bluuebunny/crossref_metadata_2025 huggingface dataset:
Schlafen 12 Is Prognostically Favorable and Reduces C-Myc and Proliferation in Lung Adenocarcinoma but Not in Lung Squamous Cell Carcinoma
Authors: Al-Marsoummi Sarmad , Pacella Jonathan , Dockter Kaylee , Soderberg Matthew , Singhal Sandeep K. , Vomhof-DeKrey Emilie E. , Basson Marc D.
Published: September 2020

Schlafen 12 (SLFN12) is an intermediate human Schlafen that induces differentiation in enterocytes, prostate, and breast cancer. We hypothesized that SLFN12 influences lung cancer biology. We investigated survival differences in high versus low SLFN12-expressing tumors in two databases. We then adenovirally overexpressed SLFN12 (AdSLFN12) in HCC827, H23, and H1975 cells to model lung adenocarcinoma (LUAD), and in H2170 and HTB-182 cells representing lung squamous cell carcinoma (LUSC). We analyzed proliferation using a colorimetric assay, mRNA expression by RT-qPCR, and protein by Western blot. To further explore the functional relevance of SLFN12, we correlated SLFN12 with seventeen functional oncogenic gene signatures in human tumors. Low tumoral SLFN12 expression predicted worse survival in LUAD patients, but not in LUSC. AdSLFN12 modulated expression of SCGB1A1, SFTPC, HOPX, CK-5, CDH1, and P63 in a complex fashion in these cells. AdSLFN12 reduced proliferation in all LUAD cell lines, but not in LUSC cells. SLFN12 expression inversely correlated with expression of a myc-associated gene signature in LUAD, but not LUSC tumors. SLFN12 overexpression reduced c-myc protein in LUAD cell lines but not in LUSC, by inhibiting c-myc translation. Our results suggest SLFN12 improves prognosis in LUAD in part via a c-myc-dependent slowing of proliferation.
Role of POT1 in Human Cancer
Authors: Wu Yangxiu , Poulos Rebecca C. , Reddel Roger R.
Published: September 2020

Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.
Modulation of Rat Cancer-Induced Bone Pain is Independent of Spinal Microglia Activity
Authors: Diaz-delCastillo Marta , Hansen Rie Bager , Appel Camilla Kristine , Nielsen Lykke , Nielsen Sascha Nolsøe , Karyniotakis Konstantinos , Dahl Louise M. , Andreasen Rikke B. , Heegaard Anne-Marie
Published: September 2020

The dissemination of cancer to bone can cause significant cancer-induced bone pain (CIBP), severely impairing the patient’s quality of life. Several rodent models have been developed to explore the nociceptive mechanisms of CIBP, including intratibial inoculation of breast carcinoma cells in syngeneic Sprague Dawley rats. Using this model, we investigated whether resident spinal microglial cells are involved in the transmission and modulation of CIBP, a long-debated disease feature. Immunohistochemical staining of ionizing calcium-binding adaptor molecule 1 (Iba-1) and phosphorylated p38-mitogen-activated protein kinase (P-p38 MAPK) showed no spinal microglial reaction in cancer-bearing rats, independently of disease stage, sex, or carcinoma cell line. As a positive control, significant upregulation of both Iba-1 and P-p38 was observed in a rat model of neuropathic pain. Additionally, intrathecal administration of the microglial inhibitor minocycline did not ameliorate pain-like behaviors in cancer-bearing rats, in contrast to spinal morphine administration. Our results indicate that microglial reaction is not a main player in CIBP, adding to the debate that even within the same models of CIBP, significant variations are seen in disease features considered potential drug targets. We suggest that this heterogeneity may reflect the clinical landscape, underscoring the need for understanding the translational value of CIBP models.
Competing Endogenous RNA Networks in the Epithelial to Mesenchymal Transition in Diffuse-Type of Gastric Cancer
Authors: Landeros Natalia , Santoro Pablo M. , Carrasco-Avino Gonzalo , Corvalan Alejandro H.
Published: September 2020

The diffuse-type of gastric cancer (DGC), molecularly associated with epithelial to mesenchymal transition (EMT), is increasing in incidence. Loss of E-cadherin expression is the hallmark of the EMT process and is largely due to the upregulation of the EMT-inducing transcription factors ZEB1/2, Snail, Slug, and Twist1/2. However, ncRNA, such as miRNA and lncRNAs, can also participate in the EMT process through the direct targeting of E-cadherin and other EMT-inducing transcription factors. Additionally, lncRNA can sponge the miRNA pool that targets these transcripts through competing endogenous RNA (ceRNA) networks. In this review, we focus on the role of ncRNA in the direct deregulation of E-cadherin, as well as EMT-inducing transcription factors. Based on the relevance of the ceRNA network hypothesis, and the lack of said networks in EMT, we performed a prediction analysis for all miRNAs and lncRNAs that target E-cadherin, as well as EMT-inducing transcription factors. This analysis resulted in novel predicted ceRNA networks for E-cadherin and EMT-inducing transcription factors (EMT-TFs), as well as the expansion of the molecular basis of the DGC.
Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma
Authors: Paíno Teresa , González-Méndez Lorena , San-Segundo Laura , Corchete Luis A. , Hernández-García Susana , Díaz-Tejedor Andrea , Algarín Esperanza M. , Mogollón Pedro , Martín-Sánchez Montserrat , Gutiérrez Norma C. , Mateos María-Victoria , Garayoa Mercedes , Ocio Enrique M.
Published: September 2020

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.
Estrogen Receptor Signaling in Cancer
Authors: Langdon Simon P.
Published: September 2020

Estrogen receptor signaling plays
Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer
Authors: Lee Hwa-Yong , Hong In-Sun
Published: September 2020

The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
Prognostic Significance of Aberrant Claudin-6 Expression in Endometrial Cancer
Authors: Kojima Manabu , Sugimoto Kotaro , Tanaka Mizuko , Endo Yuta , Kato Hitomi , Honda Tsuyoshi , Furukawa Shigenori , Nishiyama Hiroshi , Watanabe Takafumi , Soeda Shu , Fujimori Keiya , Chiba Hideki
Published: September 2020

Background: Among the claudin (CLDN) family, CLDN6 exhibits aberrant expression in various cancers, but its biological relevance has not yet been established. We generated a monoclonal antibody (mAb) against human CLDN6 and verified its specificity. By immunohistochemical staining and semi-quantification, we evaluated the relationship between CLDN6 expression and clinicopathological parameters in tissues from 173 cases of endometrial cancer. Results: The established mAb selectively recognized CLDN6 protein. Ten of the 173 cases (5.8%) showed high CLDN6 expression (score 3+), whereas 19 (11.0%), 18 (10.4%) and 126 (72.4%) cases revealed low CLDN6 expression (score 2+, 1+ and 0, respectively). In addition, intratumor heterogeneity of CLDN6 expression was observed even in the cases with high CLDN6 expression. The 5-year survival rates in the high and low CLDN6 groups was approximately 30% and 90%, respectively. Among the clinicopathological factors, the high CLDN6 expression was significantly associated with surgical stage III/IV, histological type, histological grade 3, lymphovascular space involvement, lymph node metastasis and distant metastasis. Furthermore, the high CLDN6 expression was an independent prognostic marker for overall survival of endometrial cancer patients (hazard ratio 3.50, p = 0.014). Conclusions: It can be concluded that aberrant CLDN6 expression is useful to predict poor outcome for endometrial cancer and might be a promising therapeutic target.
Prognostic Value of the Pace of Tumor Progression as Assessed by Serial 18F-FDG PET/CT Scan and Liquid Biopsy in Refractory Colorectal Cancer: The CORIOLAN Trial
Authors: Camera Silvia , Akin Telli Tugba , Woff Erwin , Vandeputte Caroline , Kehagias Pashalina , Guiot Thomas , Critchi Gabriela , Wissam Yacine , Bregni Giacomo , Trevisi Elena , Pretta Andrea , Senti Chiara , Leduc Sophia , Gkolfakis Paraskevas , Hoerner Frédéric , Rothé Françoise , Sclafani Francesco , Flamen Patrick , Deleporte Amelie , Hendlisz Alain
Published: September 2020

Introduction: Decision making in refractory colorectal cancer (rCRC) is challenging, with limited data available to predict patient outcome. We conducted a study to assess the pace of cancer progression as a potential prognostic and decision tool. Methods: CORIOLAN was a prospective, single-center, single-arm trial recruiting refractory CRC patients with an ECOG performance status of ≤1 and an estimated life expectancy of ≥12 weeks. 18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan and blood sample collection were carried out at baseline and after 2 weeks with no cancer treatment given between these timepoints. The primary objective was to evaluate the association between pace of cancer progression as defined by changes of the whole-body metabolically active tumor volume (WB-MATV) and overall survival (OS). Exploratory objectives included evaluation of the prognostic value of circulating cell-free DNA (cfDNA), circulating tumor cells (CTCs) and carcinoembryonic antigen (CEA). Results: 47 eligible patients who had received a median number of 5 (range 2–8) prior treatments were enrolled. At the time of analysis, 45 deaths had occurred, with 26% of patients dying within 12 weeks. The median OS was 6.3 months (range 0.4–14.3). The median relative delta between WB-MATV at baseline and 2 weeks was +21%. Changes of WB-MATV, however, failed to predict OS (hazard ratio (HR) 1.3, p = 0.383). Similarly, no association was observed between changes of any of the circulating biomarkers investigated and prognosis. By contrast, high WB-MATV (4.2 versus 9.4 months; HR 3.1, p = 0.003), high CEA (4.4 versus 7.0 months; HR 1.9, p = 0.053), high cfDNA (4.7 versus 7.0 months; HR 2.2, p = 0.015) and high CTC count (3.3 versus 7.5 months; HR 6.5, p < 0.001) at baseline were associated with worse OS. Conclusions: In this study, approximately 1 out of 4 refractory CRC patients who were judged to have a life expectancy >12 weeks actually died within 12 weeks. Baseline assessment of WB-MATV, cfDNA, CTCs and CEA, but not early change evaluation of the same, may help to refine patient prognostication and guide management decisions.
Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups
Authors: Centonze Giovanni , Biganzoli Davide , Prinzi Natalie , Pusceddu Sara , Mangogna Alessandro , Tamborini Elena , Perrone Federica , Busico Adele , Lagano Vincenzo , Cattaneo Laura , Sozzi Gabriella , Roz Luca , Biganzoli Elia , Milione Massimo
Published: September 2020

Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due to their rarity and biological heterogeneity there is still no consensus on the best therapeutic approach. Next-generation-sequencing analysis showed that WHO 2015 LNENs classes, could be characterized also by specific molecular alterations: frequently mutated genes involving chromatin remodeling and generally characterized by low mutational burden (MB) are frequently detected in both TC and AC; otherwise, TP53 and RB1 tumor suppressor genes alterations and high MB are usually detected in LCNEC and SCLC. We provide an overview concerning gene mutations in each WHO 2015 LNENs class in order to report the current LNENs mutational status as potential tool to better understand their clinical outcome and to drive medical treatment.
Recent Advancement of Ullmann Condensation Coupling Reaction in the Formation of Aryl-Oxygen (C-O) Bonding by Copper-Mediated Catalyst
Authors: Fui Choong Jian , Sarjadi Mohd Sani , Sarkar Shaheen M. , Rahman Md Lutfor
Published: September 2020

Transition metal-catalyzed chemical transformation of organic electrophiles and organometallic reagents belong to the most important cross coupling reaction in organic synthesis. The biaryl ether division is not only popular in natural products and synthetic pharmaceuticals but also widely found in many pesticides, polymers, and ligands. Copper catalyst has received great attention owing to the low toxicity and low cost. However, traditional Ullmann-type couplings suffer from limited substrate scopes and harsh reaction conditions. The introduction of homogeneous copper catalyst with presence of bidentate ligands over the past two decades has totally changed this situation as these ligands enable the reaction promoted in mild condition. The reaction scope has also been greatly expanded, rendering this copper-based cross-coupling attractive for both academia and industry. In this review, we will highlight the latest progress in the development of useful homogeneous copper catalyst with presence of ligand and heterogeneous copper catalyst in Ullmann type C-O cross-coupling reaction. Additionally, the application of Ullmann type C-O cross coupling reaction will be discussed.
Contact Glow Discharge Electrolysis: Effect of Electrolyte Conductivity on Discharge Voltage
Authors: Alteri Giovanni Battista , Bonomo Matteo , Decker Franco , Dini Danilo
Published: September 2020

Contact glow discharge electrolysis (CGDE) can be exploited in environmental chemistry for the degradation of pollutants in wastewater. This study focuses on the employment of cheap materials (e.g., steel and tungsten) as electrodes for experiments of CGDE conducted in electrochemical cells with variable electrolytic composition. A clear correlation between breakdown voltage (VB)/discharge (or midpoint) voltage (VD) and the conductivity of the electrolyte is shown. Regardless of the chemical nature of the ionogenic species (acid, base or salt), the higher the conductivity of the solution, the lower the applied potential required for the onset of the glow discharge. Concerning practical application, these salts could be added to poorly conductive wastewaters to increase their conductivity and thus reduce the ignition potential necessary for the development of the CGDE. Such an effect could render the process of chemical waste disposal from wastewaters more economical. Moreover, it is evidenced that both VB and VD are practically independent on the ratio anode area to cathode area if highly conductive solutions are employed.
Palladium Catalysts Based on Porous Aromatic Frameworks, Modified with Ethanolamino-Groups, for Hydrogenation of Alkynes, Alkenes and Dienes
Authors: Kulikov Leonid , Kalinina Maria , Makeeva Daria , Maximov Anton , Kardasheva Yulia , Terenina Maria , Karakhanov Eduard
Published: September 2020

The current work describes an attempt to synthesize hybrid materials combining porous aromatic frameworks (PAFs) and dendrimers and use them to obtain novel highly active and selective palladium catalysts. PAFs are carbon porous materials with rigid aromatic structure and high stability, and the dendrimers are macromolecules which can effectively stabilize metal nanoparticles and tune their activity in catalytic reactions. Two porous aromatic frameworks, PAF-20 and PAF-30, are modified step-by-step with diethanolamine and hydroxyl groups at the ends of which are replaced by new diethanolamine molecules. Then, palladium nanoparticles are applied to the synthesized materials. Properties of the obtained materials and catalysts are investigated using X-ray photoelectron spectroscopy, transmission electron microscopy, solid state nuclear magnetic resonance spectroscopy, low temperature N2 adsorption and elemental analysis. The resulting catalysts are successfully applied as an efficient and recyclable catalyst for selective hydrogenation of alkynes to alkenes at very high (up to 90,000) substrate/Pd ratios.
Thiosemicarbazone Complexes of Transition Metals as Catalysts for Cross-Coupling Reactions
Authors: Kostas Ioannis D. , Steele Barry R.
Published: September 2020

Catalysis of cross-coupling reactions under phosphane-free conditions represents an important ongoing challenge. Although transition metal complexes based on the thiosemicarbazone unit have been known for a very long time, their use in homogeneous catalysis has been studied only relatively recently. In particular, reports of cross-coupling catalytic reactions with such complexes have appeared only in the last 15 years. This review provides a survey of the research in this area and a discussion of the prospects for future developments.
Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD
Authors: Patel Chaitanya , Saad Haddas , Shenkman Marina , Lederkremer Gerardo Z.
Published: September 2020

N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.
Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy
Authors: Ranjan Alok , Kaushik Itishree , Srivastava Sanjay K.
Published: September 2020

Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC50 (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts
Authors: Cosentino Giulia , Romero-Cordoba Sandra , Plantamura Ilaria , Cataldo Alessandra , Iorio Marilena V.
Published: September 2020

Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to “corrupt” stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple negative breast cancer (TNBC) cells to enhance the transition of normal fibroblasts (NFs) into cancer-associated fibroblast (CAF)-like cells. EGF containing fibulin extracellular matrix protein 1 (EFEMP1), which encodes for the ECM glycoprotein fibulin-3, emerged as a miR-9 putative target upon miRNA’s exogenous upmodulation in NFs. Here we explored the impact of EFEMP1 downmodulation on fibroblast’s acquisition of CAF-like features, and how this phenotype influences neoplastic cells to gain chemoresistance. Indeed, upon miR-9 overexpression in NFs, EFEMP1 resulted downmodulated, both at RNA and protein levels. The luciferase reporter assay showed that miR-9 directly targets EFEMP1 and its silencing recapitulates miR-9-induced pro-tumoral phenotype in fibroblasts. In particular, EFEMP1 siRNA-transfected (si-EFEMP1) fibroblasts have an increased ability to migrate and invade. Moreover, TNBC cells conditioned with the supernatant of NFs transfected with miR-9 or si-EFEMP1 became more resistant to cisplatin. Overall, our results demonstrate that miR-9/EFEMP1 axis is crucial for the conversion of NFs to CAF-like cells under TNBC signaling.
Thermal Neutron Relative Biological Effectiveness Factors for Boron Neutron Capture Therapy from In Vitro Irradiations
Authors: Pedrosa-Rivera María , Praena Javier , Porras Ignacio , Sabariego Manuel P. , Köster Ulli , Haertlein Michael , Forsyth V. Trevor , Ramírez José C. , Jover Clara , Jimena Daniel , Osorio Juan L. , Álvarez Patricia , Ruiz-Ruiz Carmen , Ruiz-Magaña María J.
Published: September 2020

The experimental determination of the relative biological effectiveness of thermal neutron factors is fundamental in Boron Neutron Capture Therapy. The present values have been obtained while using mixed beams that consist of both neutrons and photons of various energies. A common weighting factor has been used for both thermal and fast neutron doses, although such an approach has been questioned. At the nuclear reactor of the Institut Laue-Langevin a pure low-energy neutron beam has been used to determine thermal neutron relative biological effectiveness factors. Different cancer cell lines, which correspond to glioblastoma, melanoma, and head and neck squamous cell carcinoma, and non-tumor cell lines (lung fibroblast and embryonic kidney), have been irradiated while using an experimental arrangement designed to minimize neutron-induced secondary gamma radiation. Additionally, the cells were irradiated with photons at a medical linear accelerator, providing reference data for comparison with that from neutron irradiation. The survival and proliferation were studied after irradiation, yielding the Relative Biological Effectiveness that corresponds to the damage of thermal neutrons for the different tissue types.
Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis
Authors: Machado-Oliveira Gisela , Ramos Cristiano , Marques André R. A. , Vieira Otília V.
Published: September 2020

Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders’ burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.
c-Jun N-Terminal Kinase as a Therapeutic Target in Experimental Autoimmune Encephalomyelitis
Authors: Bagnoud Maud , Briner Myriam , Remlinger Jana , Meli Ivo , Schuetz Sara , Pistor Maximilian , Salmen Anke , Chan Andrew , Hoepner Robert
Published: September 2020

c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG35-55) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG35-55. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG35-55 EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.
Multitasking by the OC Lineage during Bone Infection: Bone Resorption, Immune Modulation, and Microbial Niche
Authors: Roper Philip M. , Shao Christine , Veis Deborah J.
Published: September 2020

Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing cells that work in concert with osteoblasts and osteocytes to properly maintain skeletal health and are well known to respond to inflammation by increasing their resorptive activity. OCs have typically been viewed merely as effectors of pathologic bone resorption, but recent evidence suggests they may play an active role in the progression of infections through direct effects on pathogens and via the immune system. This review discusses the host- and pathogen-derived factors involved in the in generation of OCs during infection, the crosstalk between OCs and immune cells, and the role of OC lineage cells in the growth and survival of pathogens, and highlights unanswered questions in the field.
Characterization of Hematopoiesis in Sickle Cell Disease by Prospective Isolation of Stem and Progenitor Cells
Authors: Tolu Seda S. , Wang Kai , Yan Zi , Zhang Shouping , Roberts Karl , Crouch Andrew S. , Sebastian Gracy , Chaitowitz Mark , Fornari Eric D. , Schwechter Evan M. , Uehlinger Joan , Manwani Deepa , Minniti Caterina P. , Bouhassira Eric E.
Published: September 2020

The consequences of sickle cell disease (SCD) include ongoing hematopoietic stress, hemolysis, vascular damage, and effect of chronic therapies, such as blood transfusions and hydroxyurea, on hematopoietic stem and progenitor cell (HSPC) have been poorly characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients, stratified by treatment and control cohorts. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, a two to five-fold increase in CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors, and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a as well as high levels CD49f antigen expression. These findings were present to varying degrees in all patients with SCD, including those on chronic therapy and those who were therapy naive. HU treatment appeared to normalize many of these parameters. Chronic stress erythropoiesis and inflammation incited by SCD and HU therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.
Increased Lamin B1 Levels Promote Cell Migration by Altering Perinuclear Actin Organization
Authors: Fracchia Andrea , Asraf Tal , Salmon-Divon Mali , Gerlitz Gabi
Published: September 2020

Cell migration requires reposition and reshaping of the cell nucleus. The nuclear lamina is highly important for migration of both primary and cancer cells. B-type lamins are important for proper migration of epicardial cells and neurons and increased lamin B to lamin A ratio accelerates cancer cell migration through confined spaces. Moreover, a positive association between lamin B1 levels and tumor formation and progression is found in various cancer types. Still, the molecular mechanism by which B-type lamins promote cell migration is not fully understood. To better understand this mechanism, we tested the effects of lamin B1 on perinuclear actin organization. Here we show that induction of melanoma cell migration leads to the formation of a cytosolic Linker of Nucleoskeleton and Cytoskeleton (LINC) complex-independent perinuclear actin rim, which has not been detected in migrating cells, yet. Significantly, increasing the levels of lamin B1 but not the levels of lamin A prevented perinuclear actin rim formation while accelerated the cellular migration rate. To interfere with the perinuclear actin rim, we generated a chimeric protein that is localized to the outer nuclear membrane and cleaves perinuclear actin filaments in a specific manner without disrupting other cytosolic actin filaments. Using this tool, we found that disruption of the perinuclear actin rim accelerated the cellular migration rate in a similar manner to lamin B1 over-expression. Taken together, our results suggest that increased lamin B1 levels can accelerate cell migration by inhibiting the association of the nuclear envelope with actin filaments that may reduce nuclear movement and deformability.
FMO1 Is Involved in Excess Light Stress-Induced Signal Transduction and Cell Death Signaling
Authors: Czarnocka Weronika , Fichman Yosef , Bernacki Maciej , Różańska Elżbieta , Sańko-Sawczenko Izabela , Mittler Ron , Karpiński Stanisław
Published: September 2020

Because of their sessile nature, plants evolved integrated defense and acclimation mechanisms to simultaneously cope with adverse biotic and abiotic conditions. Among these are systemic acquired resistance (SAR) and systemic acquired acclimation (SAA). Growing evidence suggests that SAR and SAA activate similar cellular mechanisms and employ common signaling pathways for the induction of acclimatory and defense responses. It is therefore possible to consider these processes together, rather than separately, as a common systemic acquired acclimation and resistance (SAAR) mechanism. Arabidopsis thaliana flavin-dependent monooxygenase 1 (FMO1) was previously described as a regulator of plant resistance in response to pathogens as an important component of SAR. In the current study, we investigated its role in SAA, induced by a partial exposure of Arabidopsis rosette to local excess light stress. We demonstrate here that FMO1 expression is induced in leaves directly exposed to excess light stress as well as in systemic leaves remaining in low light. We also show that FMO1 is required for the systemic induction of ASCORBATE PEROXIDASE 2 (APX2) and ZINC-FINGER OF ARABIDOPSIS 10 (ZAT10) expression and spread of the reactive oxygen species (ROS) systemic signal in response to a local application of excess light treatment. Additionally, our results demonstrate that FMO1 is involved in the regulation of excess light-triggered systemic cell death, which is under control of LESION SIMULATING DISEASE 1 (LSD1). Our study indicates therefore that FMO1 plays an important role in triggering SAA response, supporting the hypothesis that SAA and SAR are tightly connected and use the same signaling pathways.
The Effect of Strain Rate on the Deformation Processes of NC Gold with Small Grain Size
Authors: Liu Jialin , Fan Xiaofeng , Shi Yunfeng , Singh David J. , Zheng Weitao
Published: September 2020

The strength of nanocrystalline (NC) metal has been found to be sensitive to strain rate. Here, by molecular dynamics simulation, we explore the strain rate effects on apparent Young’s modulus, flow stress and grain growth of NC gold with small size. The simulation results indicate that the apparent Young’s modulus of NC gold decreases with the decrease of strain rate, especially for strain rates above 1 ns−1. The rearrangement of atoms near grain boundaries is a response to the decrease of apparent Young’s modulus. Indeed, the flow stress is also sensitive to the strain rate and decreases following the strain rate’s decrease. This can be found from the change of strain rate sensitivity and activation volume with the strain rate. Temperature has little effect on the activation volume of NC gold with small grain size, but has an obvious effect on that of relatively large grain size (such as 18 nm) under low strain rate (0.01 ns−1). Finally, grain growth in the deformation process is found to be sensitive to strain rate and the critical size for grain growth increases following the decrease of strain rate.
Shear Induced TiO2 Nano Structure Using Brush-Coating for Liquid Crystal Alignment
Authors: Jang Jong In , Jeong Hae-Chang
Published: September 2020

We have developed a very useful and cost-effective liquid crystal (LC) alignment layer of brush-coated TiO2 that is solution-processable for twisted nematic (TN) LC cells. TiO2 was prepared via the sol-gel method. The TiO2 solution was brush-coated on the substrate, followed by an annealing process. During the brush-coating process, a retracting force is generated on the deposited TiO solutions along the coating direction. The annealing process hardens the TiO2 and generates shearing stress arising from the retracting force along the brush-coating direction. The shearing stress created highly oriented nano/microstructure and uniformly aligned LCs with a stable pretilt angle of 0.6°. TN mode LC cells based on brush-coated TiO2 exhibited a performance of 12.5 ms of response and a threshold voltage of 1.8 V. Our brush-coated TiO2 incorporates two steps of the film deposition and alignment process into one step.
Discovery of Two New Astyanax Cavefish Localities Leads to Further Understanding of the Species Biogeography
Authors: Espinasa Luis , Ornelas-García Claudia Patricia , Legendre Laurent , Rétaux Sylvie , Best Alexandra , Gamboa-Miranda Ramses , Espinosa-Pérez Hector , Sprouse Peter
Published: September 2020

The Astyanax species complex has two morphs: a blind, depigmented morph which inhabits caves in México and an eyed, pigmented surface-dwelling morph. The eyed morph can also be found in a few caves, sometimes hybridizing with the cave morph. This species complex has arguably become the most prominent model system among cave organisms for the study of evolutionary development and genomics. Before this study, 32 caves were known to be inhabited by the cave morph, 30 of them within the El Abra region. The purpose of this study was to conduct new surveys of the area and to assess some unconfirmed reports of caves presumably inhabited by troglomorphic fish. We describe two new localities, Sótano del Toro #2 and Sótano de La Calera. These two caves comprise a single hydrologic system together with the previously described cave of Sótano del Toro. The system is inhabited by a mixed population of troglomorphic, epigeomorphic, and presumably hybrid fish. Furthermore, Astyanax cavefish and the mysid shrimp Spelaeomysis quinterensis show a phylogeographic convergence that supports the notion that the central Sierra de El Abra is a biogeographical region that has influenced the evolutionary history of its aquatic community across species. The presumptive location of the boundaries of this biogeographical region are identified.
Panoramic Ultrasound Examination of Posterior Neck Extensors in Healthy Subjects: Intra-Examiner Reliability Study
Authors: Valera-Calero Juan Antonio , Gallego-Sendarrubias Gracia María , Fernández-de-las-Peñas César , Cleland Joshua A. , Ortega-Santiago Ricardo , Arias-Buría José Luis
Published: September 2020

Previous studies analyzing morphometry of posterior cervical muscles with ultrasound (US) imaging have mainly used Brightness mode (B-mode). Our aim was to investigate the intra-examiner reliability of panoramic US imaging for assessing posterior-lateral cervical muscle layers. Panoramic US images of the neck at C4/C5 level were acquired in 25 asymptomatic subjects (40% women; mean age: 24 years) by an experienced assessor. The cross-sectional area (CSA) of the upper trapezius, splenius, semispinalis, multifidi, rotators, and levator scapulae was measured from panoramic US scans on two separate days. Intra-class correlation coefficients (ICC3,1), standard error of measurement (SEM), minimal detectable change (MDC) and mean, absolute and percent errors were calculated. In general, intra-examiner reliability was excellent with ICC3,1 ranging from 0.978 (trapezius) to 0.993 (semispinalis). The SEM ranged from 0.02 (multifidus) to 0.07 (semispinalis/levator), whereas the MDC ranged from 0.05 (cervical multifidus) to 0.19 (levator/semispinalis). Absolute error was lower than 0.11 cm2 (levator/semispinalis). No differences between males and females were found. This study found that intra-examiner/rater reliability of panoramic US imaging was excellent for assessing the CSA of the posterior-lateral neck extensor muscles in asymptomatic subjects. The current findings suggest that panoramic US may be a reliable technique for examining the size of the cervical extensor muscles in both males and females.
Whole Exome Sequencing as a Diagnostic Tool for Unidentified Muscular Dystrophy in a Vietnamese Family
Authors: Nguyen Ngoc-Lan , Ngoc Can Thi Bich , Vu Chi Dung , Nguyen Thi Thu Huong , Nguyen Huy Hoang
Published: September 2020

Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.
Indocyanine Green-Enhanced Colorectal Surgery—between Being Superfluous and Being a Game-Changer
Authors: Alius Catalin , Tudor Corneliu , Badiu Cristinel Dumitru , Dascalu Ana Maria , Smarandache Catalin Gabriel , Sabau Alexandru Dan , Tanasescu Ciprian , Balasescu Simona Andreea , Serban Dragos
Published: September 2020

Nowadays, surgical innovations incorporate new technological conquests and must be validated by evidence-based medicine. The use of augmented reality-assisted indocyanine green (ICG) fluorescence has generated a myriad of intraoperative applications such as demonstration of key anatomical landmarks, sentinel lymph nodes, and real-time assessment of local blood flow. This paper presents a systematic review of the clinical evidence regarding the applications of ICG near-infrared (NIR) fluorescence in colorectal surgery. After we removed duplicate publications and screened for eligibility, a total of 36 articles were evaluated: 23 on perfusion assessment, 10 on lymph node mapping, and 3 on intraoperative identification of ureters. Lack of homogenous studies, low statistical power, and confounding evidence were found to be common amongst publications supporting the use of ICG in colorectal surgery, raising concerns over this seductive technique′s cost efficiency and redundancy. The compiled data showed that ICG NIR fluorescence may be a game-changer in particular situations, as proven for low colorectal anastomosis or lateral pelvic lymph node dissection, but it remains controversial for routine use and sentinel lymph node assessment. Further randomized studies are needed to confirm these conclusions. Future research directions include tumor-targeted fluorescence imaging and digital software for quantitative evaluation of fluorescence.
Imbalance Fault Detection Based on the Integrated Analysis Strategy for Marine Current Turbines under Variable Current Speed
Authors: Xie Tao , Wang Tianzhen , Diallo Demba , Razik Hubert
Published: September 2020

The conversion of marine current energy into electricity with marine current turbines (MCTs) promises renewable energy. However, the reliability and power quality of marine current turbines are degraded due to marine biological attachments on the blades. To benefit from all the information embedded in the three phases, we created a fault feature that was the derivative of the current vector modulus in a Concordia reference frame. Moreover, because of the varying marine current speed, fault features were non-stationary. A transformation based on new adaptive proportional sampling frequency (APSF) transformed them into stationary ones. The fault indicator was derived from the amplitude of the shaft rotating frequency, which was itself derived from its power spectrum. The method was validated with data collected from a test bed composed of a marine current turbine coupled to a 230 W permanent magnet synchronous generator. The results showed the efficiency of the method to detect an introduced imbalance fault with an additional mass of 80–220 g attached to blades. In comparison to methods that use a single piece of electrical information (phase current or voltage), the fault indicator based on the three currents was found to be, on average, 2.2 times greater. The results also showed that the fault indicator increased monotonically with the fault severity, with a 1.8 times-higher variation rate, as well as that the method is robust for the flow current speed that varies from 0.95 to 1.3 m/s.