bluuebunny/crossref_metadata_2025 huggingface dataset:
ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
Authors: Ghaderi Amineh , Daneshmanesh Amir Hossein , Moshfegh Ali , Kokhaei Parviz , Vågberg Jan , Schultz Johan , Olin Thomas , Harrysson Sara , Smedby Karin E , Drakos Elias , Rassidakis Georgios Z. , Österborg Anders , Mellstedt Håkan , Hojjat-Farsangi Mohammad
Published: June 2020

The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.
Impact of Local High Doses of Radiation by Neutron Activated Mn Dioxide Powder in Rat Lungs: Protracted Pathologic Damage Initiated by Internal Exposure
Authors: Shichijo Kazuko , Takatsuji Toshihiro , Abishev Zhaslan , Uzbekov Darkhan , Chaizhunusova Nailya , Shabdarbaeva Dariya , Niino Daisuke , Kurisu Minako , Takahashi Yoshio , Stepanenko Valeriy , Azhimkhanov Almas , Hoshi Masaharu
Published: June 2020

Internal radiation exposure from neutron-induced radioisotopes environmentally activated following atomic bombing or nuclear accidents should be considered for a complete picture of pathologic effects on survivors. Inhaled hot particles expose neighboring tissues to locally ultra-high doses of β-rays and can cause pathologic damage. 55MnO2 powder was activated by a nuclear reactor to make 56MnO2 which emits β-rays. Internal exposures were compared with external γ-rays. Male Wistar rats were administered activated powder by inhalation. Lung samples were observed by histological staining at six hours, three days, 14 days, two months, six months and eight months after the exposure. Synchrotron radiation—X-ray fluorescence—X-ray absorption near-edge structure (SR–XRF–XANES) was utilized for the chemical analysis of the activated 56Mn embedded in lung tissues. 56Mn beta energy spectrum around the particles was calculated to assess the local dose rate and accumulated dose. Hot particles located in the bronchiole and in damaged alveolar tissue were identified as accumulations of Mn and iron. Histological changes showed evidence of emphysema, hemorrhage and severe inflammation from six hours through eight months. Apoptosis was observed in the bronchiole epithelium. Our study shows early event damage from the locally ultra-high internal dose leads to pathogenesis. The trigger of emphysema and hemorrhage was likely early event damage to blood vessels integral to alveolar walls.
Alexithymia Is Associated with Reduced Quality of Life and Increased Caregiver Burden in Parkinson’s Disease
Authors: Klietz Martin , Schnur Theresa , Drexel Simon C. , Lange Florian , Paracka Lejla , Huber Meret K. , Dressler Dirk , Höglinger Günter U. , Wegner Florian
Published: June 2020

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease of people who are beyond 50 years of age. People with PD (PwP) suffer from a large variety of motor and non-motor symptoms resulting in reduced health-related quality of life (HR-QoL). In the last two decades, alexithymia was identified as an additional non-motor symptom in PD. Alexithymia is defined as a cognitive affective disturbance resulting in difficulty to identify and distinguish feelings from bodily sensations of emotional arousal. In PD, the frequency of patients suffering of alexithymia is increased compared to healthy controls. The aim of the present study was to determine the relationship of alexithymia to HR-QoL of the PwP and caregiver burden of the corresponding caregiver. This cross-sectional questionnaire-based study used disease specific questionnaires for HR-QoL and caregiver burden. In total 119 PwP and their corresponding caregivers were included in the study. HR-QoL of the PwP correlated significantly with alexithymia (p < 0.001), especially the sub-components “identifying feelings” (p < 0.001) and “difficulties describing feelings” (p = 0.001). Caregiver burden also correlated significantly with PwP alexithymia (p < 0.001). However, caregiver burden was associated with sub-components “identifying feelings” (p < 0.008) and “external oriented thinking” (p < 0.004). These data support the importance of alexithymia as a non-motor symptom in PD.
Pro-Oxidant Enzymes, Redox Balance and Oxidative Damage to Proteins, Lipids and DNA in Colorectal Cancer Tissue. Is Oxidative Stress Dependent on Tumour Budding and Inflammatory Infiltration?
Authors: Zińczuk Justyna , Maciejczyk Mateusz , Zaręba Konrad , Pryczynicz Anna , Dymicka-Piekarska Violetta , Kamińska Joanna , Koper-Lenkiewicz Olga , Matowicka-Karna Joanna , Kędra Bogusław , Zalewska Anna , Guzińska-Ustymowicz Katarzyna
Published: June 2020

This study is the first to assess redox homeostasis in patients with colorectal cancer (CRC) in respect to histopathological parameters associated with the tumour microenvironment such as tumour budding and inflammatory infiltration. Pro-oxidant enzymes (NADPH oxidase (NOX), xanthine oxidase (XO)), antioxidant barrier (Cu,Zn-superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced glutathione (GSH)), redox status (total antioxidant (TAC)/oxidant status (TOS)) and oxidative damage products (advanced glycation end products (AGE), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG)) were determined in both the normal and cancerous tissue of 29 CRC patients. The activity of NOX (p < 0.01) and XO (p = 0.01), as well as SOD (p < 0.0001), CAT (p < 0.0001) and TAC level (p < 0.01) were significantly higher in tumour tissue than in normal colon mucosa. Oxidative damage products (AGE—p < 0.01, AOPP—p < 0.001, MDA—p < 0.001, 8-OHdG—p < 0.0001) were also higher in cancerous colon tissue. Furthermore, we observed that CAT (p < 0.05) and XO (p < 0.05) activity depends on the intensity of inflammatory infiltration. Oxidative stress index (OSI) (p < 0.05) and MDA (p < 0.01) values were significantly higher in patients with tumour budding (TB) > 5 versus cases with TB < 5. However, OSI level did not differ significantly between cancer and normal tissue. Our results confirm that CRC is associated with enzymatic/non-enzymatic redox imbalance and increased oxidative damage to proteins, lipids and DNA. The determination of these biomarkers could be useful for the evaluation of the tumour progression.
Bromodomain-Containing Protein BRD4 Is Hyperphosphorylated in Mitosis
Authors: Wang Ranran , Yang June F. , Ho Flora , Robertson Erle S. , You Jianxin
Published: June 2020

The epigenetic reader BRD4 binds acetylated histones and plays a central role in controlling cellular gene transcription and proliferation. Dysregulation of BRD4′s activity has been implicated in the pathogenesis of a wide variety of cancers. While blocking BRD4 interaction with acetylated histones using BET inhibitors (BETis) has been tested in clinical trials, many cancers have acquired BETi resistance. However, the underlying mechanisms are poorly understood and BETi resistance remains a pressing clinical problem. We previously showed that BRD4 phosphorylation supports stronger chromatin binding and target oncogene expression. In this study, we discovered that BRD4 is hyperphosphorylated by CDK1 during mitosis and determined the major CDK1 phosphorylation sites in BRD4. Using CRISPR/Cas9 gene editing, we replaced endogenous BRD4 with a non-phosphorylatable mutant and demonstrated that CDK1-mediated BRD4 phosphorylation contributes to BETi resistance. CDK1 over-activation frequently observed in cancers has the potential to cause aberrant BRD4 hyperphosphorylation persisting outside of mitosis to strengthen its target gene binding and confer BETi resistance. We found that dual CDK1 and BET inhibition generates a synergistic effect in killing BETi-resistant cancer cells. Our study therefore suggests that CDK1 inhibition can be employed to overcome tumor BETi resistance and improve treatments for BRD4-associated cancers.
Melanoma Brain Metastases in the Era of Target Therapies: An Overview
Authors: Becco Paolo , Gallo Susanna , Poletto Stefano , Frascione Mirko Pio Manlio , Crotto Luca , Zaccagna Alessandro , Paruzzo Luca , Caravelli Daniela , Carnevale-Schianca Fabrizio , Aglietta Massimo
Published: June 2020

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.
Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells
Authors: Anania Sandy , Peiffer Raphaël , Rademaker Gilles , Hego Alexandre , Thiry Marc , Deldicque Louise , Francaux Marc , Maloujahmoum Naïma , Agirman Ferman , Bellahcène Akeila , Castronovo Vincent , Peulen Olivier
Published: June 2020

Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer.
COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma
Authors: Chu Yu-De , Lin Wey-Ran , Lin Yang-Hsiang , Kuo Wen-Hsin , Tseng Chin-Ju , Lim Siew-Na , Huang Yen-Lin , Huang Shih-Chiang , Wu Ting-Jung , Lin Kwang-Huei , Yeh Chau-Ting
Published: June 2020

The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration.
HERC Ubiquitin Ligases in Cancer
Authors: Sala-Gaston Joan , Martinez-Martinez Arturo , Pedrazza Leonardo , Lorenzo-Martín L. Francisco , Caloto Rubén , Bustelo Xosé R. , Ventura Francesc , Rosa Jose Luis
Published: June 2020

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.
MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
Authors: Cristóbal Ion , Rubio Jaime , Santos Andrea , Torrejón Blanca , Caramés Cristina , Imedio Laura , Mariblanca Sofía , Luque Melani , Sanz-Alvarez Marta , Zazo Sandra , Madoz-Gúrpide Juan , Rojo Federico , García-Foncillas Jesús
Published: June 2020

Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.
Diffusion Kurtosis Imaging—A Superior Approach to Assess Tumor–Stroma Ratio in Pancreatic Ductal Adenocarcinoma
Authors: Mayer Philipp , Jiang Yixin , Kuder Tristan A. , Bergmann Frank , Khristenko Ekaterina , Steinle Verena , Kaiser Jörg , Hackert Thilo , Kauczor Hans-Ulrich , Klauß Miriam , Gaida Matthias M.
Published: June 2020

Extensive desmoplastic stroma is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression and to the relative resistance of tumor cells towards (radio) chemotherapy. Thus, therapies that target the stroma are under intense investigation. To allow the stratification of patients who would profit from such therapies, non-invasive methods assessing the stroma content in relation to tumor mass are required. In the current prospective study, we investigated the usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI), a radiologic method that measures the random motion of water molecules in tissue, in the assessment of PDAC lesions, and more specifically in the desmoplastic tumor stroma. We made use of a sophisticated DW-MRI approach, the so-called diffusion kurtosis imaging (DKI), which possesses potential advantages over conventional and widely used monoexponential diffusion-weighted imaging analysis (cDWI). We found that the diffusion constant D from DKI is highly negatively correlated with the percentage of tumor stroma, the latter determined by histology. D performed significantly better than the widely used apparent diffusion coefficient (ADC) from cDWI in distinguishing stroma-rich (>50% stroma percentage) from stroma-poor tumors (≤50% stroma percentage). Moreover, we could prove the potential of the diffusion constant D as a clinically useful imaging parameter for the differentiation of PDAC-lesions from non-neoplastic pancreatic parenchyma. Therefore, the diffusion constant D from DKI could represent a valuable non-invasive imaging biomarker for assessment of stroma content in PDAC, which is applicable for the clinical diagnostic of PDAC.
Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process
Authors: Feola Sara , Chiaro Jacopo , Martins Beatriz , Cerullo Vincenzo
Published: June 2020

According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field.
BRAF Mutant Melanoma Adjusts to BRAF/MEK Inhibitors via Dependence on Increased Antioxidant SOD2 and Increased Reactive Oxygen Species Levels
Authors: Yuan Long , Mishra Rosalin , Patel Hima , Alanazi Samar , Wei Xin , Ma Zhijun , Garrett Joan T.
Published: June 2020

B-Rapidly Accelerated Fibrosarcoma (BRAF) mutations are found in about 50% of melanoma patients. Treatment with Food and Drug Administration (FDA)-approved BRAF and MAP/ERK kinase (MEK) inhibitors has improved progression free and overall survival of patients with BRAF mutant melanoma. However, all responders develop resistance typically within 1 year of treatment with these inhibitors. Evidence indicates that reactive oxygen species (ROS) levels are elevated after BRAF pathway inhibition treatment. We aim to decipher the role of mitochondrial antioxidant proteins relative to ROS levels and BRAF pathway inhibitor resistance. We observed BRAF mutant melanoma cells treated with the combination of a MEK inhibitor (trametinib) and a BRAF inhibitor (dabrafenib), exhibited elevated ROS levels, both in in vitro and in vivo melanoma models. We next generated trametinib- and dabrafenib-resistant (TDR) cells and found increased ROS levels after acquisition of resistance. An immunofluorescence experiment showed an increase of DNA damage in TDR cell lines. Furthermore, we observed that TDR cells increased superoxide dismutase 2 (SOD2), an antioxidant, at both mRNA and protein levels, with the upregulation of the transcription factor Nuclear Factor (NF)-κB. Knockdown of SOD2 significantly reduced the growth of BRAF pathway inhibitor-resistant cells. In addition, the results indicate that TDR cells can be re-sensitized to BRAF pathway inhibitors by the ROS scavenger, N-Acetyl Cysteine (NAC). Overall, these data indicate that BRAF pathway inhibitor-resistant cells can compensate for elevated ROS via increased expression of the antioxidant SOD2.
Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy
Authors: Verza Flávia Alves , Das Umashankar , Fachin Ana Lúcia , Dimmock Jonathan R. , Marins Mozart
Published: June 2020

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.
Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies
Authors: Mossenta Monica , Busato Davide , Dal Bo Michele , Toffoli Giuseppe
Published: June 2020

Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid–lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.
Integrating the Tumor Microenvironment into Cancer Therapy
Authors: Sanegre Sabina , Lucantoni Federico , Burgos-Panadero Rebeca , de La Cruz-Merino Luis , Noguera Rosa , Álvaro Naranjo Tomás
Published: June 2020

Tumor progression is mediated by reciprocal interaction between tumor cells and their surrounding tumor microenvironment (TME), which among other factors encompasses the extracellular milieu, immune cells, fibroblasts, and the vascular system. However, the complexity of cancer goes beyond the local interaction of tumor cells with their microenvironment. We are on the path to understanding cancer from a systemic viewpoint where the host macroenvironment also plays a crucial role in determining tumor progression. Indeed, growing evidence is emerging on the impact of the gut microbiota, metabolism, biomechanics, and the neuroimmunological axis on cancer. Thus, external factors capable of influencing the entire body system, such as emotional stress, surgery, or psychosocial factors, must be taken into consideration for enhanced management and treatment of cancer patients. In this article, we review prognostic and predictive biomarkers, as well as their potential evaluation and quantitative analysis. Our overarching aim is to open up new fields of study and intervention possibilities, within the framework of an integral vision of cancer as a functional tissue with the capacity to respond to different non-cytotoxic factors, hormonal, immunological, and mechanical forces, and others inducing stroma and tumor reprogramming.
Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up of Exocrine Pancreatic Ductal Adenocarcinoma: Evidence Evaluation and Recommendations by the Italian Association of Medical Oncology (AIOM)
Authors: Silvestris Nicola , Brunetti Oronzo , Bittoni Alessandro , Cataldo Ivana , Corsi Domenico , Crippa Stefano , D’Onofrio Mirko , Fiore Michele , Giommoni Elisa , Milella Michele , Pezzilli Raffaele , Vasile Enrico , Reni Michele
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations.
A Clinically Applicable Approach to the Classification of B-Cell Non-Hodgkin Lymphomas with Flow Cytometry and Machine Learning
Authors: Gaidano Valentina , Tenace Valerio , Santoro Nathalie , Varvello Silvia , Cignetti Alessandro , Prato Giuseppina , Saglio Giuseppe , De Rosa Giovanni , Geuna Massimo
Published: June 2020

The immunophenotype is a key element to classify B-cell Non-Hodgkin Lymphomas (B-NHL); while it is routinely obtained through immunohistochemistry, the use of flow cytometry (FC) could bear several advantages. However, few FC laboratories can rely on a long-standing practical experience, and the literature in support is still limited; as a result, the use of FC is generally restricted to the analysis of lymphomas with bone marrow or peripheral blood involvement. In this work, we applied machine learning to our database of 1465 B-NHL samples from different sources, building four artificial predictive systems which could classify B-NHL in up to nine of the most common clinico-pathological entities. Our best model shows an overall accuracy of 92.68%, a mean sensitivity of 88.54% and a mean specificity of 98.77%. Beyond the clinical applicability, our models demonstrate (i) the strong discriminatory power of MIB1 and Bcl2, whose integration in the predictive model significantly increased the performance of the algorithm; (ii) the potential usefulness of some non-canonical markers in categorizing B-NHL; and (iii) that FC markers should not be described as strictly positive or negative according to fixed thresholds, but they rather correlate with different B-NHL depending on their level of expression.
Integration of Tumor Mutation Burden and PD-L1 Testing in Routine Laboratory Diagnostics in Non-Small Cell Lung Cancer
Authors: Schatz Stefanie , Falk Markus , Jóri Balázs , Ramdani Hayat O. , Schmidt Stefanie , Willing Eva-Maria , Menon Roopika , Groen Harry J. M. , Diehl Linda , Kröger Matthias , Wesseler Claas , Griesinger Frank , Hoffknecht Petra , Tiemann Markus , Heukamp Lukas C.
Published: June 2020

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved “precision” drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC.
Pt-Amorphous Barium Aluminum Oxide/Carbon Catalysts for an Enhanced Methanol Electrooxidation Reaction
Authors: Chiang Tzu Hsuan , Hou Wan-Yu , Hsu Jia-Wei , Chen Yu-Si
Published: June 2020

A new type of amorphous barium aluminum oxide was synthesized using a polyol thermal method involving a mixture with Vulcan XC-72 carbon and supported with 20%Pt catalysts to enhance the activity of a methanol electrooxidation reaction (MOR). The maximum current density, electrochemically active surface area (ECSA), and electrochemical impedance spectra (EIS) of the obtained catalysts for MOR were determined. The MORs of barium aluminum oxide with different calcination temperatures and Ba and Al contact ratios were studied. The MOR of the uncalcined amorphous Ba0.5AlOx catalysts prepared with a mole ratio of 2/1 Ba/Al mixed with Vulcan XC-72 carbon and supported with 20%Pt catalyst (Pt-Ba0.5AlOx/C) was enhanced compared with that of 20%Pt-Al2O3/C and 20%Pt/C catalysts due to its obtained largest maximum current density of 3.89 mA/cm2 and the largest ECSA of 49.83 m2/g. Therefore, Pt-Ba0.5AlOx/C could provide a new pathway to achieve a sufficient electrical conductivity, and possible synergistic effects with other active components improved the catalytic activity and stability of the prepared catalyst in MOR.
Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis
Authors: Lin Peter Ping
Published: June 2020

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.
To Play or Not to Play: Can an Instrument Really Impact Lip and Tongue Performance?
Authors: Thiebaud Robert S. , Abe Takashi , Denning W. Matt , Loenneke Jeremy P. , Okerlund Micah J. , Ryan Joe S. J. , Boyce Whitney , McBride Maggie , Hernandez Jared
Published: June 2020

(1) Background: Increasing tongue and lip strength may help improve various speech and swallowing disorders, but it is unclear if instrumentalists who use these muscle groups for long periods of time have greater strength and endurance compared to controls. It is also unclear if instrumentalists can more accurately estimate various exercise intensities. The purpose of this study was to determine differences in lip and tongue strength and endurance between instrumentalists and non-instrumentalists (controls). A secondary purpose was to assess differences in ability to estimate various exercise intensities between the two groups. (2) Methods: Instrumentalists and controls’ maximum strength and endurance were measured using the IOPI Pro medical device. In addition, 40%, 60% and 80% of maximum strength were estimated in a randomized order. (3) Results: No significant differences were found between instrumentalists and controls in strength or endurance or the ability to estimate various intensities. Overall, participants were better at estimating tongue strength at moderate intensities and lip strength at higher intensities. (4) Conclusion: Tongue and lip strength and endurance and the ability to estimate exercise intensities are not impacted by years of instrumentalist training compared to healthy controls.
Material Properties of Zr–Cu–Ni–Al Thin Films as Diffusion Barrier Layer
Authors: Sung Po-Hsien , Chen Tei-Chen
Published: June 2020

Due to the rapid increase in current density encountered in new chips, the phenomena of thermomigration and electromigration in the solder bump become a serious reliability issue. Currently, Ni or TiN, as a barrier layer, is widely academically studied and industrially accepted to inhibit rapid copper diffusion in interconnect structures. Unfortunately, these barrier layers are polycrystalline and provide inadequate protection because grain boundaries may presumably serve as fast diffusion paths for copper and could react to form Cu–Sn intermetallic compounds (IMCs). Amorphous metallic films, however, have the potential to be the most effective barrier layer for Cu metallization due to the absence of grain boundaries and immiscibility with copper. In this article, the diffusion properties, the strength of the interface between polycrystalline and amorphous ZrCuNiAl thin film, and the effects of quenching rate on the internal microstructures of amorphous metal films were individually investigated by molecular dynamics (MD) simulation. Moreover, experimental data of the diffusion process for three different cases, i.e., without barrier layer, with an Ni barrier layer, and with a Zr53Cu30Ni9Al8 thin film metallic glass (TFMG) barrier layer, were individually depicted. The simulation results show that, for ZrCuNiAl alloy, more than 99% of the amorphous phase at a quenching rate between 0.25 K/ps and 25 K/ps can be obtained, indicating that this alloy has superior glass-forming ability. The simulation of diffusion behavior indicated that a higher amorphous ratio resulted in better barrier performance. Moreover, a very small and uniformly distributed strain appears in the ZrCuNiAl layer in the simulation of the interfacial tension test; however, almost all the voids are initiated and propagated in the Cu layer. These phenomena indicate that the strength of the ZrCuNiAl/Cu interface and ZrCuNiAl layer is greater than polycrystalline Cu. Experimental results show that the Zr53Cu30Ni9Al8 TFMG layer exhibits a superior barrier effect. Almost no IMCs appear in this TFMG barrier layer even after aging at 125 °C for 500 h.
The Steps from Batchwise to Continuous Crystallization for a Fine Chemical: A Case Study
Authors: Melches Christian , Plate Hermann , Schürhoff Jürgen , Buchfink Robert
Published: June 2020

Many processes to produce fine chemicals and precursors of pharmaceuticals are still operated in batchwise mode. However, recently, more producers have taken a change to continuous operation mode into consideration, performing studies and trials on such a change, while some have even already exchanged their production mode from batchwise to continuous operation. In this paper, the stepwise development from an initial idea to industrial implementation via laboratory testing and confirmation is revealed through the example of an organic fine chemical from the perspective of a crystallization plant manufacturer. We begin with the definition of the objectives of the project and a brief explanation of the advantages of continuous operation and the associated product properties. The results of the laboratory tests, confirming the assumptions made upfront, are reported and discussed. Finally, the implementation of an industrial plant using a draft tube baffled (DTB) crystallizer and the final product properties are shown. Product properties such as crystal size distribution, crystal shape, related storage stability and flowability have successfully been improved.
Measuring Spinal Mobility Using an Inertial Measurement Unit System: A Validation Study in Axial Spondyloarthritis
Authors: Aranda-Valera I. , Cuesta-Vargas Antonio , Garrido-Castro Juan , Gardiner Philip , López-Medina Clementina , Machado Pedro , Condell Joan , Connolly James , Williams Jonathan , Muñoz-Esquivel Karla , O’Dwyer Tom , Castro-Villegas M. , González-Navas Cristina , Collantes-Estévez Eduardo ,   on behalf of iMaxSpA Study Group
Published: June 2020

Portable inertial measurement units (IMUs) are beginning to be used in human motion analysis. These devices can be useful for the evaluation of spinal mobility in individuals with axial spondyloarthritis (axSpA). The objectives of this study were to assess (a) concurrent criterion validity in individuals with axSpA by comparing spinal mobility measured by an IMU sensor-based system vs. optical motion capture as the reference standard; (b) discriminant validity comparing mobility with healthy volunteers; (c) construct validity by comparing mobility results with relevant outcome measures. A total of 70 participants with axSpA and 20 healthy controls were included. Individuals with axSpA completed function and activity questionnaires, and their mobility was measured using conventional metrology for axSpA, an optical motion capture system, and an IMU sensor-based system. The UCOASMI, a metrology index based on measures obtained by motion capture, and the IUCOASMI, the same index using IMU measures, were also calculated. Descriptive and inferential analyses were conducted to show the relationships between outcome measures. There was excellent agreement (ICC > 0.90) between both systems and a significant correlation between the IUCOASMI and conventional metrology (r = 0.91), activity (r = 0.40), function (r = 0.62), quality of life (r = 0.55) and structural change (r = 0.76). This study demonstrates the validity of an IMU system to evaluate spinal mobility in axSpA. These systems are more feasible than optical motion capture systems, and they could be useful in clinical practice.
Development of a Deep Learning Algorithm for Periapical Disease Detection in Dental Radiographs
Authors: Endres Michael G. , Hillen Florian , Salloumis Marios , Sedaghat Ahmad R. , Niehues Stefan M. , Quatela Olivia , Hanken Henning , Smeets Ralf , Beck-Broichsitter Benedicta , Rendenbach Carsten , Lakhani Karim , Heiland Max , Gaudin Robert A.
Published: June 2020

Periapical radiolucencies, which can be detected on panoramic radiographs, are one of the most common radiographic findings in dentistry and have a differential diagnosis including infections, granuloma, cysts and tumors. In this study, we seek to investigate the ability with which 24 oral and maxillofacial (OMF) surgeons assess the presence of periapical lucencies on panoramic radiographs, and we compare these findings to the performance of a predictive deep learning algorithm that we have developed using a curated data set of 2902 de-identified panoramic radiographs. The mean diagnostic positive predictive value (PPV) of OMF surgeons based on their assessment of panoramic radiographic images was 0.69 (±0.13), indicating that dentists on average falsely diagnose 31% of cases as radiolucencies. However, the mean diagnostic true positive rate (TPR) was 0.51 (±0.14), indicating that on average 49% of all radiolucencies were missed. We demonstrate that the deep learning algorithm achieves a better performance than 14 of 24 OMF surgeons within the cohort, exhibiting an average precision of 0.60 (±0.04), and an F1 score of 0.58 (±0.04) corresponding to a PPV of 0.67 (±0.05) and TPR of 0.51 (±0.05). The algorithm, trained on limited data and evaluated on clinically validated ground truth, has potential to assist OMF surgeons in detecting periapical lucencies on panoramic radiographs.
Minimally Invasive Diastema Restoration with Prefabricated Sectional Veneers
Authors: Novelli Claudio , Scribante Andrea
Published: June 2020

This case report presents a new technique for sectional veneer fabrication and diastema restoration with a prefabricated composite veneer. For the purpose of diastema restoration, a prefabricated sectional veneer provides the same benefits of a traditional ceramic sectional veneer (highly esthetic restoration with no need for tooth preparation) but involves a less technically demanding and time-consuming clinical procedure and a less delicate restoration with a reduced risk of accidental breakage and post-bonding crack formation. The technique presented in this case report bridges the gap between a direct and indirect technique for diastema restoration and introduces a new treatment option to close anterior spacing with a highly esthetic sectional veneer in a predictable and timely manner.
Exergy and Exergoeconomic Analysis of a Cogeneration Hybrid Solar Organic Rankine Cycle with Ejector
Authors: Tashtoush Bourhan , Morosuk Tatiana , Chudasama Jigar
Published: June 2020

Solar energy is utilized in a combined ejector refrigeration system with an organic Rankine cycle (ORC) to produce a cooling effect and generate electrical power. This study aims at increasing the utilized share of the collected solar thermal energy by inserting an ORC into the system. As the ejector refrigeration cycle reaches its maximum coefficient of performance (COP), the ORC starts working and generating electrical power. This electricity is used to run the circulating pumps and the control system, which makes the system autonomous. For the ejector refrigeration system, R134a refrigerant is selected as the working fluid for its performance characteristics and environmentally friendly nature. The COP of 0.53 was obtained for the ejector refrigeration cycle. The combined cycle of the solar ejector refrigeration and ORC is modeled in EBSILON Professional. Different parameters like generator temperature and pressure, condenser temperature and pressure, and entrainment ratio are studied, and the effect of these parameters on the cycle COP is investigated. Exergy, economic, and exergoeconomic analyses of the hybrid system are carried out to identify the thermodynamic and cost inefficiencies present in various components of the system.