bluuebunny/crossref_metadata_2025 huggingface dataset:
Automatic Colorization of Anime Style Illustrations Using a Two-Stage Generator
Authors: Lee Yeongseop , Lee Seongjin
Published: December 2020

Line-arts are used in many ways in the media industry. However, line-art colorization is tedious, labor-intensive, and time consuming. For such reasons, a Generative Adversarial Network (GAN)-based image-to-image colorization method has received much attention because of its promising results. In this paper, we propose to use color a point hinting method with two GAN-based generators used for enhancing the image quality. To improve the coloring performance of drawing with various line styles, generator takes account of the loss of the line-art. We propose a Line Detection Model (LDM) which is used in measuring line loss. LDM is a method of extracting line from a color image. We also propose histogram equalizer in the input line-art to generalize the distribution of line styles. This approach allows the generalization of the distribution of line style without increasing the complexity of inference stage. In addition, we propose seven segment hint pointing constraints to evaluate the colorization performance of the model with Fréchet Inception Distance (FID) score. We present visual and qualitative evaluations of the proposed methods. The result shows that using histogram equalization and LDM enabled line loss exhibits the best result. The Base model with XDoG (eXtended Difference-Of-Gaussians)generated line-art with and without color hints exhibits FID for colorized images score of 35.83 and 44.70, respectively, whereas the proposed model in the same scenario exhibits 32.16 and 39.77, respectively.
Damage and Failure in a Statistical Crack Model
Authors: Margolin L.G.
Published: December 2020

In this paper I will take a close look at a statistical crack model (SCM) as is used in engineering computer codes to simulate fracture at high strain rates. My general goal is to understand the macroscopic behavior effected by the microphysical processes incorporated into an SCM. More specifically, I will assess the importance of including local interactions between cracks into the growth laws of an SCM. My strategy will be to construct a numerical laboratory that represents a single computational cell containing a realization of a statistical distribution of cracks. The cracks will evolve by the microphysical models of the SCM, leading to quantifiable damage and failure of the computational cell. I will use the numerical data generated by randomly generated ensembles of the fracture process to establish scaling laws that will modify and simplify the implementation of the SCM into large scale engineering codes.
Advancement in Urban Climate Modelling at Local Scale: Urban Heat Island Mitigation and Building Cooling Demand
Authors: Kubilay Aytaç , Allegrini Jonas , Strebel Dominik , Zhao Yongling , Derome Dominique , Carmeliet Jan
Published: December 2020

As cities and their population are subjected to climate change and urban heat islands, it is paramount to have the means to understand the local urban climate and propose mitigation measures, especially at neighbourhood, local and building scales. A framework is presented, where the urban climate is studied by coupling a meteorological model to a building-resolved local urban climate model, and where an urban climate model is coupled to a building energy simulation model. The urban climate model allows for studies at local scale, combining modelling of wind and buoyancy with computational fluid dynamics, radiative exchange and heat and mass transport in porous materials including evaporative cooling at street canyon and neighbourhood scale. This coupled model takes into account the hygrothermal behaviour of porous materials and vegetation subjected to variations of wetting, sun, wind, humidity and temperature. The model is driven by climate predictions from a mesoscale meteorological model including urban parametrisation. Building energy demand, such as cooling demand during heat waves, can be evaluated. This integrated approach not only allows for the design of adapted buildings, but also urban environments that can mitigate the negative effects of future climate change and increased urban heat islands. Mitigation solutions for urban heat island effect and heat waves, including vegetation, evaporative cooling pavements and neighbourhood morphology, are assessed in terms of pedestrian comfort and building (cooling) energy consumption.
Evaluation of the Stability of Carbon Conductor in the Cathode of Aqueous Rechargeable Lithium Batteries against Overcharging
Authors: Doan The Nam Long , Hoang Tuan K. A. , Saad Sameh M. I. , Chen P.
Published: December 2020

Three major components in a cathode of aqueous rechargeable lithium batteries are the active material, the polymer binder, and the carbon conductive additive. The stability of each component in the battery is the key to long service life. To evaluate the stability of the carbon component, we introduce here a quick and direct testing method. LiMn2O4 is chosen as a typical active material for the preparation of the cathode, with polyvinylidene fluoride (PVdF), and a commercial carbon, which is chosen among Acetylene black, superP, superP-Li, Ketjen black 1, Ketjen black 2, Graphite, KS-6, splintered glassy carbon, and splintered spherical carbon. This method reveals the correlation between the electrochemical stability of a carbon and its physical and structural properties. This helps researchers choose the right carbon component for a Li-ion cathode if they want the battery to be robust, especially at near full state of charge.
Nematicidal Effect and Histological Modifications Induced by Hydrolysable Tannin Extract on the Third-Stage Infective Larvae of Haemonchus contortus
Authors: Acevedo-Ramírez Perla María del Carmen , Hallal-Calleros Claudia , Flores-Pérez Iván , Alba-Hurtado Fernando , Mendoza-Garfias María Berenit , Barajas Rubén
Published: December 2020

Haemonchus contortus is the most frequent and most important nematode parasite in the ruminants production of tropical and subtropical regions. There are strains resistant to all families of available anthelmintics. Consequently, the conduction of research to find other resources that allow effective control of this parasitic disease, preferably focusing on green production, is necessary. The aim of this study was to evaluate the effect of hydrolysable tannin extract (HTE) on larvae 3 (L3) of H. contortus in vitro. L3 were exposed to different HTE concentrations and times. In addition, both light and scanning electron microscopy were used to explore physical damage on L3 subjected to HTE activity. After 72 h of incubation, the mean lethal concentration of HTE was 2 mg/mL; this concentration has been previously referred to as safe for consumption in cattle. Scanning electron microscopy revealed H. contortus L3 destruction, damage was evident by separation of the sheath mainly in the cervical and caudal regions of the larva and by rupture of the cuticle with larval evisceration. Our results suggest that hydrolysable tannin extract from chestnut could be considered as a green alternative for parasitic control in ruminants.
Elevated Dkk1 Mediates Downregulation of the Canonical Wnt Pathway and Lysosomal Loss in an iPSC Model of Neuronopathic Gaucher Disease
Authors: Srikanth Manasa P. , Feldman Ricardo A.
Published: December 2020

Gaucher Disease (GD), which is the most common lysosomal storage disorder, is caused by bi-allelic mutations in GBA1—a gene that encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The neuronopathic forms of GD (nGD) are characterized by severe neurological abnormalities that arise during gestation or early in infancy. Using GD-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs), we have previously reported that neuronal cells have neurodevelopmental defects associated with the downregulation of canonical Wnt signaling. In this study, we report that GD NPCs display elevated levels of Dkk1, which is a secreted Wnt antagonist that prevents receptor activation. Dkk1 upregulation in mutant NPCs resulted in an increased degradation of β-catenin, and there was a concomitant reduction in lysosomal numbers. Consistent with these results, incubation of the mutant NPCs with recombinant Wnt3a (rWnt3a) was able to outcompete the excess Dkk1, increasing β-catenin levels and rescuing lysosomal numbers. Furthermore, the incubation of WT NPCs with recombinant Dkk1 (rDkk1) phenocopied the mutant phenotype, recapitulating the decrease in β-catenin levels and lysosomal depletion seen in nGD NPCs. This study provides evidence that downregulation of the Wnt/β-catenin pathway in nGD neuronal cells involves the upregulation of Dkk1. As Dkk1 is an extracellular Wnt antagonist, our results suggest that the deleterious effects of Wnt/β-catenin downregulation in nGD may be ameliorated by the prevention of Dkk1 binding to the Wnt co-receptor LRP6, pointing to Dkk1 as a potential therapeutic target for GBA1-associated neurodegeneration.
Smoking Genes: A Case–Control Study of Dopamine Transporter Gene (SLC6A3) and Dopamine Receptor Genes (DRD1, DRD2 and DRD3) Polymorphisms and Smoking Behaviour in a Malay Male Cohort
Authors: Ruzilawati Abu Bakar , Islam Md Asiful , Muhamed Siti Khariem Sophia , Ahmad Imran
Published: December 2020

Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case–control study was to evaluate polymorphisms in the dopamine transporter gene (SLC6A3 (rs27072)) and the dopamine receptor genes (DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) and their contribution to smoking behaviour in a Malay male population. We identified 476 participants over the age of 18 years comprising 238 smokers and 238 non-smokers. Information such as age, height, weight, body mass index, systolic and diastolic blood pressures, marital status, and smoking status of close family members were taken. For the genetic study, we genotyped four genes (SLC6A3 (rs27072), DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) using the polymerase chain reaction–restriction fragment length polymorphism method and further confirmed our findings with sequencing. Dopamine receptor genes (DRD1, DRD2 and DRD3) were found to be associated with smoking behaviour in a Malay male population. The dopamine transporter gene (SLC6A3) did not show this association. Significant differences were observed between smokers’ and non-smokers’ age, systolic blood pressure, marital status and family members who smoke. Smoking behaviour is significantly influenced by genetic variations of DRD1, DRD2 and DRD3 in a Malay male population.
Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites
Authors: Hsu Chien-Ning , Hou Chih-Yao , Chang-Chien Guo-Ping , Lin Sufan , Yang Hung-Wei , Tain You-Lin
Published: December 2020

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.
Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding
Authors: Scafuri Bernardina , Bontempo Paola , Altucci Lucia , De Masi Luigi , Facchiano Angelo
Published: December 2020

Histone modifications through acetylation are fundamental for remodelling chromatin and consequently activating gene expression. The imbalance between acetylation and deacetylation activity causes transcriptional dysregulation associated with several disorders. Flavones, small molecules of plant origin, are known to interfere with class I histone deacetylase (HDAC) enzymes and to enhance acetylation, restoring cell homeostasis. To investigate the possible physical interactions of flavones on human HDAC1 and 2, we carried out in silico molecular docking simulations. Our data have revealed how flavone, and other two flavones previously investigated, i.e., apigenin and luteolin, can interact as ligands with HDAC1 and 2 at the active site binding pocket. Regulation of HDAC activity by dietary flavones could have important implications in developing epigenetic therapy to regulate the cell gene expression.
Second Primary Malignancy after Acute Promyelocytic Leukemia: A Population-Based Study
Authors: Lenzi Luana , Lee-Jones Lisa , Mostofa Maruf A. , de Andrade Diancarlos P. , Ribeiro Raul C. , Figueiredo Bonald C.
Published: December 2020

Acute promyelocytic leukemia (APL), is now highly curable with treatment approaches that include all-trans retinoic acid (ATRA). The high incidence of APL in the Hispanics suggests an association with genetic variants in this population. Information on second primary malignancies (SPMs) in patients with APL is limited. The Surveillance, Epidemiology, and End Results (SEER) database was used to interrogate whether the rate of SPMs in patients with APL was associated with ethnicity and/or ATRA treatment. Between 2000 and 2016, 116 cases of SPM were diagnosed among 4019 patients with APL. The mean age at diagnosis of primary APL was 53.9 years (±15.7 years), and the mean age at diagnosis of SPMs was 59.0 years (±14.5 years). Comparisons with 3774 APL survivors who did not develop SPMs revealed that age ≥40 years at diagnosis of APL (p < 0.001) and non-Hispanic white ethnicity (p = 0.025) were associated with SPMs in APL survivors. Salivary gland, liver, and soft tissue malignancies were significantly more common in patients with primary APL than in individuals with non-APL malignancies. A risk analysis comparing patients who had APL with patients who had non-APL AML suggests that SPMs after APL is associated with ATRA treatment. Therefore, patient follow-up after APL should focus on early diagnosis of SPMs.
Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer
Authors: Papaccio Federica , Roselló Susana , Huerta Marisol , Gambardella Valentina , Tarazona Noelia , Fleitas Tania , Roda Desamparados , Cervantes Andres
Published: December 2020

Most clinical practice guidelines recommend a selective approach for rectal cancer after clinical staging. In low-risk patients, upfront surgery may be an appropriate option. However, in patients with MRI-defined high-risk features such as extramural vascular invasion, multiple nodal involvement or T4 and/or tumors close to or invading the mesorectal fascia, a more intensive preoperative approach is recommended, which may include neoadjuvant or preoperative chemotherapy. The potential benefits include better compliance than postoperative chemotherapy, a higher pathological complete remission rate, which facilitates a non-surgical approach, and earlier treatment of micrometastatic disease with improved disease-free survival compared to standard preoperative chemoradiation or short-course radiation. Two recently reported phase III randomized trials, RAPIDO and PRODIGE 23, show that adding neoadjuvant chemotherapy to either standard short-course radiation or standard long-course chemoradiation in locally advanced rectal cancer patients reduces the risk of metastasis and significantly prolongs disease-related treatment failure and disease-free survival. This review discusses these potentially practice-changing trials and how they may affect our current understanding of treating locally advanced rectal cancers.
Long-Term Outcomes of Induction Chemotherapy Followed by Chemo-Radiotherapy as Intensive Neoadjuvant Protocol in Patients with Esophageal Cancer
Authors: Simoni Nicola , Pavarana Michele , Micera Renato , Weindelmayer Jacopo , Mengardo Valentina , Rossi Gabriella , Cenzi Daniela , Tomezzoli Anna , Del Bianco Paola , Giacopuzzi Simone , De Manzoni Giovanni , Mazzarotto Renzo
Published: December 2020

Background: A phase II intensive neoadjuvant chemo-radiotherapy (nCRT) protocol for esophageal cancer (EC) was previously tested at our Center with promising results. We here present an observational study to evaluate the efficacy of the protocol also in “real life” patients. Methods: We retrospectively reviewed 122 ECs (45.1% squamous cell (SCC) and 54.9% adenocarcinoma (ADC)) treated with induction docetaxel, cisplatin, and 5-fluorouracil (TCF), followed by concomitant TCF and radiotherapy (50–50.4 Gy/25–28 fractions), between 2008 and 2017. Primary endpoints were overall survival (OS), event-free survival (EFS) and pathological complete response (pCR). Results: With a median follow-up of 62.1 months (95% CI 50–67.6 months), 5-year OS and EFS rates were 54.8% (95% CI 44.7–63.9) and 42.7% (95% CI 33.1–51.9), respectively. A pCR was observed in 71.1% of SCC and 37.1% of ADC patients (p = 0.001). At multivariate analysis, ypN+ was a significant prognostic factor for OS (Hazard Ratios (HR) 4.39 [95% CI 2.36–8.18]; p < 0.0001), while pCR was a strong predictor of EFS (HR 0.38 [95% CI 0.22–0.67]; p < 0.0001). Conclusions: The nCRT protocol achieved considerable long-term survival and pCR rates also in “real life” patients. Further research is necessary to evaluate this protocol in a watch-and-wait approach.
Update on the Management of Breast Cancer during Pregnancy
Authors: Poggio Francesca , Tagliamento Marco , Pirrone Chiara , Soldato Davide , Conte Benedetta , Molinelli Chiara , Cosso Maurizio , Fregatti Piero , Del Mastro Lucia , Lambertini Matteo
Published: December 2020

The diagnosis of breast cancer during pregnancy represents a challenging situation for the patient, her caregivers and physicians. Pregnancy adds complexity to oncological treatment planning, as many therapies can be potentially dangerous to the fetus. Therefore, a multidisciplinary approach is needed to offer a proper care for obtaining the best possible outcomes for the mother and the future child. Breast surgery is feasible throughout the pregnancy while radiotherapy should be postponed after delivery. Administration of chemotherapy is considered safe and can be given during the second and third trimesters, while it is contraindicated in the first trimester due to the high risk of fetal malformations. Endocrine therapy and targeted agents are not recommended during the whole pregnancy period; however, limited data are available on the use of the majority of new anticancer drugs in this context. The aim of the current review is to provide an update on the current state of art about the management of women diagnosed with breast cancer during pregnancy.
Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments
Authors: Jünger Stephanie T. , Schödel Petra , Ruess Daniel , Ruge Maximilian , Brand Julia-Sarita , Wittersheim Maike , Eich Marie-Lisa , Schmidt Nils-Ole , Goldbrunner Roland , Grau Stefan , Proescholdt Martin
Published: December 2020

Objective: We attempted to analyze whether early presentation with brain metastases (BM) represents a poor prognostic factor in patients with non-small cell lung cancer (NSCLC), which should guide the treatment team towards less intensified therapy. Patients and methods: In a retrospective bi-centric analysis, we identified patients receiving surgical treatment for NSCLC BM. We collected demographic-, tumor-, and treatment-related parameters and analyzed their influence on further survival. Results: We included 377 patients. Development of BM was precocious in 99 (26.3%), synchronous in 152 (40.3%), and metachronous in 126 (33.4%) patients. The groups were comparable in terms of age (p = 0.76) and number of metastases (p = 0.11), and histology (p = 0.1); however, mutational status significantly differed (p = 0.002). The precocious group showed the worst clinical status as assessed by Karnofsky performance score (KPS) upon presentation (p < 0.0001). Resection followed by postoperative radiotherapy was the predominant treatment modality for precocious BM, while in syn- and metachronous BM surgical and radio-surgical treatment was balanced. Overall survival (OS) did not differ between the groups (p = 0.76). A good postoperative clinical status (KPS ≥ 70) and the application of any kind of adjuvant systemic therapy were independent predictive factors for OS. Conclusion: Early BM presentation was not associated with worse OS in NSCLC BM patients.
CNS Invasion in Meningioma—How the Intraoperative Assessment Can Improve the Prognostic Evaluation of Tumor Recurrence
Authors: Behling Felix , Fodi Christina , Gepfner-Tuma Irina , Machetanz Kathrin , Renovanz Mirjam , Skardelly Marco , Bornemann Antje , Honegger Jürgen , Tabatabai Ghazaleh , Tatagiba Marcos , Schittenhelm Jens
Published: December 2020

The detection of the infiltrative growth of meningiomas into CNS tissue has been integrated into the WHO classification as a stand-alone marker for atypical meningioma. However, its prognostic impact has been questioned. Infiltrative growth can also be detected intraoperatively. The prognostic impact of the intraoperative detection of the central nervous system tissue invasion of meningiomas was analyzed and compared to the histopathological assessment. The clinical data of 1517 cases with follow-up data regarding radiographic recurrence was collected. Histopathology and operative reports were reviewed and invasive growth was seen during resection in 23.7% (n = 345) while histopathology detected it in 4.8% (n = 73). The histopathological and intraoperative assessments were compatible in 63%. The prognostic impact of histopathological and intraoperative assessment was significant in the univariate but not in the multivariate analysis. Both methods of assessment combined reached statistical significance in the multivariate analysis (p = 0.0409). A score including all independent prognostic factors divided the cohort into three prognostic subgroups with a risk of recurrence of 33.8, 64.7 and 88.5%, respectively. The intraoperative detection of the infiltrative growth of primary meningiomas into the central nervous system tissue can complement the histopathological assessment of CNS invasion. The combined assessment is an independent prognostic factor regarding tumor recurrence and allows a risk-adapted tumor stratification.
Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma
Authors: Chen Hsiao-Ling , Tu Yu-Kang , Chang Hsiu-Mei , Lee Tai-Huang , Wu Kuan-Li , Tsai Yu-Chen , Lee Mei-Hsuan , Yang Chih-Jen , Hung Jen-Yu , Chong Inn-Wen
Published: December 2020

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.
Epigenetic Role of Histone Lysine Methyltransferase and Demethylase on the Expression of Transcription Factors Associated with the Epithelial-to-Mesenchymal Transition of Lung Adenocarcinoma Metastasis to the Brain
Authors: Lee Young Min , Kim Seok Hyun , Kim Minseok S. , Kim Dae Cheol , Lee Eun Hee , Lee Ju Suk , Lee Sung-Hun , Kim Young Zoon
Published: December 2020

Purpose: The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain. Methods: Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. Results: The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 linear = −2.723) decreased in reverse proportion. Conclusions: The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.
Circulating Methylated DNA to Monitor the Dynamics of RAS Mutation Clearance in Plasma from Metastatic Colorectal Cancer Patients
Authors: Nicolazzo Chiara , Barault Ludovic , Caponnetto Salvatore , Macagno Marco , De Renzi Gianluigi , Gradilone Angela , Belardinilli Francesca , Cortesi Enrico , Di Nicolantonio Federica , Gazzaniga Paola
Published: December 2020

The clearance of RAS mutations in plasma circulating tumor DNA (ctDNA) from originally RAS-mutant metastatic colorectal cancer (mCRC) has been recently demonstrated. Clinical trials investigating whether RAS mutant mCRC who “convert” to wild-type in plasma might benefit from EGFR blockade are ongoing. Detection of tumor-specific DNA methylation alterations in ctDNA has been suggested as a specific tool to confirm the tumoral origin of cell-free DNA. We monitored RAS clearance in plasma from patients with RAS-mutant mCRC at baseline (pre-treatment) (T0); after 4 months of first-line therapy (T1); at the time of first (T2) and second (T3) progression. A five-gene methylation panel was used to confirm the presence of ctDNA in samples in which RAS mutation clearance was detected. At T1, ctDNA analysis revealed wild-type RAS status in 83% of samples, all not methylated, suggesting at this time point the lack of ctDNA shedding. At T2, ctDNA analysis revealed wild-type RAS status in 83% of samples, of which 62.5% were found methylated. At T3, 50% of wild-type RAS samples were found methylated. Non-methylated samples were found in patients with lung or brain metastases. This five-gene methylation test might be useful to confirm the presence of ctDNA in RAS wild-type plasma samples.
Clinical and Pathological Characteristics of Metastatic Renal Cell Carcinoma Patients Needing a Second-Line Therapy: A Systematic Review
Authors: Longo Nicola , Capece Marco , Celentano Giuseppe , La Rocca Roberto , Califano Gianluigi , Collà Ruvolo Claudia , Buonerba Carlo , Esposito Fabio , Napolitano Luigi , Mangiapia Francesco , Fusco Ferdinando , Mirone Vincenzo , Creta Massimiliano
Published: December 2020

A high percentage of patients with metastatic renal cell carcinoma (mRCC) require a second-line option. We aimed to summarize available evidences about the clinicopathological profile of mRCC patients who receive a second-line therapy. A systematic review was performed in August 2020. We included papers that met the following criteria: original research; English language; human studies; enrolling mRCC patients entering a second-line therapy. Twenty-nine studies enrolling 7650 patients (73.5% male, mean age: 55 to 70 years) were included. Clear cell histology was reported in 74.4% to 100% of cases. Tyrosine kinase inhibitors, immunotherapy, bevacizumab, mTOR inhibitors, and chemotherapy were adopted as first line option in 68.5%, 29.2%, 2.9%, 0.6%, and 0.2% of patients, respectively. Discontinuation of first-line therapy was due to progression and toxicity in 18.4% to 100% and in 17% to 48.8% of patients, respectively. Eastern Cooperative Oncology Group performance status score was 0 or 1 in most cases. Most prevalent prognostic categories according to the International Metastatic RCC Database Consortium and Memorial Sloan–Kettering Cancer Centre score were intermediate and good. About 77.8% of patients harboured ≥2 metastatic sites. In conclusion, patients who enter a second-line therapy are heterogeneous in terms of a clinical-pathological profile. Tailoring of second-line treatment strategies is strongly advocated.
Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo
Authors: Qian Yanrong , Basu Reetobrata , Mathes Samuel C. , Arnett Nathan A. , Duran-Ortiz Silvana , Funk Kevin R. , Brittain Alison L. , Kulkarni Prateek , Terry Joseph C. , Davis Emily , Singerman Jordyn T. , Henry Brooke E. , List Edward O. , Berryman Darlene E. , Kopchick John J.
Published: December 2020

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.
Clinical Feasibility of a High-Resolution Thermal Monitoring Sheet for Superficial Hyperthermia in Breast Cancer Patients
Authors: Bakker Akke , Zweije Remko , Kok Henny Petra , Kolff Merel Willemijn , van den Bongard H. J. G. Desiree , Schmidt Manfred , van Tienhoven Geertjan , Crezee Hans
Published: December 2020

Background: Accurate monitoring of skin surface temperatures is necessary to ensure treatment quality during superficial hyperthermia. A high-resolution thermal monitoring sheet (TMS) was developed to monitor the skin surface temperature distribution. The influence of the TMS on applicator performance was investigated, feasibility and ability to reliably monitor the temperature distribution were evaluated in a clinical study. Methods: Phantom experiments were performed to determine the influence of the TMS on power deposition patterns, applicator efficiency, and heat transfer of the water bolus for 434 and 915 MHz applicators. Clinical feasibility was evaluated in 10 women with locoregional recurrent breast cancer. Skin surface temperatures during consecutive treatments were monitored alternatingly with either standard Amsterdam UMC thermometry or TMS. Treatments were compared using (generalized) linear mixed models. Results: The TMS did not significantly affect power deposition patterns and applicator efficiency (1–2%), the reduced heat transfer of the water boluses (51–56%) could be compensated by adjusting the water bolus flow. Skin surface temperatures were monitored reliably, and no alteration of thermal toxicity was observed compared to standard Amsterdam UMC thermometry. Conclusion: Clinical application of the TMS is feasible. Power deposition patterns and applicator efficiency were not affected. Surface temperatures were monitored reliably.
Liquid Biopsy in Small Cell Lung Cancer—A Route to Improved Clinical Care?
Authors: Church Matt , Carter Louise , Blackhall Fiona
Published: December 2020

Small cell lung cancer (SCLC) has a particularly poor prognosis despite the high initial response to first-line systemic therapy, and there is a well-recognised lack of meaningful treatments beyond the second line. A number of reasons have been put forward to explain this, including a lack of common, easily-druggable genetic mutations in SCLC and rarity of high-quality tissue samples due to late presentation. Liquid biopsies, including circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) are increasingly used as surrogates for tumour tissue and have the advantage of being easily obtained serially to inform on the biology of disease progression and acquired chemoresistance, and may provide a pathway to improve care in this notoriously refractory disease. Here we discuss the current evidence behind these liquid biopsy methods in SCLC, and how they could be employed in future clinical care.
Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors
Authors: Lito Silvin , Sidibe Adama , Ilmjarv Sten , Burda Patricie , Baumgartner Matthias , Wehrle-Haller Bernhard , Krause Karl-Heinz , Marteyn Antoine
Published: December 2020

Background: Mucopolysaccharidosis type I-Hurler (MPS1-H) is a severe genetic lysosomal storage disorder due to loss-of-function mutations in the IDUA gene. The subsequent complete deficiency of alpha l-iduronidase enzyme is directly responsible of a progressive accumulation of glycosaminoglycans (GAG) in lysosomes which affects the functions of many tissues. Consequently, MPS1 is characterized by systemic symptoms (multiorgan dysfunction) including respiratory and cardiac dysfunctions, skeletal abnormalities and early fatal neurodegeneration. Methods: To understand mechanisms underlying MPS1 neuropathology, we generated induced pluripotent stem cells (iPSC) from a MPS1-H patient with loss-of-function mutations in both IDUA alleles. To avoid variability due to different genetic background of iPSC, we established an isogenic control iPSC line by rescuing IDUA expression by a lentivectoral approach. Results: Marked differences between MPS1-H and IDUA-corrected isogenic controls were observed upon neural differentiation. A scratch assay revealed a strong migration defect of MPS1-H cells. Also, there was a massive impact of IDUA deficiency on gene expression (340 genes with an FDR < 0.05). Conclusions: Our results demonstrate a hitherto unknown connection between lysosomal degradation, gene expression and neural motility, which might account at least in part for the phenotype of MPS1-H patients.
Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4–Integrin Deficient NOD Mouse
Authors: Oulghazi Salim , Wegner Sarah K. , Spohn Gabriele , Müller Nina , Harenkamp Sabine , Stenzinger Albrecht , Papayannopoulou Thalia , Bonig Halvard
Published: December 2020

Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D.
Deregulation of Lipid Homeostasis: A Fa(c)t in the Development of Metabolic Diseases
Authors: Cisa-Wieczorek Sabina , Hernández-Alvarez María Isabel
Published: December 2020

Lipids are important molecules for human health. The quantity and quality of fats consumed in the diet have important effects on the modulation of both the natural biosynthesis and degradation of lipids. There is an important number of lipid-failed associated metabolic diseases and an increasing number of studies suggesting that certain types of lipids might be beneficial to the treatment of many metabolic diseases. The aim of the present work is to expose an overview of de novo biosynthesis, storage, and degradation of lipids in mammalian cells, as well as, to review the published data describing the beneficial effects of these processes and the potential of some dietary lipids to improve metabolic diseases.
Triage for Malnutrition Risk among Pediatric and Adolescent Outpatients with Cystic Fibrosis, Using a Disease-Specific Tool
Authors: Poulimeneas Dimitrios , Grammatikopoulou Maria G. , Petrocheilou Argyri , Kaditis Athanasios G. , Vassilakou Tonia
Published: December 2020

Malnutrition prevails in considerable proportions of children with Cystic Fibrosis (CF), and is often associated with adverse outcomes. For this, routine screening for malnutrition is pivotal. In the present cross-sectional study, we aimed to assess the risk for malnutrition in pediatric outpatients with CF. A total of 76 outpatients (44 girls, 11.9 ± 3.9 years old, 39.5% adolescents) were recruited and anthropometric, clinical, dietary and respiratory measures were collected. All outpatients were screened for malnutrition risk with a validated disease-specific instrument. Most children exhibited a low risk for malnutrition (78.9%), whereas none of the participants were characterized as having a high malnutrition risk. In the total sample, malnutrition risk was positively associated with age (r = 0.369, p = 0.001), and inversely related to the body mass index (r = −0.684, p < 0.001), height z-score (r = −0.264, p = 0.021), and forced expiratory volume (FEV1%, r = −0.616, p < 0.001). Those classified as having a low malnutrition risk were younger (p = 0.004), heavier (p < 0.001) and taller (p = 0.009) than their counterparts with a moderate risk. On the other hand, patients in the moderate risk group were more likely pubertal (p = 0.034), with a reduced mid-upper arm fat area (p = 0.011), and worse pulmonary function (p < 0.001). Interestingly, none of the children attaining ideal body weight were classified as having a moderate malnutrition. risk, whereas 37.5% of the patients allocated at the moderate risk group exhibited physiological lung function. In this cohort of outpatients with CF that were predominantly well-nourished and attained physiological lung function, malnutrition risk was identified only in small proportions of the sample. Our data support that patients that are older, pubertal, or have diminished fat mass are at greater risk for malnutrition.
Glutamate–Serine–Glycine Index: A Novel Potential Biomarker in Pediatric Non-Alcoholic Fatty Liver Disease
Authors: Leonetti Simone , Herzog Raimund I. , Caprio Sonia , Santoro Nicola , Tricò Domenico
Published: December 2020

Preliminary evidence suggests that the glutamate–serine–glycine (GSG) index, which combines three amino acids involved in glutathione synthesis, may be used as a potential biomarker of non-alcoholic fatty liver disease (NAFLD). We investigated whether the GSG index is associated with NAFLD in youth, independent of other risk factors. Intrahepatic fat content (HFF%) and abdominal fat distribution were measured by magnetic resonance imaging (MRI) in a multiethnic cohort of obese adolescents, including Caucasians, African Americans, and Hispanics. NAFLD was defined as HFF% ≥ 5.5%. Plasma amino acids were measured by mass spectrometry. The GSG index was calculated as glutamate/(serine + glycine). The GSG index was higher in NAFLD patients (p = 0.03) and positively correlated with HFF% (r = 0.26, p = 0.02), alanine aminotransferase (r = 0.39, p = 0.0006), and aspartate aminotransferase (r = 0.26, p = 0.03). Adolescents with a high GSG index had a twofold higher prevalence of NAFLD than those with a low GSG index, despite similar adiposity, abdominal fat distribution, and liver insulin resistance. NAFLD prevalence remained significantly different between groups after adjustment for age, sex, race/ethnicity, and body mass index (OR 3.07, 95% confidence interval 1.09–8.61, p = 0.03). This study demonstrates the ability of the GSG index to detect NAFLD in at-risk pediatric populations with different genetically determined susceptibilities to intrahepatic fat accumulation, independent of traditional risk factors.
Impact of the Deposition Temperature on the Structural and Electrical Properties of InN Films Grown on Self-Standing Diamond Substrates by Low-Temperature ECR-MOCVD
Authors: Wang Shuaijie , Qin Fuwen , Bai Yizhen , Zhang Dong , Zhang Jingdan
Published: December 2020

The progress of InN semiconductors is still in its infancy compared to GaN-based devices and materials. Herein, InN thin films were grown on self-standing diamond substrates using low-temperature electron cyclotron resonance plasma-enhanced metal organic chemical vapor deposition (ECR-PEMOCVD) with inert N2 used as a nitrogen source. The thermal conductivity of diamond substrates makes the as-grown InN films especially attractive for various optoelectronic applications. Structural and electrical properties which depend on deposition temperature were systematically investigated by reflection high-energy electron diffraction (RHEED), X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), and Hall effect measurement. The results indicated that the quality and properties of InN films were significantly influenced by the deposition temperature, and InN films with highly c-axis preferential orientation and surface morphology were obtained at optimized temperatures of 400 °C. Moreover, their electrical properties with deposition temperature were studied, and their tendency was correlated with the dependence on micro- structure and morphology.