bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermally and Dynamically Driven Atmospheric Circulations over Heterogeneous Atmospheric Boundary Layer: Support for Safety Protocols and Environment Management at Nuclear Central Areas
Authors: de Freitas Ramos Jacinto Larissa , Pimentel Luiz Claudio Gomes , de Oliveira Júnior José Francisco , Dragaud Ian Cunha D’Amato Viana , Silva Corbiniano , de Farias William Cossich Marcial , Marton Edilson , de Freitas Assad Luiz Paulo , Perez Guerrero Jesus Salvador , Heilbron Filho Paulo Fernando Lavalle , Landau Luiz
Published: October 2021

Ilha Grande Bay is located in Angra dos Reis, Rio de Janeiro State, Brazil. The area is characterized by different land cover, complex topography and proximity to the Atlantic Ocean. These aspects make it susceptible to thermally and dynamically induced atmospheric circulations such as those associated with valley/mountain and land/sea breeze systems, among others. The Almirante Álvaro Alberto Nuclear Complex (CNAAA) is located in this region, with a total of two nuclear power plants (NPPs) in operation in the Brazilian territory, Angra I and Angra II. Therefore, knowledge of local atmospheric circulation has become a matter of national and international security. Considering the importance of the meteorological security tool as a support for licensing, installation, routine operation and nuclear accident mitigation, the main aim of this study is the development of combined strategies of environmental statistical modeling in the analysis of thermally and dynamically driven atmospheric circulations over mountainous and coastal environments. We identified and hierarchized the influence of the thermally and mechanically driven forcing on the wind regime and stability conditions in the coastal atmospheric boundary layer over the complex topography region. A meteorological network of ground-based instruments was used along with physiographic information for the observational characterization of the atmospheric patterns in the spatial and time–frequency domain. The predominant wind directions and intensity are attributed to the combined action of multiscale weather systems, notably, the valley/mountain and continent/ocean breeze circulations, the forced channeling due to valley axis orientation, the influence of the synoptic scale systems and atmospheric thermal tide. The observational investigation of the combined influence of terrain effects and meteorological systems aimed to understand the local atmospheric circulation serves as support for safety protocols of the NPPs, contemplating operation and environmental management. The importance of the study for the adequacy and skill evaluation of computational modeling systems for atmospheric dispersion of pollutants such as radionuclide and conventional contaminants can be also highlighted, in order that such systems are used as tools for environmental planning and managing nuclear operations, particularly those located in regions over mountainous and coastal environments with a heterogeneous atmospheric boundary layer.
Investigation of Air Pollutants Related to the Vehicular Exhaust Emissions in the Kathmandu Valley, Nepal
Authors: Fukusaki Yukiko , Umehara Masataka , Kousa Yuka , Inomata Yoshimi , Nakai Satoshi
Published: October 2021

The Kathmandu Valley, which is surrounded by high hills and mountains, has been plagued by air pollution, especially in winter. We measured the levels of volatile organic compounds, nitrogen dioxide, nitrogen oxides, sulfur dioxide, ammonia, ozone, PM2.5, and carbon monoxide in the Kathmandu Valley during the winter to investigate the impact of vehicular emissions and the contribution of gaseous air pollutants to secondary pollutants. The most common gaseous pollutants were discovered to be gasoline components, which were emitted more frequently by engine combustion than gasoline evaporation. Considering the ethylene to acetylene ratio, it was discovered that most vehicles lacked a well-maintained catalyst. Compared to previous studies, it was considered that an increase in the number of gasoline vehicles offset the effect of the measures and exceeded it, increasing the level of air pollutants. Aromatics and alkenes accounted for 66–79% and 43–59% of total ozone formation potential in Koteshwor and Sanepa, respectively. In terms of individual components, it was determined that ethylene, propylene, toluene, and m-xylene all significantly contributed to photochemical ozone production. As those components correlated well with isopentane, which is abundant in gasoline vehicle exhaust, it was determined that gasoline vehicles are the primary source of those components. It was indicated that strategies for regulating gasoline vehicle exhaust emissions are critical for controlling the photochemical smog in the Kathmandu Valley.
Assessment of 5-Aminolevulinic Acid-Mediated Photodynamic Therapy on Bone Metastases: An in Vitro Study
Authors: Sachsenmaier Saskia Magdalen , Traub Frank , Cykowska Anna , Riester Rosa , Wülker Nikolaus , Walter Christian , Danalache Marina
Published: October 2021

Bone is a frequent site of metastases, being typically associated with a short-term prognosis in affected patients. Photodynamic therapy (PDT) emerges as a promising alternative treatment for controlling malignant disease that can directly target interstitial metastatic lesions. The aim of this study was to assess the effect induced by PDT treatment on both primary (giant cell bone tumor) and human bone metastatic cancer cell lines (derived from a primary invasive ductal breast carcinoma and renal carcinoma). After 24 h post light delivery (blue light-wavelength 436 nm) with 5-aminolevulinic acid, the effect on cellular migration, viability, apoptosis, and senescence were assessed. Our results showed that bone metastasis derived from breast cancer reacted with an inhibition of cell migration coupled with reduced viability and signs of apoptosis such as nuclei fragmentation following PDT exposure. A limited effect in terms of cellular viability inhibition was observed for the cells of giant cell bone tumors. In contrast, bone metastasis derived from renal carcinoma followed a different fate—cells were characterized by senescent features, without a notable effect on cell migration or viability. Collectively, our study illustrates that PDT could act as a successful therapy concept for local tumor control in some entities of bone metastases.
First Crystal Structure of Bacterial Oligopeptidase B in an Intermediate State: The Roles of the Hinge Region Modification and Spermine
Authors: Petrenko Dmitry E. , Timofeev Vladimir I. , Britikov Vladimir V. , Britikova Elena V. , Kleymenov Sergey Y. , Vlaskina Anna V. , Kuranova Inna P. , Mikhailova Anna G. , Rakitina Tatiana V.
Published: October 2021

Oligopeptidase B (OpB) is a two-domain, trypsin-like serine peptidase belonging to the S9 prolyloligopeptidase (POP) family. Two domains are linked by a hinge region that participates in the transition of the enzyme between two major states—closed and open—in which domains and residues of the catalytic triad are located close to each other and separated, respectively. In this study, we described, for the first time, a structure of OpB from bacteria obtained for an enzyme from Serratia proteomaculans with a modified hinge region (PSPmod). PSPmod was crystallized in a conformation characterized by a disruption of the catalytic triad together with a domain arrangement intermediate between open and closed states found in crystals of ligand-free and inhibitor-bound POP, respectively. Two additional derivatives of PSPmod were crystallized in the same conformation. Neither wild-type PSP nor its corresponding mutated variants were susceptible to crystallization, indicating that the hinge region modification was key in the crystallization process. The second key factor was suggested to be polyamine spermine since all crystals were grown in its presence. The influences of the hinge region modification and spermine on the conformational state of PSP in solution were evaluated by small-angle X-ray scattering. SAXS showed that, in solution, wild-type PSP adopted the open state, spermine caused the conformational transition to the intermediate state, and spermine-free PSPmod contained molecules in the open and intermediate conformations in dynamic equilibrium.
Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells
Authors: New-Aaron Moses , Thomes Paul G. , Ganesan Murali , Dagur Raghubendra Singh , Donohue Terrence M. , Kusum Kharbanda K. , Poluektova Larisa Y. , Osna Natalia A.
Published: October 2021

Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored “second hit” for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also known as RLW) cells to an acetaldehyde-generating system (AGS) for 24 h. We then infected (or not) the cells with HIV-1ADA then exposed them again to AGS for another 48 h. Lysosome damage was assessed by galectin 3/LAMP1 co-localization and cathepsin leakage. Expression of lysosome biogenesis–transcription factor, TFEB, was measured by its protein levels and by in situ immunofluorescence. Exposure of cells to both AGS + HIV caused the greatest amount of lysosome leakage and its impaired lysosomal biogenesis, leading to intrinsic apoptosis. Furthermore, the movement of TFEB from cytosol to the nucleus via microtubules was impaired by AGS exposure. The latter impairment appeared to occur by acetylation of α-tubulin. Moreover, ZKSCAN3, a repressor of lysosome gene activation by TFEB, was amplified by AGS. Both these changes contributed to AGS-elicited disruption of lysosome biogenesis. Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby exacerbating HIV-induced hepatotoxicity.
LRP-1 Matricellular Receptor Involvement in Triple Negative Breast Cancer Tumor Angiogenesis
Authors: Campion Océane , Thevenard Devy Jessica , Billottet Clotilde , Schneider Christophe , Etique Nicolas , Dupuy Jean-William , Raymond Anne-Aurélie , Boulagnon Rombi Camille , Meunier Marie , Djermoune El-Hadi , Lelièvre Elodie , Wahart Amandine , Bour Camille , Hachet Cathy , Cairo Stefano , Bikfalvi Andréas , Dedieu Stéphane , Devy Jérôme
Published: October 2021

Background: LRP-1 is a multifunctional scavenger receptor belonging to the LDLR family. Due to its capacity to control pericellular levels of various growth factors and proteases, LRP-1 plays a crucial role in membrane proteome dynamics, which appears decisive for tumor progression. Methods: LRP-1 involvement in a TNBC model was assessed using an RNA interference strategy in MDA-MB-231 cells. In vivo, tumorigenic and angiogenic effects of LRP-1-repressed cells were evaluated using an orthotopic xenograft model and two angiogenic assays (Matrigel® plugs, CAM). DCE-MRI, FMT, and IHC were used to complete a tumor longitudinal follow-up and obtain morphological and functional vascular information. In vitro, HUVECs’ angiogenic potential was evaluated using a tumor secretome, subjected to a proteomic analysis to highlight LRP-1-dependant signaling pathways. Results: LRP-1 repression in MDA-MB-231 tumors led to a 60% growth delay because of, inter alia, morphological and functional vascular differences, confirmed by angiogenic models. In vitro, the LRP-1-repressed cells secretome restrained HUVECs’ angiogenic capabilities. A proteomics analysis revealed that LRP-1 supports tumor growth and angiogenesis by regulating TGF-β signaling and plasminogen/plasmin system. Conclusions: LRP-1, by its wide spectrum of interactions, emerges as an important matricellular player in the control of cancer-signaling events such as angiogenesis, by supporting tumor vascular morphology and functionality.
Circulating Exosomal miRNAs as Biomarkers in Epithelial Ovarian Cancer
Authors: Shiao Meng-Shin , Chang Jia-Ming , Lertkhachonsuk Arb-Aroon , Rermluk Naparat , Jinawath Natini
Published: October 2021

Failure to detect early-stage epithelial ovarian cancer (EOC) is a major contributing factor to its low survival rate. Increasing evidence suggests that different subtypes of EOC may behave as distinct diseases due to their different cells of origins, histology and treatment responses. Therefore, the identification of EOC subtype-specific biomarkers that can early detect the disease should be clinically beneficial. Exosomes are extracellular vesicles secreted by different types of cells and carry biological molecules, which play important roles in cell-cell communication and regulation of various biological processes. Multiple studies have proposed that exosomal miRNAs present in the circulation are good biomarkers for non-invasive early detection of cancer. In this review, the potential use of exosomal miRNAs as early detection biomarkers for EOCs and their accuracy are discussed. We also review the differential expression of circulating exosomal miRNAs and cell-free miRNAs between different biofluid sources, i.e., plasma and serum, and touch on the issue of endogenous reference miRNA selection. Additionally, the current clinical trials using miRNAs for detecting EOCs are summarized. In conclusion, circulating exosomal miRNAs as the non-invasive biomarkers have a high potential for early detection of EOC and its subtypes, and are likely to be clinically important in the future.
Plant Alkaloids Inhibit Membrane Fusion Mediated by Calcium and Fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 Fusion Peptides
Authors: Shekunov Egor V. , Efimova Svetlana S. , Yudintceva Natalia M. , Muryleva Anna A. , Zarubaev Vladimir V. , Slita Alexander V. , Ostroumova Olga S.
Published: October 2021

To rationalize the antiviral actions of plant alkaloids, the ability of 20 compounds to inhibit calcium-mediated fusion of lipid vesicles composed of phosphatidylglycerol and cholesterol was investigated using the calcein release assay and dynamic light scattering. Piperine, tabersonine, hordenine, lupinine, quinine, and 3-isobutyl-1-methylxanthine demonstrated the most potent effects (inhibition index greater than 50%). The introduction of phosphatidylcholine into the phosphatidylglycerol/cholesterol mixture led to significant changes in quinine, hordenine, and 3-isobutyl-1-methylxanthine efficiency. Comparison of the fusion inhibitory ability of the tested alkaloids, and the results of the measurements of alkaloid-induced alterations in the physical properties of model membranes indicated a potent relationship between a decrease in the cooperativity of the phase transition of lipids and the ability of alkaloids to prevent calcium-mediated vesicle fusion. In order to use this knowledge to combat the novel coronavirus pandemic, the ability of the most effective compounds to suppress membrane fusion induced by fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 fusion peptides was studied using the calcein release assay and confocal fluorescence microscopy. Piperine was shown to inhibit vesicle fusion mediated by both coronavirus peptides. Moreover, piperine was shown to significantly reduce the titer of SARS-CoV2 progeny in vitro in Vero cells when used in non-toxic concentrations.
A New Light on Potential Therapeutic Targets for Colorectal Cancer Treatment
Authors: Tsai Wei-Lun , Wang Chih-Yang , Lee Yu-Cheng , Tang Wan-Chun , Anuraga Gangga , Ta Hoang Dang Khoa , Wu Yung-Fu , Lee Kuen-Haur
Published: October 2021

The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells.
Bis-thiobarbiturates as Promising Xanthine Oxidase Inhibitors: Synthesis and Biological Evaluation
Authors: Serrano João L. , Lopes Diana , Reis Melani J. A. , Boto Renato E. F. , Silvestre Samuel , Almeida Paulo
Published: October 2021

Xanthine oxidase (XO) is the enzyme responsible for the conversion of endogenous purines into uric acid. Therefore, this enzyme has been associated with pathological conditions caused by hyperuricemia, such as the disease commonly known as gout. Barbiturates and their congeners thiobarbiturates represent a class of heterocyclic drugs capable of influencing neurotransmission. However, in recent years a very large group of potential pharmaceutical and medicinal applications have been related to their structure. This great diversity of biological activities is directly linked to the enormous opportunities found for chemical change off the back of these findings. With this in mind, sixteen bis-thiobarbiturates were synthesized in moderate to excellent reactional yields, and their antioxidant, anti-proliferative, and XO inhibitory activity were evaluated. In general, all bis-thiobarbiturates present a good antioxidant performance and an excellent ability to inhibit XO at a concentration of 30 µM, eight of them are superior to those observed with the reference drug allopurinol (Allo), nevertheless they were not as effective as febuxostat. The most powerful bis-thiobarbiturate within this set showed in vitro IC50 of 1.79 μM, which was about ten-fold better than Allo inhibition, together with suitable low cytotoxicity. In silico molecular properties such as drug-likeness, pharmacokinetics, and toxicity of this promising barbiturate were also analyzed and herein discussed.
Alginate Bead Biosystem for the Determination of Lactate in Sweat Using Image Analysis
Authors: Garcia-Rey Sandra , Ojeda Edilberto , Gunatilake Udara Bimendra , Basabe-Desmonts Lourdes , Benito-Lopez Fernando
Published: October 2021

Lactate is present in sweat at high concentrations, being a metabolite of high interest in sport science and medicine. Therefore, the potential to determine lactate concentrations in physiological fluids, at the point of need with minimal invasiveness, is very valuable. In this work, the synthesis and performance of an alginate bead biosystem was investigated. Artificial sweat with different lactate concentrations was used as a proof of concept. The lactate detection was based on a colorimetric assay and an image analysis method using lactate oxidase, horseradish peroxidase and tetramethyl benzidine as the reaction mix. Lactate in artificial sweat was detected with a R² = 0.9907 in a linear range from 10 mM to 100 mM, with a limit of detection of 6.4 mM and a limit of quantification of 21.2 mM. Real sweat samples were used as a proof of concept to test the performance of the biosystem, obtaining a lactate concentration of 48 ± 3 mM. This novel sensing configuration, using alginate beads, gives a fast and reliable method for lactate sensing, which could be integrated into more complex analytical systems.
A New Approach to Assess Blinding for Transcranial Direct Current Stimulation Treatment in Patients with Fibromyalgia. A Randomized Clinical Trial
Authors: Arroyo-Fernández Rubén , Avendaño-Coy Juan , Velasco-Velasco Rafael , Palomo-Carrión Rocío , Bravo-Esteban Elisabeth , Ferri-Morales Asunción
Published: October 2021

Correct blinding is essential for preventing potential biases. The aim of this study was to assess the blinding of participants and a therapist following treatment with transcranial direct current stimulation in subjects with fibromyalgia using James’ and Bang’s blinding indexes. Eighty subjects were randomly allocated either active or sham stimulation groups in an intervention of five sessions lasting 20 min each. A questionnaire was delivered to both the therapist and patients after the last session to record their guess of which treatment had been applied. No differences between the groups were noted at baseline in terms of demographic or clinical data. James’ BI was 0.83 (CI 95%: 0.76–0.90) for the patients and 0.55 (CI 95%: 0.45–0.64) for the therapist. Bang’s BI for subjects was −0.08 (CI 95%: −0.24–0.09) and −0.8 (CI 95%: −0.26–0.1) for the active and sham transcranial direct current stimulation groups, respectively. Bang’s BI for the therapist was 0.21 (CI 95%: −0.02–0.43) and 0.13 (CI 95%: −0.09–0.35) for the active and sham transcranial direct current stimulation groups, respectively. Protocols of active and sham transcranial direct current stimulation applied in this study have shown satisfactory blinding of the therapist and subjects with fibromyalgia.
An Image-Based Steel Rebar Size Estimation and Counting Method Using a Convolutional Neural Network Combined with Homography
Authors: Shin Yoonsoo , Heo Sekojae , Han Sehee , Kim Junhee , Na Seunguk
Published: October 2021

Conventionally, the number of steel rebars at construction sites is manually counted by workers. However, this practice gives rise to several problems: it is slow, human-resource-intensive, time-consuming, error-prone, and not very accurate. Consequently, a new method of quickly and accurately counting steel rebars with a minimal number of workers needs to be developed to enhance work efficiency and reduce labor costs at construction sites. In this study, the authors developed an automated system to estimate the size and count the number of steel rebars in bale packing using computer vision techniques based on a convolutional neural network (CNN). A dataset containing 622 images of rebars with a total of 186,522 rebar cross sections and 409 poly tags was established for segmentation rebars and poly tags in images. The images were collected in a full HD resolution of 1920 × 1080 pixels and then center-cropped to 512 × 512 pixels. Moreover, data augmentation was carried out to create 4668 images for the training dataset. Based on the training dataset, YOLACT-based steel bar size estimation and a counting model with a Box and Mask of over 30 mAP was generated to satisfy the aim of this study. The proposed method, which is a CNN model combined with homography, can estimate the size and count the number of steel rebars in an image quickly and accurately, and the developed method can be applied to real construction sites to efficiently manage the stock of steel rebars.
The Cellular Prion Protein and the Hallmarks of Cancer
Authors: Mouillet-Richard Sophie , Ghazi Alexandre , Laurent-Puig Pierre
Published: October 2021

Beyond its causal involvement in a group of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies, the cellular prion protein PrPC is now taking centre stage as an important contributor to cancer progression in various types of solid tumours. The prion cancer research field has progressively expanded in the last few years and has yielded consistent evidence for an involvement of PrPC in cancer cell proliferation, migration and invasion, therapeutic resistance and cancer stem cell properties. Most recent data have uncovered new facets of the biology of PrPC in cancer, ranging from its control on enzymes involved in immune tolerance to its radio-protective activity, by way of promoting angiogenesis. In the present review, we aim to summarise the body of literature dedicated to the study of PrPC in relation to cancer from the perspective of the hallmarks of cancer, the reference framework defined by Hanahan and Weinberg.
Neuregulin 1 Gene (NRG1). A Potentially New Targetable Alteration for the Treatment of Lung Cancer
Authors: Rosas Daniel , Raez Luis E. , Russo Alessandro , Rolfo Christian
Published: October 2021

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to unregulated cell proliferation by different mechanisms in a wide variety of cancer. This has led to the development of directed therapies to antagonize a variety of mechanisms that lead to cell growth or proliferation. Multiple oncogene fusions are currently targeted in lung cancer treatment, such as those involving ALK, RET, NTRK and ROS1 among many others. Neuregulin (NRG) gene fusion has been described in the development of normal tissue as well as in a variety of diseases, such as schizophrenia, Hirschsprung’s disease, atrial fibrillation and, most recently, the development of various types of solid tumors, such as renal, gastric, pancreatic, breast, colorectal and, more recently, lung cancer. The mechanism for this is that the NRG1 chimeric ligand leads to aberrant activation of ERBB2 signaling via PI3K-AKT and MAPK cellular cascades, leading to cell division and proliferation. Details regarding the incidence of these gene rearrangements are lacking. Limited case reports and case series have evaluated their clinicopathologic features and prognostic significance in the lung cancer population. Taking this into account, NRG1 could become a targetable alteration in selected patients. This review highlights how the knowledge of new molecular mechanisms of NRG1 fusion may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel targetable molecular marker.
Predicting Short-Term Survival after Gross Total or Near Total Resection in Glioblastomas by Machine Learning-Based Radiomic Analysis of Preoperative MRI
Authors: Cepeda Santiago , Pérez-Nuñez Angel , García-García Sergio , García-Pérez Daniel , Arrese Ignacio , Jiménez-Roldán Luis , García-Galindo Manuel , González Pedro , Velasco-Casares María , Zamora Tomas , Sarabia Rosario
Published: October 2021

Radiomics, in combination with artificial intelligence, has emerged as a powerful tool for the development of predictive models in neuro-oncology. Our study aims to find an answer to a clinically relevant question: is there a radiomic profile that can identify glioblastoma (GBM) patients with short-term survival after complete tumor resection? A retrospective study of GBM patients who underwent surgery was conducted in two institutions between January 2019 and January 2020, along with cases from public databases. Cases with gross total or near total tumor resection were included. Preoperative structural multiparametric magnetic resonance imaging (mpMRI) sequences were pre-processed, and a total of 15,720 radiomic features were extracted. After feature reduction, machine learning-based classifiers were used to predict early mortality (<6 months). Additionally, a survival analysis was performed using the random survival forest (RSF) algorithm. A total of 203 patients were enrolled in this study. In the classification task, the naive Bayes classifier obtained the best results in the test data set, with an area under the curve (AUC) of 0.769 and classification accuracy of 80%. The RSF model allowed the stratification of patients into low- and high-risk groups. In the test data set, this model obtained values of C-Index = 0.61, IBS = 0.123 and integrated AUC at six months of 0.761. In this study, we developed a reliable predictive model of short-term survival in GBM by applying open-source and user-friendly computational means. These new tools will assist clinicians in adapting our therapeutic approach considering individual patient characteristics.
Semi-Mechanistic Model for the Antitumor Response of a Combination Cocktail of Immuno-Modulators in Non-Inflamed (Cold) Tumors
Authors: Sancho-Araiz Aymara , Zalba Sara , Garrido María J. , Berraondo Pedro , Topp Brian , de Alwis Dinesh , Parra-Guillen Zinnia P. , Mangas-Sanjuan Víctor , Trocóniz Iñaki F.
Published: October 2021

Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm3 and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8+ T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.
Thyroid Hormone Replacement Therapy Is Associated with Longer Overall Survival in Patients with Resectable Gastroesophageal Cancer: A Retrospective Single-Center Analysis
Authors: Puhr Hannah C. , Reiter Thorsten J. , El-Mahrouk Mohamed , Saliternig Lena , Wolf Peter , Mair Maximilian J. , Steindl Ariane , Paireder Matthias , Asari Reza , Schoppmann Sebastian F. , Berghoff Anna S. , Preusser Matthias , Ilhan-Mutlu Aysegül
Published: October 2021

Introduction: As thyroid hormones modulate proliferative pathways it is surmised that they can be associated with cancer development. Since the potential association of gastroesophageal cancer and thyroid disorders has not been addressed so far, the aim of this study was to investigate the association of thyroid hormone parameters with the outcome of these patients, so novel prognostic and even potentially therapeutic markers can be defined. Material and Methods: Clinical and endocrinological parameters of patients with resectable gastroesophageal cancer treated between 1990 and 2018 at the Vienna General Hospital, Austria, including history of endocrinological disorders and laboratory analyses of thyroid hormones at first cancer diagnosis were investigated and correlated with the overall survival (OS). Results: In a total of 865 patients, a tendency towards prolonged OS in hypothyroid patients (euthyroid, n = 647: median OS 29.7 months; hyperthyroid, n = 50: 23.1 months; hypothyroid, n = 70: 47.9 months; p = 0.069) as well as a significant positive correlation of thyroid hormone replacement therapy with the OS was observed (without, n = 53: median OS 30.6 months; with, n = 67: 51.3 months; p = 0.017). Furthermore, triiodothyronine (T3) levels were also associated with the OS (median OS within the limit of normal: 23.4, above: 32.4, below: 9.6 months; p = 0.045). Conclusions: Thyroid disorders and their therapeutic interventions might be associated with the OS in patients with resectable gastroesophageal cancer. As data on the correlation of these parameters is scarce, this study proposes an important impulse for further analyses concerning the association of thyroid hormones with the outcome in patients with gastroesophageal tumors.
Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia
Authors: Ribeiro Sara , Eiring Anna M. , Khorashad Jamshid S.
Published: October 2021

Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation or block differentiation of hematopoietic progenitors. A combination of cytogenetic profiling and gene mutation analyses are essential for the proper diagnosis, classification, prognosis, and treatment of AML. In the present review, we provide a summary of genomic abnormalities in AML that have emerged as both markers of disease and therapeutic targets. We discuss the abnormalities of RARA, FLT3, BCL2, IDH1, and IDH2, their significance as therapeutic targets in AML, and how various mechanisms cause resistance to the currently FDA-approved inhibitors. We also discuss the limitations of current genomic approaches for producing a comprehensive picture of the activated signaling pathways at diagnosis or at relapse in AML patients, and how innovative technologies combining genomic and functional methods will improve the discovery of novel therapeutic targets in AML. The ultimate goal is to optimize a personalized medicine approach for AML patients and possibly those with other types of cancers.
Quality of Life as a Mediator between Cancer Stage and Long-Term Mortality in Nasopharyngeal Cancer Patients Treated with Intensity-Modulated Radiotherapy
Authors: Liao Kuan-Cho , Chuang Hui-Ching , Chien Chih-Yen , Lin Yu-Tsai , Tsai Ming-Hsien , Su Yan-Ye , Yang Chao-Hui , Lai Chi-Chih , Huang Tai-Lin , Li Shau-Hsuan , Lee Tsair-Fwu , Lin Wei-Ting , Lee Chien-Hung , Fang Fu-Min
Published: October 2021

Background: Quality of life (QoL) attained before, during, or after treatments is recognized as a vital factor associated with therapeutic benefits in cancer patients. This nasopharyngeal cancer (NPC) patient longitudinal study assessed the relationship among QoL, cancer stage, and long-term mortality in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Patients and Methods: The European Organization for Research and Treatment of Cancer (EORTC) core QoL questionnaire (QLQ-C30) and the head and neck cancer-specific QoL questionnaire module (QLQ-HN35) were employed to evaluate four-dimensional QoL outcomes at five time points: pre- (n = 682), during (around 40 Gy) (n = 675), 3 months (n = 640), 1 year (n = 578) and 2 years post-IMRT (n = 505), respectively, for 682 newly diagnosed NPC patients treated between 2003 and 2017 at a single institute. The median followed-up time was 7.5 years, ranging from 0.3 to 16.1 years. Generalized estimating equations, multivariable proportional hazards models, and Baron and Kenny’s method were used to assess the investigated effects. Results: Advanced AJCC stage (III–IV) patients revealed a 2.26-fold (95% CI—1.56 to 3.27) higher covariate-adjusted mortality risk than early-stage (I–II) patients. Compared with during IMRT, advanced-stage patients had a significantly low global health QoL and a significantly high QoL-HN35 symptom by a large magnitude at pre-, 3 months, and 2 years post-IMRT. QoL scales at pre-IMRT, 1 year, and 2 years post-IMRT were significantly associated with mortality. The effect changes of mortality risk explained by global health QoL, QoL-C30, and QoL-HN35 symptom were 5.8–9.8% at pre-IMRT but at 2 years post-IMRT were 39.4–49.4% by global health QoL and QoL-HN35 symptoms. Conclusions: We concluded advanced cancer stage correlates with a long-term high mortality in NPC patients treated with IMRT and the association is partially intermediated by QoL at pre-IMRT and 2 years post-IMRT. Therefore, QoL-HN35 symptom and global health QoL-dependent medical support and care should be focused and tailored at 2 years post-IMRT.
Recent Advances in the Management of Pediatric Acute Myeloid Leukemia—Report of the Hungarian Pediatric Oncology-Hematology Group
Authors: Gaál Zsuzsanna , Jakab Zsuzsanna , Kárai Bettina , Ujfalusi Anikó , Petrás Miklós , Kállay Krisztián , Kelemen Ágnes , Simon Réka , Kriván Gergely , Kovács Gábor T. , Kiss Csongor , Szegedi István
Published: October 2021

Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to hematopoietic stem cell transplantation (HSCT), and to targeted therapies. The major aim of our study was to evaluate AML treatment results of HPOG between 2012 and 2019 with 92 new patients registered (52 males, 40 females, mean age 7.28 years). Two periods were distinguished: 2012–2015 and 2016–2019 (55 and 37 patients, respectively). During these periods, 2 y OS increased from 63.6% to 71.4% (p = 0.057), and the 2 y EFS increased significantly from 56.4% to 68.9% (p = 0.02). HSCT was performed in 37 patients (5 patients received a second HSCT). We demonstrate advances in the diagnosis and treatment of acute promyelocytic leukemia (APL) in two cases. Early diagnosis and follow-up were achieved by multidimensional flow cytometry and advanced molecular methods. Both patients were successfully treated with all-trans retinoic acid and arsenic-trioxide, in addition to chemotherapy. In order to meet international standards of pediatric AML management, HPOG will further centralize treatment centers and diagnostic facilities and join efforts with international study groups.
The Roles of Precursor-Induced Metal–Support Interaction on the Selective Hydrogenation of Crotonaldehyde over Ir/TiO2 Catalysts
Authors: Jia Aiping , Peng Hantao , Zhang Yunshang , Song Tongyang , Ye Yanwen , Luo Mengfei , Lu Jiqing , Huang Weixin
Published: October 2021

Various supported Ir/TiO2 catalysts were prepared using different Ir precursors (i.e., H2IrCl6, (NH4)2IrCl6 and Ir(acac)3) and tested for vapor phase selective hydrogenation of crotonaldehyde. The choice of Ir precursor significantly altered the Ir-TiOx interaction in the catalyst, which thus had essential influences on the geometric and electronic properties of the Ir species, reducibility, and surface acidity, and, consequently, their reaction behaviors. The Ir/TiO2-N catalyst using (NH4)2IrCl6 as the precursor gave the highest initial reaction rates and turnover frequencies of crotyl alcohol formation. Such high performance was ascribed to the high Ir dispersion and high surface concentration of Ir0 species, as well as a higher surface acidity, in the Ir/TiO2-N catalyst compared to its counterparts, indicating the synergistic roles of the Ir-TiOx interface in the reaction, as the interfacial sites were responsible for the adsorption/activation of H2 and the C=O bond in the crotonaldehyde molecule.
Electron Mediation and Photocurrent Enhancement in Dunalliela salina Driven Bio-Photo Electrochemical Cells
Authors: Shlosberg Yaniv , Tóth Tünde N. , Eichenbaum Benjamin , Keysar Lee , Schuster Gadi , Adir Noam
Published: October 2021

In recent years, finding alternatives for fossil fuels has become a major concern. One promising solution is microorganism-based bio-photo electrochemical cells (BPECs) that utilize photosynthetic solar energy conversion as an energy source while absorbing CO2 from the atmosphere. It was previously reported that in cyanobacterial-based BPECs, the major endogenous electron mediator that can transfer electrons from the thylakoid membrane photosynthetic complexes and external anodes is NADPH. However, the question of whether the same electron transfer mechanism is also valid for live eukaryotic microalgae, in which NADPH must cross both the chloroplast outer membrane and the cell wall to be secreted from the cell has remained elusive. In this work, we show that NADPH is also the major endogenous electron mediator in the microalgae Dunalliela salina (Ds). We show that the ability of Ds to tolerate high salinity enables the production of a photocurrent that is 5–6 times greater than previously reported for freshwater cyanobacterial-based BPECs in the presence or absence of exogenous electron mediators. Additionally, we show that the electron mediator Vitamin B1 can also function as an electron mediator enhancing photocurrent production. Finally, we show that the addition of both FeCN and NADP+ to Ds has a synergistic effect enhancing the photocurrent beyond the effect of adding each mediator separately.
Integrated CGH/WES Analyses Advance Understanding of Aggressive Neuroblastoma Evolution: A Case Study
Authors: Corallo Diana , Zanon Carlo , Pantile Marcella , Tonini Gian Paolo , Zin Angelica , Francescato Samuela , Rossi Bartolomeo , Trevisson Eva , Pinato Claudia , Monferrer Ezequiel , Noguera Rosa , Aliño Salvador F. , Herrero Maria Jose , Biffi Alessandra , Viscardi Elisabetta , Aveic Sanja
Published: October 2021

Neuroblastoma (NB) is the most common extra-cranial malignancy in preschool children. To portray the genetic landscape of an overly aggressive NB leading to a rapid clinical progression of the disease, tumor DNA collected pre- and post-treatment has been analyzed. Array comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and pharmacogenetics approaches, respectively, have identified relevant copy number alterations (CNAs), single nucleotide variants (SNVs), and polymorphisms (SNPs) that were then combined into an integrated analysis. Spontaneously formed 3D tumoroids obtained from the recurrent mass have also been characterized. The results prove the power of combining CNAs, SNVs, and SNPs analyses to assess clonal evolution during the disease progression by evidencing multiple clones at disease onset and dynamic genomic alterations during therapy administration. The proposed molecular and cytogenetic integrated analysis empowers the disease follow-up and the prediction of tumor recurrence.
Enhanced Expression of microRNA-1273g-3p Contributes to Alzheimer’s Disease Pathogenesis by Regulating the Expression of Mitochondrial Genes
Authors: Kim So Hee , Choi Kyu Yeong , Park Yega , McLean Catriona , Park Jiyu , Lee Jung Hoon , Lee Kyung-Hwa , Kim Byeong C. , Huh Yun Hyun , Lee Kun Ho , Song Woo Keun
Published: October 2021

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, but its underlying cause has not been fully elucidated. Recent studies have shown that microRNAs (miRNAs) play important roles in regulating the expression levels of genes associated with AD development. In this study, we analyzed miRNAs in plasma and cerebrospinal fluid (CSF) from AD patients and cognitively normal (including amyloid positive) individuals. miR-1273g-3p was identified as an AD-associated miRNA and found to be elevated in the CSF of early-stage AD patients. The overexpression of miR-1273g-3p enhanced amyloid beta (Aβ) production by inducing oxidative stress and mitochondrial impairments in AD model cell lines. A biotin-streptavidin pull-down assay demonstrated that miR-1273g-3p primarily interacts with mitochondrial genes, and that their expression is downregulated by miR-1273g-3p. In particular, the miR-1273g-3p-target gene TIMM13 showed reduced expression in brain tissues from human AD patients. These results suggest that miR-1273g-3p expression in an early stage of AD notably contributes to Aβ production and mitochondrial impairments. Thus, miR-1273g-3p might be a biomarker for early diagnosis of AD and a potential therapeutic target to prevent AD progression.
Lineage-Selective Disturbance of Early Human Hematopoietic Progenitor Cell Differentiation by the Commonly Used Plasticizer Di-2-ethylhexyl Phthalate via Reactive Oxygen Species: Fatty Acid Oxidation Makes the Difference
Authors: Kaiser Lars , Quint Isabel , Csuk René , Jung Manfred , Deigner Hans-Peter
Published: October 2021

Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An analysis of the underlying mechanism revealed that MEHP promotes increases in reactive oxygen species (ROS) by reducing the activity of superoxide dismutase in all lineages, possibly via its actions at the aryl hydrocarbon receptor. This leads to a metabolic shift away from glycolysis toward the pentose phosphate pathway and ultimately results in the death of hematopoietic cells that rely on glycolysis for energy production. By contrast, cells that utilize fatty acid oxidation for energy production are not susceptible to this outcome due to their capacity to uncouple ATP production. These responses were also detected in non-hematopoietic cells exposed to alternate inducers of ROS.
Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase
Authors: Fuseya Yasuhiro , Iwai Kazuhiro
Published: October 2021

The ubiquitin system modulates protein functions by decorating target proteins with ubiquitin chains in most cases. Several types of ubiquitin chains exist, and chain type determines the mode of regulation of conjugated proteins. LUBAC is a ubiquitin ligase complex that specifically generates N-terminally Met1-linked linear ubiquitin chains. Although linear ubiquitin chains are much less abundant than other types of ubiquitin chains, they play pivotal roles in cell survival, proliferation, the immune response, and elimination of bacteria by selective autophagy. Because linear ubiquitin chains regulate inflammatory responses by controlling the proinflammatory transcription factor NF-κB and programmed cell death (including apoptosis and necroptosis), abnormal generation of linear chains can result in pathogenesis. LUBAC consists of HOIP, HOIL-1L, and SHARPIN; HOIP is the catalytic center for linear ubiquitination. LUBAC is unique in that it contains two different ubiquitin ligases, HOIP and HOIL-1L, in the same ligase complex. Furthermore, LUBAC constitutively interacts with the deubiquitinating enzymes (DUBs) OTULIN and CYLD, which cleave linear ubiquitin chains generated by LUBAC. In this review, we summarize the current status of linear ubiquitination research, and we discuss the intricate regulation of LUBAC-mediated linear ubiquitination by coordinate function of the HOIP and HOIL-1L ligases and OTULIN. Furthermore, we discuss therapeutic approaches to targeting LUBAC-mediated linear ubiquitin chains.
Vascular Endothelial Cells: Heterogeneity and Targeting Approaches
Authors: Hennigs Jan K. , Matuszcak Christiane , Trepel Martin , Körbelin Jakob
Published: October 2021

Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations.