ganglion implantation when maxillary nerve stimulation is possible.
Split-Attention U-Net: A Fully Convolutional Network for Robust Multi-Label Segmentation from Brain MRI
Authors: Lee Minho , Kim JeeYoung , EY Kim Regina , Kim Hyun Gi , Oh Se Won , Lee Min Kyoung , Wang Sheng-Min , Kim Nak-Young , Kang Dong Woo , Rieu ZunHyan , Yong Jung Hyun , Kim Donghyeon , Lim Hyun Kook
Published: December 2020

Multi-label brain segmentation from brain magnetic resonance imaging (MRI) provides valuable structural information for most neurological analyses. Due to the complexity of the brain segmentation algorithm, it could delay the delivery of neuroimaging findings. Therefore, we introduce Split-Attention U-Net (SAU-Net), a convolutional neural network with skip pathways and a split-attention module that segments brain MRI scans. The proposed architecture employs split-attention blocks, skip pathways with pyramid levels, and evolving normalization layers. For efficient training, we performed pre-training and fine-tuning with the original and manually modified FreeSurfer labels, respectively. This learning strategy enables involvement of heterogeneous neuroimaging data in the training without the need for many manual annotations. Using nine evaluation datasets, we demonstrated that SAU-Net achieved better segmentation accuracy with better reliability that surpasses those of state-of-the-art methods. We believe that SAU-Net has excellent potential due to its robustness to neuroanatomical variability that would enable almost instantaneous access to accurate neuroimaging biomarkers and its swift processing runtime compared to other methods investigated.
Effects of a Person Centered Dementia Training Program in Greek Hospital Staff—Implementation and Evaluation
Authors: Gkioka Mara , Teichmann Birgit , Moraitou Despina , Papagiannopoulos Sotirios , Tsolaki Magda
Published: December 2020

People with Dementia (PwD) are frequently admitted in general hospitals. However, health care professionals have lack of dementia knowledge, negative attitudes toward dementia, and lack of confidence in caring those patients. The aim of this study is to develop, implement and evaluate a dementia staff training program in Greek general hospitals. It was a repeated-measures research design. Fourteen (14) two-day workshops were conducted, consisting of six targeted and interactive modules. Staff members (N = 242) attended the program and were assessed according to (1) individual performance: questionnaires about attitudes towards dementia, confidence in care, knowledge about dementia and anxiety before, immediately after the training and three months later, (2) an overall training evaluation immediately after the training and (3) an evaluation of training implementation three months later. Positive attitudes towards dementia, improvement of confidence in care and decrease of feeling of anxiety as a trait, were sustained over time. Knowledge about dementia also increased after the training and sustained, with, however, a slight decrease over time. A well applied training program seems to provide the basis of a better care in PwD during hospitalization. However, changes in the organizational level and a transformation of care culture are necessary for training sustainability over time.
Maternal Depression Affects Infants’ Lexical Processing Abilities in the Second Year of Life
Authors: Brookman Ruth , Kalashnikova Marina , Conti Janet , Xu Rattanasone Nan , Grant Kerry-Ann , Demuth Katherine , Burnham Denis
Published: December 2020

Maternal depression and anxiety have been proposed to increase the risk of adverse outcomes of language development in the early years of life. This study investigated the effects of maternal depression and anxiety on language development using two approaches: (i) a categorical approach that compared lexical abilities in two groups of children, a risk group (mothers with clinical-level symptomatology) and a control non-risk group, and (ii) a continuous approach that assessed the relation between individual mothers’ clinical and subclinical symptomatology and their infants’ lexical abilities. Infants’ lexical abilities were assessed at 18 months of age using an objective lexical processing measure and a parental report of expressive vocabulary. Infants in the risk group exhibited lower lexical processing abilities compared to controls, and maternal depression scores were negatively correlated to infants’ lexical processing and vocabulary measures. Furthermore, maternal depression (not anxiety) explained the variance in infants’ individual lexical processing performance above the variance explained by their individual expressive vocabulary size. These results suggest that significant differences are emerging in 18-month-old infants’ lexical processing abilities, and this appears to be related, in part, to their mothers’ depression and anxiety symptomatology during the postnatal period.
Double-Blinded Randomized Pilot Clinical Trial Comparing Cognitive Side Effects of Standard Ultra-Brief Right Unilateral ECT to 0.5 A Low Amplitude Seizure Therapy (LAP-ST)
Authors: Youssef Nagy A. , McCall William V. , Ravilla Dheeraj , McCloud Laryssa , Rosenquist Peter B.
Published: December 2020

Background: Concerns over cognitive side effects (CSE) of electroconvulsive therapy (ECT) still limit its broader usage for treatment-resistant depression (TRD). The objectives of this study were to (1) examine the CSE of Low Amplitude Seizure Therapy (LAP-ST) at 0.5 A compared to Ultra-brief Right Unilateral (UB-RUL) ECT using Time to Reorientation (TRO) as the main acute primary outcome, and (2) to compare effects on depressive symptoms between the two treatment groups. Methods: Participants were referred for ECT, consented for the study, and were randomized to a course of LAP-ST or standard UB-RUL ECT. TRO and depression were measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: Eleven patients consented. Of these, eight with a current major depressive episode (MDE) of unipolar or bipolar disorders were randomized. TRO was faster for the LAP-ST (mean = 6.8 min; SE = 4.9) than standard RUL ECT (mean = 15.5 min; SE = 6.5). Depression improved similarly in the two arms of the study from baseline (MADRS: LAP-ST = 41.0; SE = 2.0, RUL = 39.0; SE = 3.8) to endpoint (MADRS score: LAP-ST = 8.0; SE7.2, RUL = 9.5; SE = 3.8). Conclusions: This pilot, randomized and blinded clinical trial, suggests that the LAP-ST (at 0.5 A) has faster reorientation and possibly lower CSE compared to standard RUL-UB ECT. Caution is advised in interpreting these results due to the small sample size of this pilot study. Thus, future studies with similar design are warranted for replicating these findings.
Expression of Extracellular Matrix-Related Genes and Their Regulatory microRNAs in Problematic Colorectal Polyps
Authors: Žlajpah Margareta , Boštjančič Emanuela , Tepeš Bojan , Zidar Nina
Published: December 2020

Colorectal carcinoma usually evolves gradually, forming a spectrum of lesions, due to accumulation of genetic mutations and epigenetic alterations. Many early lesions are detected since the introduction of screening programs. The greatest challenge is to distinguish between adenomas with epithelial misplacement (AEM) and adenomas with early carcinoma (AEC), considering the diagnosis affects prognosis and treatment. We analyzed the expression of selected extracellular matrix (ECM)-related genes and proteins, and their regulatory microRNAs using RT-qPCR and immunohistochemistry in biopsies from 44 patients. Differences were observed in AEM in comparison to AEC for DCN, EPHA4, FN1, SPON2, and SPP1, reflecting inflammatory stromal reaction to traumatisation and misplacement of dysplastic glands in the submucosa in the former, and desmoplastic stromal reaction to true invasion of dysplastic glands in the submucosa in the latter. Expression of regulatory microRNAs hsa-miR-200c and hsa-miR-146a significantly negatively correlated with the expression of their regulated genes, while significant difference between AEM and AEC was observed only for hsa-miR-29c. The described expression patterns are too complex to be used in diagnostic work, but might contribute to better understanding ECM changes in colorectal carcinoma development, helping to find new markers in the future.
Satellitosis, a Crosstalk between Neurons, Vascular Structures and Neoplastic Cells in Brain Tumours; Early Manifestation of Invasive Behaviour
Authors: Civita Prospero , Valerio Ortenzi , Naccarato Antonio Giuseppe , Gumbleton Mark , Pilkington Geoffrey J.
Published: December 2020

The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse, invasive, high-grade gliomas. They are recognised as perineuronal satellitosis when clusters of neoplastic glial cells surround neurons cell bodies and perivascular satellitosis when such tumour cells surround blood vessels infiltrating Virchow–Robin spaces. In this review, we provide an overview of emerging knowledge regarding how interactions between neurons and glioma cells can modulate tumour evolution and how neurons play a key role in glioma growth and progression, as well as the role of perivascular satellitosis into mechanisms of glioma cells spread. At the same time, we review the current knowledge about the role of perineuronal satellitosis and perivascular satellitosis within the tumour microenvironment (TME), in order to highlight critical knowledge gaps in research space.
Establishment of an Immunocompetent Metastasis Rat Model with Hepatocyte Cancer Stem Cells
Authors: Wu Semon , Tseng I-Chieh , Huang Wen-Cheng , Su Cheng-Wen , Lai Yu-Heng , Lin Che , Lee Alan Yueh-Luen , Kuo Chan-Yen , Su Li-Yu , Lee Ming-Cheng , Hsu Te-Cheng , Yu Chun-Hsien
Published: December 2020

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We have recently established two new rat HCC cell lines HTC and TW-1, which we isolated from diethylnitrosamine-induced rat liver cancer. Results showed that TW-1 expressed the genetic markers of CSCs, including CD133, GSTP1, CD44, CD90, and EpCAM. Moreover, TW-1 showed higher tolerance to sorafenib than HTC did. In addition, tumorigenesis and metastasis were observed in nude mice and wild-type rats with TW-1 xenografts. Finally, we combined highly expressed genes in TW-1/HTC with well-known biomarkers from recent HCC studies to predict HCC-related biomarkers and able to identify HCC with AUCs > 0.9 after machine learning. These results indicated that TW-1 was a novel rat CSC line, and the mice or rat models we established with TW-1 has great potential on HCC studies in the future.
Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma
Authors: Mozhei Oleg , G. Teschemacher Anja , Kasparov Sergey
Published: December 2020

In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in experimental neuroscience. We review molecular strategies and current clinical trials and argue that approaches which are based on targeting a specific biochemical pathway or a characteristic mutation are inherently prone to failure because of the high genomic instability and clonal selection characteristics of GBM. For the same reasons, attempts to develop a viral system which selectively transduces only GBM cells are also unlikely to be universally successful. One of the common gene therapy approaches is to use cytotoxic viruses which replicate and cause preferential lysis of the GBM cells. This strategy, in addition to its reliance on the specific biochemical makeup of the GBM cells, bears a risk of necrotic cell death accompanied by release of large quantities of pro-inflammatory molecules. On the other hand, engaging the immune system in the anti-GBM response seems to be a potential avenue to explore further. We suggest that a plausible strategy is to focus on viral vectors which efficiently transduce brain cells via a non-selective, ubiquitous mechanism and which target (ideally irreversibly) processes that are critical only for dividing tumor cells and are dispensable for quiescent brain cells.
Comparison of Mutated KRAS and Methylated HOXA9 Tumor-Specific DNA in Advanced Lung Adenocarcinoma
Authors: Wen Sara W. C. , Andersen Rikke F. , Petersen Lena Marie S. , Hager Henrik , Hilberg Ole , Jakobsen Anders , Hansen Torben F.
Published: December 2020

Circulating tumor DNA (ctDNA) has been suggested as a biomarker in non-small cell lung cancer. The optimal target for measuring ctDNA has not yet been established. This study aimed to investigate methylated Homeobox A9 (meth-HOXA9) as an approach to detect ctDNA in advanced lung adenocarcinoma and compare it with mutated Kirsten rat sarcoma viral oncogene homolog (mut-KRAS) in order to determine the mutual agreement. DNA was purified from formalin-fixed, paraffin-embedded non-malignant lung tissue and lung adenocarcinoma tissue, and plasma from healthy donors and lung adenocarcinoma patients, respectively. KRAS mutations in tumor tissue were identified by next-generation sequencing and quantified in tumor and plasma by droplet digital polymerase chain reaction (ddPCR). The meth-HOXA9 analysis was based on bisulfite-converted DNA from tumor and plasma and quantified by ddPCR. Samples consisted of 20 archival non-malignant lung tissues, 48 advanced lung adenocarcinomas with matched plasma samples, and 100 plasma samples from healthy donors. A KRAS mutation was found in the tumor in 34/48 (70.8%) adenocarcinoma patients. All tumors were positive for meth-HOXA9, while none of the non-malignant lung tissues were. Meth-HOXA9 was detected in 36/48 (75%) of plasma samples, and the median level was 0.7% (range of 0–46.6%, n = 48). Mut-KRAS was detected in 29/34 (85.3%) of the plasma samples, and the median level was 1.2% (range of 0–46.1%, n = 34). There was a good correlation between meth-HOXA9 and mut-KRAS in plasma (Spearman’s rho 0.83, p < 0.001). Meth-HOXA9 is present in tissue from incurable lung adenocarcinoma but not in non-malignant lung tissue. It may be used as an approach for detecting ctDNA. The results demonstrated a high agreement between meth-HOXA9 and mut-KRAS in patients with advanced lung adenocarcinoma.
A Mediterranean Dietary Intervention in Female Carriers of BRCA Mutations: Results from an Italian Prospective Randomized Controlled Trial
Authors: Bruno Eleonora , Oliverio Andreina , Paradiso Angelo Virgilio , Daniele Antonella , Tommasi Stefania , Tufaro Antonio , Terribile Daniela Andreina , Magno Stefano , Filippone Alessio , Venturelli Elisabetta , Morelli Daniele , Baldassari Ivan , Cravana Maria Luisa , Manoukian Siranoush , Pasanisi Patrizia
Published: December 2020

Background: Women carriers of BRCA1/2 mutations face a high lifetime risk (penetrance) of developing breast and/or ovarian cancer. Insulin-like growth factor I (IGF-I), body weight and markers of insulin resistance affect BRCA penetrance. We conducted a multicenter prospective two-armed (1:1) randomized controlled trial (NCT03066856) to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduces IGF-I and other metabolic modulators of BRCA penetrance. Methods: BRCA carriers, with or without a previous cancer, aged 18–70 years and without metastases were randomly assigned to an active dietary intervention group (IG) or to a control group (CG). The primary endpoint of the intervention was the IGF-I reduction. Results: 416 women (216 in the IG and 200 in the CG) concluded the six-month dietary intervention. The IG showed significantly lowered serum levels of IGF-I (−11.3 ng/mL versus −1.3 ng/mL, p = 0.02), weight (−1.5 Kg versus −0.5 Kg, p < 0.001), waist circumference (−2 cm versus −0.7 cm, p = 0.01), hip circumference (−1.6 cm versus −0.5 cm, p = 0.01), total cholesterol (−10.2 mg/dL versus −3.6 mg/dL, p = 0.04) and triglycerides (−8.7 mg/dL versus + 5.5 mg/dL, p = 0.01) with respect to the CG. Conclusions: A Mediterranean dietary intervention with moderate protein restriction is effective in reducing IGF-I and other potential modulators of BRCA penetrance.
Immunotherapy Advances for Epithelial Ovarian Cancer
Authors: Hartnett Erin G. , Knight Julia , Radolec Mackenzy , Buckanovich Ronald J. , Edwards Robert P. , Vlad Anda M.
Published: December 2020

New treatment modalities are needed in order to improve the prognosis of women diagnosed with epithelial ovarian cancer (EOC), the most aggressive gynecologic cancer type. Most ovarian tumors are infiltrated by immune effector cells, providing the rationale for targeted approaches that boost the existing or trigger new anti-tumor immune mechanisms. The field of immuno-oncology has experienced remarkable progress in recent years, although the results seen with single agent immunotherapies in several categories of solid tumors have yet to extend to ovarian cancer. The challenge remains to determine what treatment combinations are most suitable for this disease and which patients are likely to benefit and to identify how immunotherapy should be incorporated into EOC standard of care. We review here some of the most promising immune therapies for EOC and focus on those currently tested in clinical trials.
HDAC6 Degradation Inhibits the Growth of High-Grade Serous Ovarian Cancer Cells
Authors: Ali Ahlam , Zhang Fengyu , Maguire Aaron , Byrne Tara , Weiner-Gorzel Karolina , Bridgett Stephen , O’Toole Sharon , O’Leary John , Beggan Caitlin , Fitzpatrick Patricia , McCann Amanda , Furlong Fiona
Published: December 2020

Histone deacetylase 6 (HDAC6) is a unique histone deacetylating enzyme that resides in the cell cytoplasm and is linked to the modulation of several key cancer related responses, including cell proliferation and migration. The promising anti-cancer response of the first-generation HDAC6 catalytic inhibitors continues to be assessed in clinical trials, although its role in high grade serous ovarian cancer is unclear. This study investigated HDAC6 tumor expression by immunohistochemistry in high-grade serous ovarian cancer (HGSOC) tissue samples and a meta-analysis of HDAC6 gene expression in ovarian cancer from publicly available data. The pharmacological activity of HDAC6 inhibition was assessed in a patient-derived model of HGSOC. HDAC6 was found to be highly expressed in HGSOC tissue samples and in the patient-derived HGSOC cell lines where higher HDAC6 protein and gene expression was associated with a decreased risk of death (hazard ratio (HR) 0.38, (95% confidence interval (CI), 0.16–0.88; p = 0.02); HR = 0.88 (95% CI, 0.78–0.99; p = 0.04)). Similarly, the multivariate analysis of HDAC6 protein expression, adjusting for stage, grade, and cytoreduction/cytoreductive surgery was associated with a decreased risk of death (HR = 0.19 (95% CI, 0.06–0.55); p = 0.002). Knock-down of HDAC6 gene expression with siRNA and protein expression with a HDAC6 targeting protein degrader decreased HGSOC cell proliferation, migration, and viability. Conversely, the selective inhibition of HDAC6 with the catalytic domain inhibitor, Ricolinostat (ACY-1215), inhibited HDAC6 deacetylation of α-tubulin, resulting in a sustained accumulation of acetylated α-tubulin up to 24 h in HGSOC cells, did not produce a robust inhibition of HDAC6 protein function. Inhibition of HGSOC cell proliferation by ACY-1215 was only achieved with significantly higher and non-selective doses of ACY-1215. In summary, we demonstrated, for the first time, that HDAC6 over-expression in HGSOC and all ovarian cancers is a favorable prognostic marker. We provide evidence to suggest that inhibition of HDAC6 catalytic activity with first generation HDAC6 inhibitors has limited efficacy as a monotherapy in HGSOC.
Epithelial/Mesenchymal Characteristics and PD-L1 Co-Expression in CTCs of Metastatic Breast Cancer Patients Treated with Eribulin: Correlation with Clinical Outcome
Authors: Polioudaki Hara , Mala Anastasia , Gkimprixi Eleni , Papadaki Maria , Chantziou Amanda , Tzardi Maria , Mavroudis Dimitris , Agelaki Sofia , Theodoropoulos Panayiotis
Published: December 2020

We aimed to evaluate the co-expression of PD-L1 and epithelial-mesenchymal markers in CTCs from metastatic breast cancer (MBC) patients and to determine if there is any relationship with patients’ outcome after eribulin treatment. Using cytospin preparations of peripheral blood mononuclear cells (PBMCs) from MBC patients treated with eribulin and a combination of immunocytochemistry and immunofluorescence, we quantified PD-L1, keratins and vimentin in single and cluster CTCs on days 1 and 8 of the first-treatment cycle. CTCs (n = 173) were found in 31 out of 38 patients. At baseline, the presence of cluster CTCs (p = 0.048), cluster mesenchymal CTCs (mCTCs) (p = 0.0003) or cluster PD-L1+mCTCs (p = 0.006) was associated with shorter overall survival (OS). In multivariate cox regression analysis, the detection of cluster mCTCs was the only parameter associated with increased risk of death (p = 0.024). On day 8 post-eribulin administration, PD-L1+mCTCs and especially single PD-L1+mCTCs decreased in 75% and 89% of patients, respectively. The detection of single PD-L1+mCTCs after eribulin treatment was correlated with shorter PFS (p = 0.047) and OS (p = 0.020). In conclusion, our study identified for the first time that cluster and single PD-L1+mCTCs subpopulations are of clinical significance in patients with MBC and highlighted the importance of CTC phenotyping during treatment with eribulin.
Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy
Authors: Knebel Franciele H. , Barber Louise J. , Newey Alice , Kleftogiannis Dimitrios , Woolston Andrew , Griffiths Beatrice , Fenwick Kerry , Bettoni Fabiana , Ribeiro Maurício Fernando Silva Almeida , da Fonseca Leonardo , Costa Frederico , Capareli Fernanda Cunha , Hoff Paulo M. , Sabbaga Jorge , Camargo Anamaria A. , Gerlinger Marco
Published: December 2020

Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.
Cardiovascular Health during and after Cancer Therapy
Authors: Ruddy Kathryn J. , Patel Shruti R. , Higgins Alexandra S. , Armenian Saro H. , Herrmann Joerg
Published: December 2020

Certain cancer treatments have been linked to specific cardiovascular toxicities, including (but not limited to) cardiomyopathy, atrial fibrillation, arterial hypertension, and myocarditis. Radiation, anthracyclines, human epidermal growth factor receptor 2 (Her2)-directed therapies, fluoropyrimidines, platinums, tyrosine kinase inhibitors and proteasome inhibitors, immune checkpoint inhibitors, and chimeric antigen-presenting (CAR)-T cell therapy can all cause cardiovascular side effects. Management of cardiovascular dysfunction that occurs during cancer therapy often requires temporary or permanent cessation of the risk-potentiating anti-neoplastic drug as well as optimization of medical management from a cardiovascular standpoint. Stem cell or bone marrow transplant recipients face unique cardiovascular challenges, as do patients at extremes of age.
Widespread Aberrant Alternative Splicing despite Molecular Remission in Chronic Myeloid Leukaemia Patients
Authors: Schmitz Ulf , Shah Jaynish S. , Dhungel Bijay P. , Monteuuis Geoffray , Luu Phuc-Loi , Petrova Veronika , Metierre Cynthia , Nair Shalima S. , Bailey Charles G. , Saunders Verity A. , Turhan Ali G. , White Deborah L. , Branford Susan , Clark Susan J. , Hughes Timothy P. , Wong Justin J.-L. , Rasko John E.J.
Published: December 2020

Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.
Human Hepatocellular Carcinoma (HCC)
Authors: Buonaguro Luigi
Published: December 2020

Hepatocellular carcinoma (HCC) is the fifth most common cancer and accounts for 8 [...]
Trabectedin Plus Radiotherapy for Advanced Soft-Tissue Sarcoma: Experience in Forty Patients Treated at a Sarcoma Reference Center
Authors: Hindi Nadia , Carrasco García Irene , Sánchez-Camacho Alberto , Gutierrez Antonio , Peinado Javier , Rincón Inmaculada , Benedetti Johanna , Sancho Pilar , Santos Paloma , Sánchez-Bustos Paloma , Marcilla David , Encinas Victor , Chacon Sara , Muñoz-Casares Cristobal , Moura David , Martin-Broto Javier
Published: December 2020

Symptomatic control and tumoral shrinkage is an unmet need in advanced soft-tissue sarcoma (STS) patients beyond first-line. The combination of trabectedin and radiotherapy showed activity in a recently reported clinical trial in this setting. This retrospective series aims to analyze our experience with the same regimen in the real-life setting. We retrospectively reviewed advanced sarcoma patients treated with trabectedin concomitantly with radiotherapy with palliative intent. Growth-modulation index (GMI) was calculated as a surrogate of efficacy. Forty metastatic patients were analyzed. According to RECIST, there was one (2.5%) complete response, 12 (30%) partial responses, 18 (45%) disease stabilizations, and nine (22.5%) progressions. After a median follow-up of 15 months (range 2–38), median progression-free survival (PFS) and overall survival (OS) were 7.5 months (95% CI 2.8–12.2) and 23.5 months (95% CI 1.1–45.8), respectively. Median GMI was 1.42 (range 0.19–23.76), and in 16 (53%) patients, it was >1.33. In patients with GMI >1.33, median OS was significantly longer than in those with GMI 0–1.33 (median OS 52.1 months (95% CI not reached) vs. 8.9 months (95% CI 6.3–11.6), p = 0.028). The combination of trabectedin plus radiotherapy is an active therapeutic option in patients with advanced STS, especially when tumor shrinkage for symptomatic relief is needed.
Interrupting Neuron—Tumor Interactions to Overcome Treatment Resistance
Authors: Hunt Patrick J. , Kabotyanski Katherine E. , Calin George A. , Xie Tongxin , Myers Jeffrey N. , Amit Moran
Published: December 2020

Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.