bluuebunny/crossref_metadata_2025 huggingface dataset:
Ruxolitinib-Associated Infections in Polycythemia Vera: Review of the Literature, Clinical Significance, and Recommendations
Authors: Sadjadian Parvis , Wille Kai , Griesshammer Martin
Published: October 2020

Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, is approved for second-line therapy in patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea. Due to the immunomodulatory and immunosuppressive effect of RUX, there is an increased susceptibility to infections. However, an increased risk of infection is inherent to even untreated myeloproliferative neoplasms (MPN). To obtain more information on the clinical significance of RUX-associated infections in PV, we reviewed the available literature. There is no evidence-based approach to managing infection risks. Most data on RUX-associated infections are available for MF. In all studies, the infection rates in the RUX and control groups were fairly similar, with the exception of infections with the varicella zoster virus (VZV). However, individual cases of bilateral toxoplasmosis retinitis, disseminated molluscum contagiosum, or a mycobacterium tuberculosis infection or a hepatitis B reactivation are reported. A careful assessment of the risk of infection for PV patients is required at the initial presentation and before the start of RUX. Screening for hepatitis B is recommended in all patients. The risk of RUX-associated infections is lower with PV than with MF, but compared to a normal population there is an increased risk of VZV infection. However, primary VZV prophylaxis for PV patients is not recommended, while secondary prophylaxis can be considered individually. As early treatment is most effective for VZV, patients should be properly informed and trained to seek medical advice immediately if cutaneous signs of VZV develop. Vaccination against influenza, herpes zoster, and pneumococci should be considered in all PV patients at risk of infection, especially if RUX treatment is planned. Current recommendations do not support adjusting or discontinuing JAK inhibition in MPN patients to reduce the risk of COVID-19.
Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia
Authors: Weinhäuser Isabel , Pereira-Martins Diego A. , Ortiz Cesar , Silveira Douglas R. , Simões Luíse A. A. , Bianco Thiago M. , Araujo Cleide L. , Koury Luisa C. , Melo Raul A. M. , Bittencourt Rosane I. , Pagnano Katia , Pasquini Ricardo , Nunes Elenaide C. , Fagundes Evandro M. , Gloria Ana B. , Kerbauy Fábio , Chauffaille Maria de Lourdes , Keating Armand , Tallman Martin S. , Ribeiro Raul C. , Dillon Richard , Ganser Arnold , Löwenberg Bob , Valk Peter , Lo-Coco Francesco , Sanz Miguel A. , Berliner Nancy , Ammatuna Emanuele , Lucena-Araujo Antonio R. , Schuringa Jan Jacob , Rego Eduardo M.
Published: October 2020

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
Functional Characterization of Cholinergic Receptors in Melanoma Cells
Authors: Lucianò Anna Maria , Tata Ada Maria
Published: October 2020

In the last two decades, the scientific community has come to terms with the importance of non-neural acetylcholine in light of its multiple biological and pathological functions within and outside the nervous system. Apart from its well-known physiological role both in the central and peripheral nervous systems, in the autonomic nervous system, and in the neuromuscular junction, the expression of the acetylcholine receptors has been detected in different peripheral organs. This evidence has contributed to highlight new roles for acetylcholine in various biological processes, (e.g., cell viability, proliferation, differentiation, migration, secretion). In addition, growing evidence in recent years has also demonstrated new roles for acetylcholine and its receptors in cancer, where they are involved in the modulation of cell proliferation, apoptosis, angiogenesis, and epithelial mesenchymal transition. In this review, we describe the functional characterization of acetylcholine receptors in different tumor types, placing attention on melanoma. The latest set of data accessible through literature, albeit limited, highlights how cholinergic receptors both of muscarinic and nicotinic type can play a relevant role in the migratory processes of melanoma cells, suggesting their possible involvement in invasion and metastasis.
Genetic Landscape of Papillary Thyroid Carcinoma and Nuclear Architecture: An Overview Comparing Pediatric and Adult Populations
Authors: Rangel-Pozzo Aline , Sisdelli Luiza , Cordioli Maria Isabel V. , Vaisman Fernanda , Caria Paola , Mai Sabine , Cerutti Janete M.
Published: October 2020

Thyroid cancer is a rare malignancy in the pediatric population that is highly associated with disease aggressiveness and advanced disease stages when compared to adult population. The biological and molecular features underlying pediatric and adult thyroid cancer pathogenesis could be responsible for differences in the clinical presentation and prognosis. Despite this, the clinical assessment and treatments used in pediatric thyroid cancer are the same as those implemented for adults and specific personalized target treatments are not used in clinical practice. In this review, we focus on papillary thyroid carcinoma (PTC), which represents 80–90% of all differentiated thyroid carcinomas. PTC has a high rate of gene fusions and mutations, which can influence the histologic subtypes in both children and adults. This review also highlights telomere-related genomic instability and changes in nuclear organization as novel biomarkers for thyroid cancers.
Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives
Authors: Pellerin Laurence , Carrié Lorry , Dufau Carine , Nieto Laurence , Ségui Bruno , Levade Thierry , Riond Joëlle , Andrieu-Abadie Nathalie
Published: October 2020

Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.
Prostate Cancer Proliferation Is Affected by the Subcellular Localization of MCT2 and Accompanied by Significant Peroxisomal Alterations
Authors: Valença Isabel , Ferreira Ana Rita , Correia Marcelo , Kühl Sandra , van Roermund Carlo , Waterham Hans R. , Máximo Valdemar , Islinger Markus , Ribeiro Daniela
Published: October 2020

Reprogramming of lipid metabolism directly contributes to malignant transformation and progression. The increased uptake of circulating lipids, the transfer of fatty acids from stromal adipocytes to cancer cells, the de novo fatty acid synthesis, and the fatty acid oxidation support the central role of lipids in many cancers, including prostate cancer (PCa). Fatty acid β-oxidation is the dominant bioenergetic pathway in PCa and recent evidence suggests that PCa takes advantage of the peroxisome transport machinery to target monocarboxylate transporter 2 (MCT2) to peroxisomes in order to increase β-oxidation rates and maintain the redox balance. Here we show evidence suggesting that PCa streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Moreover, we show that MCT2 is required for PCa cell proliferation and, importantly, that its specific localization at the peroxisomal membranes is essential for this role. Our results highlight the importance of peroxisomes in PCa development and uncover different cellular mechanisms that may be further explored as possible targets for PCa therapy.
Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma
Authors: Miyake Makito , Hori Shunta , Owari Takuya , Oda Yuki , Tatsumi Yoshihiro , Nakai Yasushi , Fujii Tomomi , Fujimoto Kiyohide
Published: October 2020

Over the past decade, an “immunotherapy tsunami”, more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.
Size-Exclusion Chromatography as a Technique for the Investigation of Novel Extracellular Vesicles in Cancer
Authors: Liu Daniel S. K. , Upton Flora M. , Rees Eleanor , Limb Christopher , Jiao Long R. , Krell Jonathan , Frampton Adam E.
Published: October 2020

Cancer cells release extracellular vesicles, which are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. Size-exclusion chromatography (SEC) is an increasingly popular technique, which has been rediscovered for the purposes of extracellular vesicle (EV) isolation and purification from diverse biofluids. A systematic review was undertaken to identify all papers that described size exclusion as their primary EV isolation method in cancer research. In all, 37 papers were identified and discussed, which showcases the breadth of applications in which EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. EVs isolated using SEC are able to identify cancer cells, highlight active pathways in tumourigenesis, clinically distinguish cohorts, and remain functionally active for further experiments.
The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation against Cancer
Authors: Iurescia Sandra , Fioretti Daniela , Rinaldi Monica
Published: October 2020

Over the last 15 years, the ability to harness a patient’s own immune system has led to significant progress in cancer therapy. For instance, immunotherapeutic strategies, including checkpoint inhibitors or adoptive cell therapy using chimeric antigen receptor T-cell (CAR-T), are specifically aimed at enhancing adaptive anti-tumour immunity. Several research groups demonstrated that adaptive anti-tumour immunity is highly sustained by innate immune responses. Host innate immunity provides the first line of defence and mediates recognition of danger signals through pattern recognition receptors (PRRs), such as cytosolic sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMP) signals. The retinoic acid-inducible gene I (RIG-I) is a cytosolic RNA helicase, which detects viral double-strand RNA and, once activated, triggers signalling pathways, converging on the production of type I interferons, proinflammatory cytokines, and programmed cell death. Approaches aimed at activating RIG-I within cancers are being explored as novel therapeutic treatments to generate an inflammatory tumour microenvironment and to facilitate cytotoxic T-cell cross-priming and infiltration. Here, we provide an overview of studies regarding the role of RIG-I signalling in the tumour microenvironment, and the most recent preclinical studies that employ RIG-I agonists. Lastly, we present a selection of clinical trials designed to prove the antitumour role of RIG I and that may result in improved therapeutic outcomes for cancer patients.
Role of Stromal Cells in Determining Tumor and Cancer Stem Cell Behaviors and Therapeutic Response
Authors: Reshkin Stephan J. , Cardone Rosa Angela
Published: October 2020

While research previously focused extensively on the tumor cells, over the last two decades, the tumor microenvironment (TME) has received increasing attention with a particular emphasis in its role in tumor development, metabolism, progression, and treatment response [...]
Effect of 1α,25(OH)2 Vitamin D3 in Mutant P53 Glioblastoma Cells: Involvement of Neutral Sphingomyelinase1
Authors: Cataldi Samuela , Arcuri Cataldo , Lazzarini Andrea , Nakashidze Irina , Ragonese Francesco , Fioretti Bernard , Ferri Ivana , Conte Carmela , Codini Michela , Beccari Tommaso , Curcio Francesco , Albi Elisabetta
Published: October 2020

Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector.
O-GlcNAcylation Links Nutrition to the Epigenetic Downregulation of UNC5A during Colon Carcinogenesis
Authors: Decourcelle Amélie , Very Ninon , Djouina Madjid , Loison Ingrid , Thévenet Julien , Body-Malapel Mathilde , Lelièvre Eric , Coqueret Olivier , Leprince Dominique , Yazidi-Belkoura Ikram El , Dehennaut Vanessa
Published: October 2020

While it is now accepted that nutrition can influence the epigenetic modifications occurring in colorectal cancer (CRC), the underlying mechanisms are not fully understood. Among the tumor suppressor genes frequently epigenetically downregulated in CRC, the four related genes of the UNC5 family: UNC5A, UNC5B, UNC5C and UNC5D encode dependence receptors that regulate the apoptosis/survival balance. Herein, in a mouse model of CRC, we found that the expression of UNC5A, UNC5B and UNC5C was diminished in tumors but only in mice subjected to a High Carbohydrate Diet (HCD) thus linking nutrition to their repression in CRC. O-GlcNAcylation is a nutritional sensor which has enhanced levels in CRC and regulates many cellular processes amongst epigenetics. We then investigated the putative involvement of O-GlcNAcylation in the epigenetic downregulation of the UNC5 family members. By a combination of pharmacological inhibition and RNA interference approaches coupled to RT-qPCR (Reverse Transcription-quantitative Polymerase Chain Reaction) analyses, promoter luciferase assay and CUT&RUN (Cleavage Under Target & Release Using Nuclease) experiments, we demonstrated that the O-GlcNAcylated form of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) represses the transcription of UNC5A in human colon cancer cells. Collectively, our data support the hypothesis that O-GlcNAcylation could represent one link between nutrition and epigenetic downregulation of key tumor suppressor genes governing colon carcinogenesis including UNC5A.
Quantifying PD-L1 Expression to Monitor Immune Checkpoint Therapy: Opportunities and Challenges
Authors: Nimmagadda Sridhar
Published: October 2020

Therapeutics targeting programmed death ligand 1 (PD-L1) protein and its receptor PD-1 are now dominant players in restoring anti-tumor immune responses. PD-L1 detection by immunohistochemistry (IHC) is emerging as a reproducible biomarker for guiding patient stratification for those therapies in some cancers. However, PD-L1 expression in the tumor microenvironment is highly complex. It is upregulated by aberrant genetic alterations, and is highly regulated at the transcriptional, posttranscriptional, and protein levels. Thus, PD-L1 IHC is inadequate to fully understand the relevance of PD-L1 levels in the whole body and their dynamics to improve therapeutic outcomes. Imaging technologies could potentially assist in meeting that need. Early clinical investigations show promising results in quantifying PD-L1 expression in the whole body by positron emission tomography (PET). Within this context, this review summarizes advancements in regulation of PD-L1 expression and imaging agents, and in PD-L1 PET for drug development, and discusses opportunities and challenges presented by these innovations for guiding immune checkpoint therapy (ICT).
Non-Invasive Measurement of Drug and 2-HG Signals Using 19F and 1H MR Spectroscopy in Brain Tumors Treated with the Mutant IDH1 Inhibitor BAY1436032
Authors: Wenger Katharina J. , Richter Christian , Burger Michael C. , Urban Hans , Kaulfuss Stefan , Harter Patrick N. , Sreeramulu Sridhar , Schwalbe Harald , Steinbach Joachim P. , Hattingen Elke , Bähr Oliver , Pilatus Ulrich
Published: October 2020

Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using 1H/19F-Magnetic Resonance Spectroscopy (MRS). Methods: 19F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze 19F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up 1H/19F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Results: Evaluation of 1H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by 19F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. Conclusions: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible.
Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer
Authors: Steendam Christi M. J. , Veerman G. D. Marijn , Pruis Melinda A. , Atmodimedjo Peggy , Paats Marthe S. , van der Leest Cor , von der Thüsen Jan H. , Yick David C. Y. , Oomen-de Hoop Esther , Koolen Stijn L. W. , Dinjens Winand N. M. , van Schaik Ron H. N. , Mathijssen Ron H. J. , Aerts Joachim G. J. V. , Dubbink Hendrikus Jan , Dingemans Anne-Marie C.
Published: October 2020

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the preferred treatment for patients with EGFR-mutated non-small cell lung cancer (NSCLC), not all patients benefit. We therefore explored the impact of the presence of mutations found in cell-free DNA (cfDNA) and TKI plasma concentrations during treatment on progression-free survival (PFS). In the prospective START-TKI study blood samples from 41 patients with EGFR-mutated NSCLC treated with EGFR-TKIs were available. Next generation sequencing (NGS) on cfDNA was performed, and plasma TKI concentrations were measured. Patients without complete plasma conversion of EGFR mutation at week 6 had a significantly shorter PFS (5.5 vs. 17.0 months, p = 0.002) and OS (14.0 vs. 25.5 months, p = 0.003) compared to patients with plasma conversion. In thirteen (second line) osimertinib-treated patients with a (plasma or tissue) concomitant TP53 mutation at baseline, PFS was significantly shorter compared to six wild-type cases; 8.8 vs. 18.8 months, p = 0.017. Erlotinib Cmean decrease of ≥10% in the second tertile of treatment was also associated with a significantly shorter PFS; 8.9 vs. 23.6 months, p = 0.037. We obtained evidence that absence of plasma loss of the primary EGFR mutation, isolated plasma p.T790M loss after six weeks, baseline concomitant TP53 mutations, and erlotinib Cmean decrease during treatment are probably related to worse outcome.
Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role
Authors: De Lorenzo Stefania , Tovoli Francesco , Mazzotta Alessandro , Vasuri Francesco , Edeline Julien , Malvi Deborah , Boudjema Karim , Renzulli Matteo , Jeddou Heithem , D’Errico Antonietta , Turlin Bruno , Cescon Matteo , Uguen Thomas , Granito Alessandro , Lièvre Astrid , Brandi Giovanni
Published: October 2020

Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA (n = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723–7.626, p < 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, p = 0.003) and similar to that of patients with known risk factors (31.9 months, p = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156–2.718, p = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.
Clinicopathological Features as Prognostic Predictors of Poor Outcome in Papillary Thyroid Carcinoma
Authors: Póvoa Antónia Afonso , Teixeira Elisabete , Bella-Cueto Maria Rosa , Melo Miguel , Oliveira Maria João , Sobrinho-Simões Manuel , Maciel Jorge , Soares Paula
Published: October 2020

Papillary thyroid cancer (PTC) has an indolent nature and usually excellent prognosis. Some PTC clinicopathological features may contribute to the development of aggressive metastatic disease. In this work, we want to evaluate PTC clinicopathological features that are presurgical prognostic predictors of patients’ outcomes and find which indicators are more adequate for tailoring surgical procedures and follow-up. We studied a series of 241 PTC patients submitted to surgery. All patients’ files and histological tumor samples were reviewed. The 8th edition AJCC/UICC (American Joint Committee on Cancer/Union for International Cancer) Controlstaging system and the 2015 American Thyroid Association risk stratification system were used. Total thyroidectomy was performed in 228 patients, lymphadenectomy in 28 patients. Gross extrathyroidal extension (ETE) was present in 10 patients and 31 tumor resection margins were incomplete. Cervical lymph node metastases (LNMs) were present in 34 patients and distant metastases at diagnosis in four patients. In multivariate analysis, male gender (OR = 15.4, p = 0.015), venous invasion (OR = 16.7, p = 0.022), and lateral compartment LNM (OR = 26.7, p = 0.004) were predictors of mortality; psammoma bodies (PBs) (OR = 4.5, p = 0.008), lymph vessel invasion (OR = 6.9, p < 0.001), and gross ETE (OR = 16.1, p = 0.001) were predictors of structural disease status; male gender (OR = 2.9, p = 0.011), lymph vessel invasion (OR = 2.8, p = 0.006), and incomplete resection margins (OR = 4.6, p < 0.001) were predictors of recurrent/persistent disease. Our study supports that the factors helping to tailor patient’s surgery are male gender, presence of PBs, gross ETE, and lateral compartment LNM. Together with pathological factors, lymph vessel invasion, venous invasion, necrosis, and incomplete surgical resection, should be taken into consideration regarding treatment and follow-up of patients.
Brain Metastasis in Breast Cancer Patients—Need for Improvement
Authors: Witzel Isabell , Oliveira-Ferrer Leticia , Müller Volkmar
Published: October 2020

The incidence of brain metastases (BM) in breast cancer patients is increasing [...]
Change in Age at Diagnosis of Oropharyngeal Cancer in the United States, 1975–2016
Authors: Cline Brittany J. , Simpson Matthew C. , Gropler Matthew , Bukatko Aleksandr R. , Adjei Boakye Eric , Mohammed Kahee A. , Osazuwa-Peters Nosayaba
Published: October 2020

The emergence of the human papillomavirus (HPV) as the primary etiology of oropharyngeal cancer has changed head and neck cancer (HNC) epidemiology. This study described change in the age at diagnosis of oropharyngeal and non-oropharyngeal HNC in the United States in the last four decades. Using a retrospective cohort analysis, the Surveillance, Epidemiology, and End Results dataset from 1975 to 2016 was queried for eligible adult cases of HNC, grouped as oropharyngeal (n = 31,702) versus non-oropharyngeal (n = 87,108). Age at diagnosis was compared by gender (female, male) using independent t-test, and by race/ethnicity (Hispanic, non-Hispanic black, non-Hispanic white, non-Hispanic other) using analysis of variance. Joinpoint regression estimated yearly increases/decreases in age of diagnosis by sex and race/ethnicity through annual percent changes (APC), which were summarized with average annual percent changes (AAPC). Mean age at diagnosis for oropharyngeal cancer was 60.3 years. While there was initially a decrease in age at diagnosis, a 0.37% annual increase occurred from 2002 to 2016 (APC = 0.37, 95% confidence interval (CI) 0.28, 0.45). For non-oropharyngeal cancer, mean age at diagnosis was 63.2 years, with a continuous increase in age at diagnosis throughout the study period (1975–2016 AAPC = 0.08, 95% CI 0.04, 0.12). Females had higher average age at diagnosis than males for both sites, while blacks (57.4 years for oropharyngeal cancer; 59.0 years for non-oropharyngeal) had the lowest age at diagnosis of all races/ethnicity. Age at diagnosis of oropharyngeal cancer has increased significantly since 2002, while non-oropharyngeal HNC has increased significantly in the last four decades.
Complex Mandibular Reconstruction for Head and Neck Squamous Cell Carcinoma—The Ongoing Challenge in Reconstruction and Rehabilitation
Authors: Zrnc Tomislav A. , Tomic Josip , Tomazic Peter V. , Hassanzadeh Hamid , Feichtinger Matthias , Zemann Wolfgang , Metzler Philipp , Pau Mauro
Published: October 2020

Large head and neck squamous cell carcinoma (HNSCC) tumors affecting the mandible require a versatile reconstruction to maintain form, function, and quality of life. Large defect reconstruction of soft and hard tissue in the head and neck necessitates, at best, one vascular system including various tissues by large dimensions. The subscapular flap system seems to meet these standards. A retrospective study was conducted focusing on clinical data, including an analysis of the quality of life with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires, (QLQ-C30 and QLQ-H&N43). A total of 154 patients (122 males, 32 females; age range: 31–71 years, mean: 54.5 years) treated at our department from 1983 through to 2019 were included. Of the subscapular system free flaps (SFFs), 147 were based on the angular artery branch of the thoracodorsal pedicle (95.45%), and the remaining seven cases (4.55%) were lateral scapular border flaps. Mean mandible defect length was 7.3 cm. The mean skin paddle dimension was 86.8 cm2. The most common recipient artery was the thyroid superior artery (79.22%). Major postoperative complications occurred in 13 patients (8.44%). This study confirms that SFFs offer excellent soft and hard tissue quality, component independence, a large arc of rotation length, and a large gauge of pedicle, making them the gold standard for the reconstruction of large composite defects of mandibular HNSCC tumors.
Fostering Prevention of Cervical Cancer by a Correct Diagnosis of Precursors: A Structured Case-Based Colposcopy Course in Finland, Norway and UK
Authors: Sabrina Forsell , Ilkka Kalliala , Mervi Halttunen-Nieminen , Charles Redman , Simon Leeson , Ameli Tropé , Esther Moss , Maria Kyrgiou , Eeva Pyörälä , Pekka Nieminen
Published: October 2020

High-quality colposcopy is essential in cervical cancer prevention. We performed a multicentre prospective interventional pilot-study, evaluating the effect of a six-hour case-based colposcopy course on short- and long-term learning of colposcopy-related knowledge, diagnostic accuracy levels and confidence. We recruited 213 colposcopists participating in three European Federation of Colposcopy (EFC) basic colposcopy courses (Finland, Norway, UK). The study consisted of three tests with identical content performed before, after and 2 months after the course, including ten colposcopic images, ten patient cases and scales for marking confidence in the answers. Outcome measures where mean scores in correct case-management, diagnosis (including high-grade lesion recognition), transformation-zone recognition and confidence in answers. Results were compared between the three tests and stratified according to experience. Mean test scores improved after the course for all participants. The increase was highest for beginners. Confidence in answers improved and the number of colposcopists showing high confidence with low scores decreased. A structured case-based course improves skills and confidence especially for inexperienced colposcopists; however, trainers should be aware of the risk of overconfidence. To complement theoretical training, further hands-on training including high-quality feedback is recommended. Conclusions drawn from long-term learning are limited due to the low participation in the follow-up test.
Publisher’s Note: Continued Publication of Cardiogenetics by MDPI
Authors: Vicario Unai , Vazquez Franck , Lin Shu-Kun
Published: October 2020

Cardiogenetics was launched in 2011 and it has been published over the past nine years by PAGEPress Publications [...]
Ruthenium-Catalyzed C–H Activations for the Synthesis of Indole Derivatives
Authors: Zhu Haoran , Zhao Sen , Zhou Yu , Li Chunpu , Liu Hong
Published: October 2020

The synthesis of substituted indoles has received great attention in the field of organic synthesis methodology. C–H activation makes it possible to obtain a variety of designed indole derivatives in mild conditions. Ruthenium catalyst, as one of the most significant transition-metal catalysts, has been contributing in the synthesis of indole scaffolds through C–H activation and C–H activation on indoles. Herein, we attempt to present an overview about the construction strategies of indole scaffold and site-specific modifications for indole scaffold via ruthenium-catalyzed C–H activations in recent years.
Cleaner Production of Epoxidized Cooking Oil Using A Heterogeneous Catalyst
Authors: Kurańska Maria , Niemiec Magdalena
Published: October 2020

A cleaner solvent-free process of used cooking oil epoxidation has been developed. The epoxidation reactions were carried out using “in situ”-formed peroxy acid. A variety of ion exchange resins with different cross-linking percentages and particle sizes such as Dowex 50WX2 50-100, Dowex 50WX2 100-200, Dowex 50WX2 200-400, Dowex 50WX4 50-100, Dowex 50WX4 100-200, Dowex 50WX4 200-400, Dowex 50WX8 50-100, Dowex 50WX8 100-200, Dowex 50WX8 200-400 were used in the synthesis as heterogeneous catalysts. No significant effect of the size as well as porosity of the catalysts on the properties of the final products was observed. In order to develop a more economically beneficial process, a much cheaper heterogeneous catalyst—Amberlite IR-120—was used and the properties of the epoxidized oil were compared with the bio-components obtained in the reaction catalyzed by the Dowex resins. The epoxidized waste oils obtained in the experiments were characterized by epoxy values in the range of 0.32–0.35 mol/100 g. To reduce the amount of waste, the reusability of the ion exchange resin in the epoxidation reaction was studied. Ten reactions were carried out using the same catalyst and each synthesis was monitored by determination of epoxy value changes vs. time of the reactions. It was noticed that in the case of the reactions where the catalyst was reused for the third and fourth time the content of oxirane rings was higher by 8 and 6%, respectively, compared to the reaction where the catalyst was used only one time. Such an observation has not been reported so far. The epoxidation process with catalyst recirculation is expected to play an important role in the development of a new approach to the environmentally friendly solvent-free epoxidation process of waste oils.
The Role of Sumoylation in the Response to Hypoxia: An Overview
Authors: Filippopoulou Chrysa , Simos George , Chachami Georgia
Published: October 2020

Sumoylation is the covalent attachment of the small ubiquitin-related modifier (SUMO) to a vast variety of proteins in order to modulate their function. Sumoylation has emerged as an important modification with a regulatory role in the cellular response to different types of stress including osmotic, hypoxic and oxidative stress. Hypoxia can occur under physiological or pathological conditions, such as ischemia and cancer, as a result of an oxygen imbalance caused by low supply and/or increased consumption. The hypoxia inducible factors (HIFs), and the proteins that regulate their fate, are critical molecular mediators of the response to hypoxia and modulate procedures such as glucose and lipid metabolism, angiogenesis, erythropoiesis and, in the case of cancer, tumor progression and metastasis. Here, we provide an overview of the sumoylation-dependent mechanisms that are activated under hypoxia and the way they influence key players of the hypoxic response pathway. As hypoxia is a hallmark of many diseases, understanding the interrelated connections between the SUMO and the hypoxic signaling pathways can open the way for future molecular therapeutic interventions.
Ribosome Biogenesis Alterations in Colorectal Cancer
Authors: Nait Slimane Sophie , Marcel Virginie , Fenouil Tanguy , Catez Frédéric , Saurin Jean-Christophe , Bouvet Philippe , Diaz Jean-Jacques , Mertani Hichem
Published: October 2020

Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.
Neurofibromin Structure, Functions and Regulation
Authors: Bergoug Mohammed , Doudeau Michel , Godin Fabienne , Mosrin Christine , Vallée Béatrice , Bénédetti Hélène
Published: October 2020

Neurofibromin is a large and multifunctional protein encoded by the tumor suppressor gene NF1, mutations of which cause the tumor predisposition syndrome neurofibromatosis type 1 (NF1). Over the last three decades, studies of neurofibromin structure, interacting partners, and functions have shown that it is involved in several cell signaling pathways, including the Ras/MAPK, Akt/mTOR, ROCK/LIMK/cofilin, and cAMP/PKA pathways, and regulates many fundamental cellular processes, such as proliferation and migration, cytoskeletal dynamics, neurite outgrowth, dendritic-spine density, and dopamine levels. The crystallographic structure has been resolved for two of its functional domains, GRD (GAP-related (GTPase-activating protein) domain) and SecPH, and its post-translational modifications studied, showing it to be localized to several cell compartments. These findings have been of particular interest in the identification of many therapeutic targets and in the proposal of various therapeutic strategies to treat the symptoms of NF1. In this review, we provide an overview of the literature on neurofibromin structure, function, interactions, and regulation and highlight the relationships between them.
Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants
Authors: Sutherland Heidi G. , Maksemous Neven , Albury Cassie L. , Ibrahim Omar , Smith Robert A. , Lea Rod A. , Haupt Larisa M. , Jenkins Bronwyn , Tsang Benjamin , Griffiths Lyn R.
Published: October 2020

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.
Exploring the Roles of lncRNAs in GBM Pathophysiology and Their Therapeutic Potential
Authors: Stackhouse Christian T. , Gillespie G. Yancey , Willey Christopher D.
Published: October 2020

Glioblastoma (GBM) remains the most devastating primary central nervous system malignancy with a median survival of around 15 months. The past decades of research have not yielded significant advancements in the treatment of GBM. In that same time, a novel class of molecules, long non-coding RNAs (lncRNAs), has been found to play a multitude of roles in cancer and normal biology. The increased accessibility of next generation sequencing technologies and the advent of lncRNA-specific microarrays have facilitated the study of lncRNA etiology. Molecular and computational methods can be applied to predict lncRNA function. LncRNAs can serve as molecular decoys, scaffolds, super-enhancers, or repressors. These molecules can serve as phenotypic switches for GBM cells at the expression and/or epigenetic levels. LncRNAs can affect stemness/differentiation, proliferation, invasion, survival, DNA damage response, and chromatin dynamics. Aberrant expression of these transcripts may facilitate therapy resistance, leading to tumor recurrence. LncRNAs could serve as novel theragnostic or prognostic biomarkers in GBM and other cancers. RNA-based therapeutics may also be employed to target lncRNAs as a novel route of treatment for primary or recurrent GBM. In this review, we explore the roles of lncRNAs in GBM pathophysiology and posit their novel therapeutic potential for GBM.
Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy
Authors: Laferrière Florent , He Xin , Zinghirino Federica , Doudnikoff Evelyne , Faggiani Emilie , Meissner Wassilios G. , Bezard Erwan , De Giorgi Francesca , Ichas François
Published: October 2020

The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson’s disease (PD) where the pathological α-syn aggregates are almost exclusively neuronal, the α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of α-syn, yet pathogenic amyloid α-syn seeds require significant amounts of α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (>80%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (>95%). Using primary cultures of OLs from PLP-αSyn mice we observed a variable association of S129-phosphorylated α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between α-syn aggregation and the development of a clinical phenotype in these transgenic animals.