bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring of Expansive Clays over Drought-Rewetting Cycles Using Satellite Remote Sensing
Authors: Burnol André , Foumelis Michael , Gourdier Sébastien , Deparis Jacques , Raucoules Daniel
Published: September 2021

New capabilities for measuring and monitoring are needed to prevent the shrink-swell risk caused by drought-rewetting cycles. A clayey soil in the Loire Valley at Chaingy (France) has been instrumented with two extensometers and several soil moisture sensors. Here we show by direct comparison between remote and in situ data that the vertical ground displacements due to clay expansion are well-captured by the Multi-Temporal Synthetic Aperture Radar Interferometry (MT-InSAR) technique. In addition to the one-year period, two sub-annual periods that reflect both average ground shrinking and swelling timeframes are unraveled by a wavelet-based analysis. Moreover, the relative phase difference between the vertical displacement and surface soil moisture show local variations that are interpreted in terms of depth and thickness of the clay layer, as visualized by an electrical resistivity tomography. With regard to future works, a similar treatment relying fully on remote sensing observations may be scaled up to map larger areas in order to better assess the shrink-swell risk.
Water-Soluble Anions in PM10 Samples Collected in the Metropolitan Area of Costa Rica: Temporal and Spatial Variations
Authors: Herrera-Murillo Jorge , Soto-Murillo Tomas , Rojas-Marín José Félix , Beita-Guerrero Victor Hugo , Hidalgo-Gutiérrez María
Published: September 2021

The concentrations of water-soluble anions present in PM10 collected from ambient air in four sites of Costa Rica’s greater metropolitan area (GAM) were analyzed. Samples were collected over a 24-h period for three days during the 2011–2018 period, using high-volume air samplers with mass flow controller. The PM10 samples were collected using quartz fiber filters, which were analyzed using ion chromatography to identify organic and inorganic ions. The annual averages for PM10, F−, Cl−, and SO42− showed significant differences between the sampling sites, with Uruca (UR) consistently registering annual averages above the maximum concentration established by Costa Rica’s air quality regulations (30 µgm−3). The ions analyzed contributed 33%, 34%, 35%, and 37% of the PM10 mass for sampling sites UR, HA, AL, and CA, respectively. Using Spearman correlations and principal component analysis (PCA), the following contributions were identified: biomass burning, secondary particle formation processes from mobile and stationary emissions, and biogenic emissions. For each variable, seasonal patterns and trends were analyzed using time series with additive decomposition.
Sex Determination and Differentiation in Teleost: Roles of Genetics, Environment, and Brain
Authors: Rajendiran Preetha , Jaafar Faizul , Kar Sonika , Sudhakumari Chenichery , Senthilkumaran Balasubramanian , Parhar Ishwar S.
Published: September 2021

The fish reproductive system is a complex biological system. Nonetheless, reproductive organ development is conserved, which starts with sex determination and then sex differentiation. The sex of a teleost is determined and differentiated from bipotential primordium by genetics, environmental factors, or both. These two processes are species-specific. There are several prominent genes and environmental factors involved during sex determination and differentiation. At the cellular level, most of the sex-determining genes suppress the female pathway. For environmental factors, there are temperature, density, hypoxia, pH, and social interaction. Once the sexual fate is determined, sex differentiation takes over the gonadal developmental process. Environmental factors involve activation and suppression of various male and female pathways depending on the sexual fate. Alongside these factors, the role of the brain during sex determination and differentiation remains elusive. Nonetheless, GnRH III knockout has promoted a male sex-biased population, which shows brain involvement during sex determination. During sex differentiation, LH and FSH might not affect the gonadal differentiation, but are required for regulating sex differentiation. This review discusses the role of prominent genes, environmental factors, and the brain in sex determination and differentiation across a few teleost species.
Plasticity in Cervical Motor Circuits following Spinal Cord Injury and Rehabilitation
Authors: Walker John , Detloff Megan
Published: September 2021

Neuroplasticity is a robust mechanism by which the central nervous system attempts to adapt to a structural or chemical disruption of functional connections between neurons. Mechanical damage from spinal cord injury potentiates via neuroinflammation and can cause aberrant changes in neural circuitry known as maladaptive plasticity. Together, these alterations greatly diminish function and quality of life. This review discusses contemporary efforts to harness neuroplasticity through rehabilitation and neuromodulation to restore function with a focus on motor recovery following cervical spinal cord injury. Background information on the general mechanisms of plasticity and long-term potentiation of the nervous system, most well studied in the learning and memory fields, will be reviewed. Spontaneous plasticity of the nervous system, both maladaptive and during natural recovery following spinal cord injury is outlined to provide a baseline from which rehabilitation builds. Previous research has focused on the impact of descending motor commands in driving spinal plasticity. However, this review focuses on the influence of physical therapy and primary afferent input and interneuron modulation in driving plasticity within the spinal cord. Finally, future directions into previously untargeted primary afferent populations are presented.
Gut Microbiota as the Link between Elevated BCAA Serum Levels and Insulin Resistance
Authors: Gojda Jan , Cahova Monika
Published: September 2021

The microbiota-harboring human gut is an exquisitely active ecosystem that has evolved in a constant symbiosis with the human host. It produces numerous compounds depending on its metabolic capacity and substrates availability. Diet is the major source of the substrates that are metabolized to end-products, further serving as signal molecules in the microbiota-host cross-talk. Among these signal molecules, branched-chain amino acids (BCAAs) has gained significant scientific attention. BCAAs are abundant in animal-based dietary sources; they are both produced and degraded by gut microbiota and the host circulating levels are associated with the risk of type 2 diabetes. This review aims to summarize the current knowledge on the complex relationship between gut microbiota and its functional capacity to handle BCAAs as well as the host BCAA metabolism in insulin resistance development. Targeting gut microbiota BCAA metabolism with a dietary modulation could represent a promising approach in the prevention and treatment of insulin resistance related states, such as obesity and diabetes.
HMG-CoA Reductase Inhibitor, Simvastatin Is Effective in Decreasing Degree of Myocarditis by Inhibiting Metalloproteinases Activation
Authors: Skrzypiec-Spring Monika , Sapa-Wojciechowska Agnieszka , Haczkiewicz-Leśniak Katarzyna , Piasecki Tomasz , Kwiatkowska Joanna , Podhorska-Okołów Marzenna , Szeląg Adam
Published: September 2021

Background: Acute myocarditis often progresses to heart failure because there is no effective, etiology-targeted therapy of this disease. Simvastatin has been shown to be cardioprotective by decreasing matrix metalloproteinases’ (MMPs) activity. The study was designed to determine whether simvastatin inhibits MMPs activity, decreases the severity of inflammation and contractile dysfunction of the heart in experimental autoimmune myocarditis (EAM). Methods: Simvastatin (3 or 30 mg/kg/day) was given to experimental rats with EAM by gastric gavage for 21 days. Then transthoracic echocardiography was performed, MMPs activity and troponin I level were determined and tissue samples were assessed under a light and transmission electron microscope. Results: Hearts treated with simvastatin did not show left ventricular enlargement. As a result of EAM, there was an enhanced activation of MMP-9, which was significantly reduced in the high-dose simvastatin group compared to the low-dose group. It was accompanied by prevention of myofilaments degradation and reduction of severity of inflammation. Conclusions: The cardioprotective effects of simvastatin in the acute phase of EAM are, at least in part, due to its ability to decrease MMP-9 activity and subsequent decline in myofilaments degradation and suppression of inflammation. These effects were achieved in doses equivalent to therapeutic doses in humans.
Kinetic Analysis of the Interaction of Nicking Endonuclease BspD6I with DNA
Authors: Abrosimova Liudmila A. , Kuznetsov Nikita A. , Astafurova Natalia A. , Samsonova Anastasiia R. , Karpov Andrey S. , Perevyazova Tatiana A. , Oretskaya Tatiana S. , Fedorova Olga S. , Kubareva Elena A.
Published: September 2021

Nicking endonucleases (NEs) are enzymes that incise only one strand of the duplex to produce a DNA molecule that is ‘nicked’ rather than cleaved in two. Since these precision tools are used in genetic engineering and genome editing, information about their mechanism of action at all stages of DNA recognition and phosphodiester bond hydrolysis is essential. For the first time, fast kinetics of the Nt.BspD6I interaction with DNA were studied by the stopped-flow technique, and changes of optical characteristics were registered for the enzyme or DNA molecules. The role of divalent metal cations was estimated at all steps of Nt.BspD6I–DNA complex formation. It was demonstrated that divalent metal ions are not required for the formation of a non-specific complex of the protein with DNA. Nt.BspD6I bound five-fold more efficiently to its recognition site in DNA than to a random DNA. DNA bending was confirmed during the specific binding of Nt.BspD6I to a substrate. The optimal size of Nt.BspD6I’s binding site in DNA as determined in this work should be taken into account in methods of detection of nucleic acid sequences and/or even various base modifications by means of NEs.
Age-Related Alterations in the Behavior and Serotonin-Related Gene mRNA Levels in the Brain of Males and Females of Short-Lived Turquoise Killifish (Nothobranchius furzeri)
Authors: Evsiukova Valentina S. , Kulikova Elizabeth A. , Kulikov Alexander V.
Published: September 2021

Short-lived turquoise killifish (Nothobranchius furzeri) have become a popular model organism for neuroscience. In the present paper we study for the first time their behavior in the novel tank diving test and the levels of mRNA of various 5-HT-related genes in brains of 2-, 4- and 6-month-old males and females of N. furzeri. The marked effect of age on body mass, locomotor activity and the mRNA level of Tph1b, Tph2, Slc6a4b, Mao, Htr1aa, Htr2a, Htr3a, Htr3b, Htr4, Htr6 genes in the brains of N. furzeri males was shown. Locomotor activity and expression of the Mao gene increased, while expression of Tph1b, Tph2, Slc6a4b, Htr1aa, Htr2a, Htr3a, Htr3b, Htr4, Htr6 genes decreased in 6-month-old killifish. Significant effects of sex on body mass as well as on mRNA level of Tph1a, Tph1b, Tph2, Slc6a4b, Htr1aa, 5-HT2a, Htr3a, Htr3b, Htr4, and Htr6 genes were revealed: in general both the body mass and the expression of these genes were higher in males. N. furzeri is a suitable model with which to study the fundamental problems of age-related alterations in various mRNA levels related with the brains 5-HT system.
Cardiovascular Diseases and Pharmacomicrobiomics: A Perspective on Possible Treatment Relevance
Authors: Curini Lavinia , Amedei Amedeo
Published: September 2021

Cardiovascular diseases (CVDs), the most common cause of mortality in rich countries, include a wide variety of pathologies of the heart muscle and vascular system that compromise the proper functioning of the heart. Most of the risk factors for cardiovascular diseases are well-known: lipid disorders, high serum LDL cholesterol, hypertension, smoking, obesity, diabetes, male sex and physical inactivity. Currently, much evidence shows that: (i) the human microbiota plays a crucial role in maintaining the organism’s healthy status; and (ii) a link exists between microbiota and cardiovascular function that, if dysregulated, could potentially correlate with CVDs. This scenario led the scientific community to carefully analyze the role of the microbiota in response to drugs, considering this the right path to improve the effectiveness of disease treatment. In this review, we examine heart diseases and highlight how the microbiota actually plays a preponderant role in their development. Finally, we investigate pharmacomicrobiomics—a new interesting field—and the microbiota’s role in modulating the response to drugs, to improve their effectiveness by making their action targeted, focusing particular attention on cardiovascular diseases and on innovative potential treatments.
The Prognostic Value of the m6A Score in Multiple Myeloma Based on Machine Learning
Authors: Xiao Gong , Yuan Qiongjing , Wang Wei
Published: September 2021

Background: Multiple myeloma (MM) is one of the most common cancers of the blood system. N6-methyladenosine (m6A) plays an important role in cancer progression. We aimed to investigate the prognostic relevance of the m6A score in multiple myeloma through a series of bioinformatics analyses. Methods: The microarray dataset GSE4581 and GSE57317 used in this study were downloaded from the Gene Expression Omnibus (GEO) database. The m6A score was calculated using the GSVA package. The Random forests, univariate Cox regression analysis and Lasso analyses were performed for the differentially expressed genes (DEGs). Kaplan–Meier analysis and an ROC curve were used to diagnose the effectiveness of the model. Results: The GSVA R software package was used to predict the function. A total of 21 m6A genes were obtained, and 286 DEGs were identified between high and low m6A score groups. The risk model was constructed and composed of PRX, LBR, RB1, FBXL19-AS1, ARSK, MFAP3L, SLC44A3, UNC119 and SHCBP1. Functional analysis of risk score showed that with the increase in the risk score, Activated CD4 T cells, Memory B cells and Type 2 T helper cells were highly infiltrated. Conclusions: Immune checkpoints such as HMGB1, TGFB1, CXCL9 and HAVCR2 were significantly positively correlated with the risk score. We believe that the m6A score has a certain prognostic value in multiple myeloma.
Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons
Authors: Li Muxue , Hamilton Rachel , Salapa Hannah E. , Levin Michael C.
Published: September 2021

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a significant neurodegenerative component. Dysfunctional RNA-binding proteins (RBPs) are causally linked to neuronal damage and are a feature of MS, including the mislocalization of the RBP heterogeneous nuclear ribonucleoprotein A1 (A1). Here, we show that primary neurons exposed to pro-inflammatory cytokines and anti-A1 antibodies, both characteristic of an MS autoimmune response, displayed increased A1 mislocalization, stress granule formation, and decreased neurite length, a marker of neurodegeneration. These findings illustrate a significant relationship between secreted immune factors, A1 dysfunction, and neuronal damage in a disease-relevant model system.
Special Issue: Neural Bases of Cognitive Processing
Authors: Di Russo Francesco , Lucia Stefania
Published: September 2021

The main aim of Cognitive Neuroscience is investigating how brain functions lead to mental processes and behavior [...]
Seismic Performance Assessment of Buildings
Authors: Bento Rita , Simões Ana
Published: September 2021

The seismic performance assessment of buildings is a challenging process [...]
Optimization of an Eco-Friendly Hydraulic Road Binders Comprising Clayey Dam Sediments and Ground Granulated Blast-Furnace Slag
Authors: Bellara Selma , Hidjeb Mustapha , Maherzi Walid , Mezazigh Salim , Senouci Ahmed
Published: September 2021

This study investigated the potential use of Zerdezas dam Calcined Sediments (CS) and El-Hadjar Blast Furnace Slag (GGBS) from northern Algeria as a partial replacement of cement (C) in normal hardening hydraulic road binders. Two binder mix designs were optimized using a Response Surface Methodology (RSM). The first mix, 50C35GGBS15CS, consisted of 50% cement, 35% blast furnace slag, and 15% calcined sediment. The second mix, 80C10GGBS10CS, consisted of 80% cement, 10% blast furnace slag, and 10% calcined sediments. The tests of workability, setting time, volume expansion, compressive and flexural strengths, porosity, and SEM were conducted to ensure that both mixes meet the standard requirements for road construction binders. The two proposed mixes were qualified as normal hardening hydraulic road binder. The reuse of the sediments will contribute to a better disposal of dam sediments and steel industry waste and to preserve natural resources that are used for manufacturing cement. It will also contribute to the environmental impact reduction of cement clinker production by reducing greenhouse gas emissions.
Primary Lung Cancer Organoids for Personalized Medicine—Are They Ready for Clinical Use?
Authors: Werner Raphael S. , Kirschner Michaela B. , Opitz Isabelle
Published: September 2021

Despite many developments in recent years, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. Therefore, additional research, aiming to further elucidate the underlying molecular mechanisms of malignant transformation and development of therapy resistance, as well as the identification of additional novel therapeutic avenues, is crucial. For this purpose, reliable in vitro models are indispensable, as they allow for quick identification of suspected oncogenic drivers or evaluation of novel therapeutic strategies in a timely and cost-effective fashion. However, standard two-dimensional cell culture systems, the most frequently used in vitro model, are usually not truly representative of the situation in a patient as these models lack the tumor heterogeneity, the surrounding tumor microenvironment and the three-dimensional complexity of a tumor in vitro. For this reason, 3D cell culture systems, in particular organoids generated from normal non-malignant cells or tumor cell-based organoids (tumoroids), have in recent years gained much attention as alternative in vitro model systems that more closely resemble the actual primary tumor. In this review, we provide an overview of the available literature in the field of NSCLC organoids, which might still be in its infancy, but is gaining momentum.
Multiparametric Magnetic Resonance Imaging-Ultrasound Fusion Transperineal Prostate Biopsy: Diagnostic Accuracy from a Single Center Retrospective Study
Authors: Fulco Andrea , Chiaradia Francesco , Ascalone Luigi , Andracchio Vincenzo , Greco Antonio , Cappa Manlio , Scarcia Marcello , Ludovico Giuseppe Mario , Pagliarulo Vincenzo , Palmieri Camillo , Alba Stefano
Published: September 2021

The management of prostate biopsy in men with clinical suspicion of prostate cancer has changed in the last few years, especially with the introduction of imaging techniques, to overcome the low efficacy of risk stratification based on PSA levels. Here, we aimed to compare the diagnostic accuracy of multiparametric MRI with fusion ultrasound-guided prostate biopsy and standard biopsy, both performed through the transperineal route. To this end, we retrospectively analyzed 272 patients who underwent combined transperineal targeted and standard biopsy during the same session. The primary outcome was to compare the cancer detection rate between targeted and standard biopsy. The secondary outcome was to evaluate the added value of combined targeted and standard biopsy approach as compared to only targeted or standard biopsy. Results showed that a rate of 16.7% clinically significant tumors (International Society of Urological Pathology (ISUP) grade ≥ 2) would have been lost if only the standard biopsy had been used. The combined targeted and standard biopsy showed an added value of 10.3% and 9.9% in reducing the risk of prostate cancer missing after targeted or standard biopsy alone, respectively. The combined targeted and standard biopsy pathway is recommended to reduce the risk of missing clinically significant prostate cancer.
Low Levels of TRIM28-Interacting KRAB-ZNF Genes Associate with Cancer Stemness and Predict Poor Prognosis of Kidney Renal Clear Cell Carcinoma Patients
Authors: Czerwinska Patrycja , Mackiewicz Andrzej Adam
Published: September 2021

Krüppel-associated box zinc finger (KRAB-ZNF) proteins are known to regulate diverse biological processes, such as embryonic development, tissue-specific gene expression, and cancer progression. However, their involvement in the regulation of cancer stemness-like phenotype acquisition and maintenance is scarcely explored across solid tumor types, and to date, there are no data for kidney renal clear cell cancer (KIRC). We have harnessed The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database transcriptomic data and used several bioinformatic tools (i.e., GEPIA2, GSCALite, TISIDB, GSEA, CIBERSORT) to verify the relation between the expression and genomic alterations in KRAB-ZNFs and kidney cancer, focusing primarily on tumor dedifferentiation status and antitumor immune response. Our results demonstrate a significant negative correlation between KRAB-ZNFs and kidney cancer dedifferentiation status followed by an attenuated immune-suppressive response. The transcriptomic profiles of high KRAB-ZNF-expressing kidney tumors are significantly enriched with stem cell markers and show a depletion of several inflammatory pathways known for favoring cancer stemness. Moreover, we show for the first time the prognostic role for several KRAB-ZNFs in kidney cancer. Our results provide new insight into the role of selected KRAB-ZNF proteins in kidney cancer development. We believe that our findings may help better understand the molecular basis of KIRC.
Metabolic Plasticity and Combinatorial Radiosensitisation Strategies in Human Papillomavirus-Positive Squamous Cell Carcinoma of the Head and Neck Cell Lines
Authors: Wilkie Mark D. , Anaam Emad A. , Lau Andrew S. , Rubbi Carlos P. , Vlatkovic Nikolina , Jones Terence M. , Boyd Mark T.
Published: September 2021

Background: A major objective in the management of human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) is to reduce long-term functional ramifications while maintaining oncological outcomes. This study examined the metabolic profile of HPV-positive SCCHN and the potential role of anti-metabolic therapeutics to achieve radiosensitisation as a potential means to de-escalate radiation therapy. Methods: Three established HPV-positive SCCHN cell lines were studied (UM-SCC-104, UPCI:SCC154, and VU-SCC-147), together with a typical TP53 mutant HPV-negative SCCHN cell line (UM-SCC-81B) for comparison. Metabolic profiling was performed using extracellular flux analysis during specifically designed mitochondrial and glycolytic stress tests. Sensitivity to ionising radiation (IR) was evaluated using clonogenic assays following no treatment, or treatment with: 25 mM 2-deoxy-D-glucose (glycolytic inhibitor) alone; 20 mM metformin (electron transport chain inhibitor) alone; or 25 mM 2-deoxy-D-glucose and 20 mM metformin combined. Expression levels of p53 and reporters of p53 function (MDM2, p53, Phospho-p53 [Ser15], TIGAR and p21 [CDKN1A]) were examined by western blotting. Results: HPV-positive SCCHN cell lines exhibited a diverse metabolic phenotype, displaying robust mitochondrial and glycolytic reserve capacities. This metabolic profile, in turn, correlated with IR response following administration of anti-metabolic agents, in that both 2-deoxy-D-glucose and metformin were required to significantly potentiate the effects of IR in these cell lines. Conclusions: In contrast to our recently published data on HPV-negative SCCHN cells, which display relative glycolytic dependence, HPV-positive SCCHN cells can only be sensitised to IR using a complex anti-metabolic approach targeting both mitochondrial respiration and glycolysis, reflecting their metabolically diverse phenotype. Notionally, this may provide an attractive platform for treatment de-intensification in the clinical setting by facilitating IR dose reduction to minimise the impact of treatment on long-term function.
Morphological Features Extracted by AI Associated with Spatial Transcriptomics in Prostate Cancer
Authors: Chelebian Eduard , Avenel Christophe , Kartasalo Kimmo , Marklund Maja , Tanoglidi Anna , Mirtti Tuomas , Colling Richard , Erickson Andrew , Lamb Alastair , Lundeberg Joakim , Wählby Carolina
Published: September 2021

Prostate cancer is a common cancer type in men, yet some of its traits are still under-explored. One reason for this is high molecular and morphological heterogeneity. The purpose of this study was to develop a method to gain new insights into the connection between morphological changes and underlying molecular patterns. We used artificial intelligence (AI) to analyze the morphology of seven hematoxylin and eosin (H&E)-stained prostatectomy slides from a patient with multi-focal prostate cancer. We also paired the slides with spatially resolved expression for thousands of genes obtained by a novel spatial transcriptomics (ST) technique. As both spaces are highly dimensional, we focused on dimensionality reduction before seeking associations between them. Consequently, we extracted morphological features from H&E images using an ensemble of pre-trained convolutional neural networks and proposed a workflow for dimensionality reduction. To summarize the ST data into genetic profiles, we used a previously proposed factor analysis. We found that the regions were automatically defined, outlined by unsupervised clustering, associated with independent manual annotations, in some cases, finding further relevant subdivisions. The morphological patterns were also correlated with molecular profiles and could predict the spatial variation of individual genes. This novel approach enables flexible unsupervised studies relating morphological and genetic heterogeneity using AI to be carried out.
Risks and Benefits of Fiducial Marker Placement in Tumor Lesions for Robotic Radiosurgery: Technical Outcomes of 357 Implantations
Authors: Kord Melina , Kluge Anne , Kufeld Markus , Kalinauskaite Goda , Loebel Franziska , Stromberger Carmen , Budach Volker , Gebauer Bernhard , Acker Gueliz , Senger Carolin
Published: September 2021

Fiducial markers (FM) inserted into tumors increase the precision of irradiation during robotic radiosurgery (RRS). This retrospective study evaluated the clinical complications, marker migration, and motion amplitude of FM implantations by analyzing 288 cancer patients (58% men; 63.1 ± 13.0 years) who underwent 357 FM implantations prior to RRS with CyberKnife, between 2011 and 2019. Complications were classified according to the Society of Interventional Radiology (SIR) guidelines. The radial motion amplitude was calculated for tumors that moved with respiration. A total of 725 gold FM was inserted. SIR-rated complications occurred in 17.9% of all procedures. Most complications (32.0%, 62/194 implantations) were observed in Synchrony®-tracked lesions affected by respiratory motion, particularly in pulmonary lesions (46.9% 52/111 implantations). Concurrent biopsy sampling was associated with a higher complication rate (p = 0.001). FM migration occurred in 3.6% after CT-guided and clinical FM implantations. The largest motion amplitudes were observed in hepatic (20.5 ± 11.0 mm) and lower lung lobe (15.4 ± 10.5 mm) lesions. This study increases the awareness of the risks of FM placement, especially in thoracic lesions affected by respiratory motion. Considering the maximum motion amplitude, FM placement remains essential in hepatic and lower lung lobe lesions located >100.0 mm from the spine.
High Prevalence of 5T4/Trophoblast Glycoprotein in Soft Tissue Sarcomas
Authors: Groothuis Patrick , Penel Nicola , Italiano Antoine , Kotecki Nuria , Dijcks Fred , Dokter Wim
Published: September 2021

The expression of 5T4/trophoblast glycoprotein was evaluated in several histological subtypes of soft tissue sarcoma (STS) to determine whether the prevalence and level of expression of this membrane-associated glycoprotein is sufficient for use in targeted therapies. Tumor tissue microarrays containing cores from different histological subtypes of STS were stained using a standardized immunohistochemical staining method to detect 5T4; the level of staining was assessed using a semi-quantitative scoring method. No 5T4 staining was seen in the angiosarcomas and liposarcomas investigated in this study. 5T4 staining in the other STS subtypes was seen in more than 50% of cases, warranting further investigation into whether this antigen could evoke an anti-tumor immune response or can be used as target for the delivery of more potent toxins through antibody drug conjugates.
Clinical and Tumor Characteristics of Patients with High Serum Levels of Growth Differentiation Factor 15 in Advanced Pancreatic Cancer
Authors: Suzuki Hidetaka , Mitsunaga Shuichi , Ikeda Masafumi , Aoyama Takao , Yoshizawa Kazumi , Yoshimatsu Hiroki , Kawai Norisuke , Masuda Mari , Miura Tomofumi , Ochiai Atsushi
Published: September 2021

We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood samples, and biopsy specimens of liver metastasis were collected prior to anti-cancer treatment. Serum GDF-15 levels and multiple protein expressions in lysates extracted from liver metastasis were measured by enzyme-linked immuno-sorbent assay and reverse-phase protein array, respectively. The cut-off for serum GDF-15 was determined as 3356.6 pg/mL, the mean plus two standard deviations for benign pancreatic disease. The high-GDF-15 group was characterized as showing low Karnofsky performance status (KPS) (p = 0.037), poor Eastern Cooperative Oncology Group performance status (ECOG-PS) (p = 0.049), severe appetite loss (p = 0.011), and high serum levels of carbohydrate antigen 19-9 (p = 0.019) and C-reactive protein (p = 0.009). Tumors of the high-GDF-15 group expressed high levels of phosphorylated (p)JNK (p = 0.007) and pAkt (p = 0.040). APC patients with high serum GDF-15 showed signatures of cachexia and activation of the signaling pathways involving Akt and JNK in the tumor. This study indicated circulating GDF-15 could be associated with cachectic symptoms in APC.
Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication
Authors: Waldenmaier Mareike , Seibold Tanja , Seufferlein Thomas , Eiseler Tim
Published: September 2021

Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30–150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.
Neuronal Differentiation-Related Epigenetic Regulator ZRF1 Has Independent Prognostic Value in Neuroblastoma but Is Functionally Dispensable In Vitro
Authors: Jiménez Carlos , Antonelli Roberta , Masanas Marc , Soriano Aroa , Devis-Jauregui Laura , Camacho Jessica , Magdaleno Ainara , Guillén Gabriela , Hladun Raquel , Jubierre Luz , Roma Josep , Llobet-Navas David , Sánchez de Toledo Josep , Moreno Lucas , Gallego Soledad , Segura Miguel F.
Published: September 2021

Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments. In this study, we characterized the role of ZRF1, an epigenetic activator recruited to genes involved in the maintenance of the identity of neural progenitors. We combined analysis of patient sample expression datasets with loss- and gain-of-function studies on neuroblastoma cell lines. Functional analyses revealed that ZRF1 is functionally dispensable for those cellular functions related to cell differentiation, proliferation, migration, and invasion, and does not affect the cellular response to chemotherapeutic agents. However, we found that high levels of ZRF1 mRNA expression are associated to shorter overall survival of neuroblastoma patients, even when those patients with the most common molecular alterations used as prognostic factors are removed from the analyses, thereby suggesting that ZRF1 expression could be used as an independent prognostic factor in neuroblastoma.
Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC—Real World Efficacy
Authors: Mouritzen Mette T. , Carus Andreas , Ladekarl Morten , Meldgaard Peter , Nielsen Anders W. M. , Livbjerg Anna , Larsen Jacob W. , Skuladottir Halla , Kristiansen Charlotte , Wedervang Kim , Schytte Tine , Hansen Karin H. , Østby Anne-Cathrine , Frank Malene S. , Lauritsen Jakob , Sørensen Jens B. , Langer Seppo W. , Persson Gitte F. , Andersen Jon L. , Frary Johanna M. C. , Drivsholm Lars B. , Vesteghem Charles , Christensen Heidi S. , Bjørnhart Birgitte , Pøhl Mette
Published: September 2021

Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6–20.0) and 6% (95% CI 5.1–7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.
Adolescent and Young Adult (AYA) Cancer Survivorship Practices: An Overview
Authors: Janssen Silvie H. M. , van der Graaf Winette T. A. , van der Meer Daniël J. , Manten-Horst Eveliene , Husson Olga
Published: September 2021

Worldwide, more than 1.2 million adolescents and young adults (AYAs; those aged 15–39 years) are diagnosed with cancer each year. Although considerable variability exists according to cancer site and stage of disease, the 5-year relative survival at the time of diagnosis has been estimated at >80% for all AYA patients with cancer combined. Extensive survivorship research in recent decades has focused on patients diagnosed with cancer as children (<15 years) and older adults (>39 years), yet few studies to date have reported outcomes specifically for patients diagnosed as AYAs. With increasing incidence and improving survival for many tumor types, leading to the majority of AYA patients with cancer becoming long-term survivors, there is a critical need for research efforts to inform the survivorship care of this growing population. This article describes the population of AYA cancer survivors according to their epidemiology and late and long-term effects, the challenges and models of AYA survivorship care, as well as future opportunities for research and healthcare.
At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention
Authors: Tundo Grazia R. , Sbardella Diego , Oddone Francesco , Kudriaeva Anna A. , Lacal Pedro M. , Belogurov Alexey A. , Graziani Grazia , Marini Stefano
Published: September 2021

Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers.
Image-Guided Liver Stereotactic Body Radiotherapy Using VMAT and Real-Time Adaptive Tumor Gating: Evaluation of the Efficacy and Toxicity for Hepatocellular Carcinoma
Authors: Cantaloube Marie , Castan Florence , Creoff Morgane , Prunaretty Jessica , Bordeau Karl , Michalet Morgan , Assenat Eric , Guiu Boris , Pageaux Georges-Philippe , Ychou Marc , Aillères Norbert , Fenoglietto Pascal , Azria David , Riou Olivier
Published: September 2021

Liver SBRT is a therapeutic option for the treatment of HCC in patients not eligible for other local therapies. We retrospectively report the outcomes of a cohort of consecutive patients treated with SBRT for HCC at the Montpellier Cancer Institute. Between March 2013 and December 2018, 66 patients were treated with image-guided liver SBRT using VMAT and real-time adaptive tumor gating in our institute. The main endpoints considered in this study were local control, disease-free survival, overall survival, and toxicity. The median follow-up was 16.8 months. About 66.7% had prior liver treatment. Most patients received 50 Gy in five fractions of 10 Gy. No patient had local recurrence. Overall survival and disease-free survival were, respectively, 83.9% and 46.7% at one year. In multivariate analysis, the diameter of the lesions was a significant prognostic factor associated with disease-free survival (HR = 2.57 (1.19–5.53) p = 0.02). Regarding overall survival, the volume of PTV was associated with lower overall survival (HR = 2.84 (1.14–7.08) p = 0.025). No grade 3 toxicity was observed. One patient developed a grade 4 gastric ulcer, despite the dose constraints being respected. Image-guided liver SBRT with VMAT is an effective and safe treatment in patients with inoperable HCC, even in heavily pre-treated patients. Further prospective evaluation will help to clarify the role of SBRT in the management of HCC patients.
Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer
Authors: Ebersbach Celina , Beier Alicia-Marie K. , Thomas Christian , Erb Holger H. H.
Published: September 2021

Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials.
Prognostic Impact of Serum Free Light Chain Ratio Normalization in Patients with Multiple Myeloma Treated within the GMMG-MM5 Trial
Authors: Klein Eva-Maria , Tichy Diana , Salwender Hans , Mai Elias , Duerig Jan , Weisel Katja , Benner Axel , Bertsch Uta , Akhavanpoor Mabast , Besemer Britta , Munder Markus , Lindemann Hans-Walter , Hose Dirk , Seckinger Anja , Luntz Steffen , Jauch Anna , Elmaagacli Ahmet , Fuhrmann Stephan , Brossart Peter , Goerner Martin , Bernhard Helga , Raab Marc , Blau Igor , Haenel Mathias , Scheid Christof , Goldschmidt Hartmut ,   on behalf of the German-Speaking Myeloma Multicenter Group (GMMG)
Published: September 2021

We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) (p < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47–0.79) and overall survival (OS) (p = 0.02, HR = 0.67, 95% CI = 0.48–0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS (p = 0.04, HR = 0.77, 95% CI = 0.60–0.99) and OS (p = 0.01, HR = 0.59, 95% CI = 0.41–0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.
Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer
Authors: Murugan Sengottuvelan , Rousseau Bénédicte , Sarkar Dipak K.
Published: September 2021

Cancer progression is known to be promoted by increased body stress caused by elevated beta-adrenergic and opioidergic nervous system activities. The effects of β2-adrenergic blocker propranolol (PRO) and μ-opioid receptor antagonist naltrexone (NTX) were tested using a preclinical model of human breast cancer. These drugs, individually, and more potently when combined, inhibited the cell growth and progression of breast cancer cells in vitro in cultures, and in vivo in rat xenografts. The antitumor activities of these drugs were associated with direct cell intrinsic effects, including increased cell growth arrest, elevated levels of apoptotic proteins, and reduced production of epithelial–mesenchymal transition factors by the tumor cells, as well as effects on innate immune activation and reduced inflammatory cytokine levels in plasma. These data suggest that the combined treatments of PRO and NTX produce impressive antitumor effects in the preclinical breast cancer model, and thereby may provide a new combinatorial treatment strategy with more clinical treatment modalities.
Impact of p16 Status and Anatomical Site in Anti-PD-1 Immunotherapy-Treated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients
Authors: Clancy Kate , Hamill Chelsea S. , O’Neill W. Quinn , Vu Brandon , Thuener Jason , Gui Shanying , Li Shawn , Fowler Nicole , Rezaee Rod , Lavertu Pierre , Wasman Jay , Patel Monaliben , Shaikh Hira , Vick Eric , Madabhushi Anant , Wise-Draper Trisha M. , Burkitt Kyunghee , Teknos Theodoros N. , Pan Quintin
Published: September 2021

In head and neck squamous cell carcinoma (HNSCC), anti-PD-1 inhibitors are approved for recurrent/metastatic (R/M) disease and anticipated to expand to other indications. The impact of p16 status and anatomical site on overall survival (OS) in immunotherapy-treated HNSCC patients remains unresolved. We performed a retrospective analysis of R/M HNSCC patients receiving anti-PD-1 immunotherapy at our academic medical center with an extensive community satellite network. Fifty-three R/M HNSCC patients were treated with anti-PD-1 immunotherapy and had a median OS of 6 months. Anatomical site was associated with distinct OS; oropharynx and larynx patients have superior OS compared to oral cavity patients. Analysis of the OPSCC subset showed p16+ status as a favorable, independent prognostic biomarker (HR 7.67 (1.23–47.8); p = 0.029). Further studies to assess the link between anatomical site, p16 status, and anti-PD-1 treatment outcomes in large cohorts of R/M HNSCC patients managed in real-world clinical practices and clinical trials should be prioritized.