bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical Analysis of Surface-Level Ozone Exceedances during the 2015 Pan American Games
Authors: Stroud Craig , Ren Shuzhan , Zhang Junhua , Moran Michael , Akingunola Ayodeji , Makar Paul , Munoz-Alpizar Rodrigo , Leroyer Sylvie , Bélair Stéphane , Sills David , Brook Jeffrey
Published: June 2020

Surface-level ozone (O3) continues to be a significant health risk in the Greater Toronto Hamilton Area (GTHA) of Canada even though precursor emissions in the area have decreased significantly over the past two decades. In July 2015, Environment and Climate Change Canada (ECCC) led an intensive field study coincident with Toronto hosting the 2015 Pan American Games. During the field study, the daily 1-h maximum O3 standard (80 ppbv) was exceeded twice at a measurement site in North Toronto, once on July 12 and again on July 28. In this study, ECCC’s 2.5-km configuration of the Global Environmental Multi-scale (GEM) meteorological model was combined with the Modelling Air-quality and CHemistry (MACH) on-line atmospheric chemistry model and the Town Energy Balance (TEB) urban surface parameterization to create a new urban air quality modelling system. In general, the model results showed that the nested 2.5-km grid-spaced urban air quality model performed better in statistical scores compared to the piloting 10-km grid-spaced GEM-MACH model without TEB. Model analyses were performed with GEM-MACH-TEB for the two exceedance periods. The local meteorology for both cases consisted of light winds with the highest O3 predictions situated along lake-breeze fronts. For the July 28 case, O3 production sensitivity analysis along the trajectory of the lake-breeze circulation showed that the region of most efficient O3 production occurred in the updraft region of the lake-breeze front, as the precursors to O3 formation underwent vertical mixing. In this updraft region, the ozone production switches from volatile organic compound (VOC)-sensitive to NOx-sensitive, and the local net O3 production rate reaches a maximum. This transition in the chemical regime is a previously unidentified factor for why O3 surface-level mixing ratios maximize along the lake-breeze front. For the July 12 case, differences between the model and observed Lake Ontario water temperature and the strength of lake-breeze opposing wind flow play a role in differences in the timing of the lake-breeze, which impacts the predicted location of the O3 maximum north of Toronto.
Chemical Migration from Beverage Packaging Materials—A Review
Authors: Schmid Petra , Welle Frank
Published: June 2020

The packaging of a beverage is an essential element for customer convenience and the preservation of beverage quality. On the other hand, chemical compounds present in the packaging materials, either intentionally added or non-intentionally, may be transferred to the food. With a huge variety of materials used in the production, beverage packaging requires safety assessments with respect to the migration of packaging compounds into the filled beverages. The present article deals with potential migrants from different materials for beverage packaging, including PET bottles, glass bottles, metal cans and cardboard multilayers. The list of migrants comprises monomers and additives, oligomers or degradation products. The article presents a review on scientific literature and summarizes European food regulatory requirements. The review shows no evidence of critical substances migrating from packaging into beverages. Testing the migration in real beverages during and at the end of the shelf life shows compliance with the specific migration limits. Accelerated testing using food simulants, however, shows higher migration in some cases, especially at high temperatures in ethanolic simulants. For some migrants, more realistic testing conditions should be applied in order to show compliance with their specific migration limits.
Rapid Clathrin-Mediated Uptake of Recombinant α-Gal-A to Lysosome Activates Autophagy
Authors: Ivanova Margarita M. , Dao Julia , Kasaci Neil , Adewale Benjamin , Fikry Jacqueline , Goker-Alpan Ozlem
Published: June 2020

Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A (rh-α-Gal A) is the standard treatment for Fabry disease (FD). ERT has shown a significant impact on patients; however, there is still morbidity and mortality in FD, resulting in progressive cardiac, renal, and cerebrovascular pathology. The main pathway for delivery of rh-α-Gal A to lysosome is cation-independent mannose-6-phosphate receptor (CI-M6PR) endocytosis, also known as insulin-like growth factor 2 receptor (IGF2R) endocytosis. This study aims to investigate the mechanisms of uptake of rh-α-Gal-A in different cell types, with the exploration of clathrin-dependent and caveolin assisted receptor-mediated endocytosis and the dynamics of autophagy-lysosomal functions. rh-α-Gal-A uptake was evaluated in primary fibroblasts, urine originated kidney epithelial cells, and peripheral blood mononuclear cells derived from Fabry patients and healthy controls, and in cell lines HEK293, HTP1, and HUVEC. Uptake of rh-α-Gal-A was more efficient in the cells with the lowest endogenous enzyme activity. Chloroquine and monensin significantly blocked the uptake of rh-α-Gal-A, indicating that the clathrin-mediated endocytosis is involved in recombinant enzyme delivery. Alternative caveolae-mediated endocytosis coexists with clathrin-mediated endocytosis. However, clathrin-dependent endocytosis is a dominant mechanism for enzyme uptake in all cell lines. These results show that the uptake of rh-α-Gal-A occurs rapidly and activates the autophagy-lysosomal pathway.
Recent Advances in CRISPR/Cas9 Delivery Strategies
Authors: Yip Bon
Published: June 2020

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has revolutionized the field of gene editing. Continuous efforts in developing this technology have enabled efficient in vitro, ex vivo, and in vivo gene editing through a variety of delivery strategies. Viral vectors are commonly used in in vitro, ex vivo, and in vivo delivery systems, but they can cause insertional mutagenesis, have limited cloning capacity, and/or elicit immunologic responses. Physical delivery methods are largely restricted to in vitro and ex vivo systems, whereas chemical delivery methods require extensive optimization to improve their efficiency for in vivo gene editing. Achieving a safe and efficient in vivo delivery system for CRISPR/Cas9 remains the most challenging aspect of gene editing. Recently, extracellular vesicle-based systems were reported in various studies to deliver Cas9 in vitro and in vivo. In comparison with other methods, extracellular vesicles offer a safe, transient, and cost-effective yet efficient platform for delivery, indicating their potential for Cas9 delivery in clinical trials. In this review, we first discuss the pros and cons of different Cas9 delivery strategies. We then specifically review the development of extracellular vesicle-mediated gene editing and highlight the strengths and weaknesses of this technology.
Transcriptome-Wide Analysis of CXCR5 Deficient Retinal Pigment Epithelial (RPE) Cells Reveals Molecular Signatures of RPE Homeostasis
Authors: Saddala Madhu Sudhana , Lennikov Anton , Mukwaya Anthony , Huang Hu
Published: June 2020

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population. In our previous studies, we found that deficiency of CXCR5 causes AMD-like pathological phenotypes in mice, characterized by abnormalities and dysfunction of the retinal pigment epithelium (RPE) cells. The abnormalities included abnormal cellular shape and impaired barrier function. In the present study, primary RPE cells were derived separately from CXCR5 knockout (KO) mice and from C57BL6 wild type (WT). The isolated primary cells were cultured for several days, and then total RNA was isolated and used for library preparation, sequencing, and the resultant raw data analyzed. Relative to the WT, a total of 1392 differentially expressed genes (DEG) were identified. Gene ontology analysis showed various biological processes, cellular components, and molecular functions were enriched. Pathway enrichment analysis revealed several pathways, including the PI3K-Akt signaling, mTOR signaling, FoxO, focal adhesion, endocytosis, ubiquitin-mediated proteolysis, TNFα-NF-kB Signaling, adipogenesis genes, p53 signaling, Ras, autophagy, epithelial–mesenchymal transition (EMT), and mitochondrial pathway. This study explores molecular signatures associated with deficiency of CXCR5 in RPE cells. Many of these signatures are important for homeostasis of this tissue. The identified pathways and genes require further evaluation to better understand the pathophysiology of AMD.
Hand Fine Motor Skill Disability Correlates with Cognition in Patients with Moderate-to-Advanced Parkinson’s Disease
Authors: Tan Shennie , Hong Chien Tai , Chen Jia-Hung , Chan Lung , Chi Wen-Chou , Yen Chia-Feng , Liao Hua-Fang , Liou Tsan-Hon , Wu Dean
Published: June 2020

In older individuals, hand fine motor skill disability is associated with cognitive levels. Similarly, patients with moderate-to-advanced Parkinson’s disease (PD) often have cognitive dysfunction. Here, we investigated the association between hand fine motor skill and cognitive dysfunction in patients with moderate-to-advanced PD. Moderate and advanced PD patients with and without dementia were identified from the Taiwan Data Bank of Persons with Disability. Hand fine motor capacities, namely pen holding, buttoning, and knotting, were assessed with the World Health Organization Disability Assessment Schedule 2.0. Statistical analyses were performed on Statistical Analysis System (SAS) and a p value of <0.05 was considered significant. In total, 3440 patients with PD were enrolled, of which 612 had dementia, exhibiting significant disability in all three tasks. After adjustments for age, sex, and PD severity, pen holding and knotting were significantly associated with PD dementia. The presence of any disability in either task was not only sensitive to the presence of dementia but also associated with cognitive disability in moderate and advanced PD patients without dementia. In conclusion, hand fine motor skill disability was associated with cognitive disability in patients with moderate-to-advanced PD. These simple hand fine motor skills may thus be applicable in screening tests for the early identification of cognitive dysfunction in patients with moderate-to-advanced PD.
Inhibition Effect of Tartrate Ions on the Localized Corrosion of Steel in Pore Solution at Different Chloride Concentrations
Authors: Cabrini Marina , Lorenzi Sergio , Coffetti Denny , Coppola Luigi , Pastore Tommaso
Published: June 2020

The aim of this work is the evaluation of the inhibition effect of tartrate ions with respect to the localized corrosion of steel reinforcements in alkaline solution as a function of the concentration of chlorides ions. Weight loss tests and electrochemical tests were carried out in saturated Ca(OH)2 solution with NaOH at pH 12.7 and 13.2. The results only evidence a slight inhibition effect at pH 12.7, whereas at pH 13.2 the pitting onset is inhibited also for chloride concentration up to 3 M. Tartaric acid is a dicarboxylic acid with nucleophile substituents, which can act as a chelating agent both adsorbing on the surface of the passive film and forming a soluble complex with ferrous and ferric ions. Tartrate causes an increase in the passive current density but it prevents the depassivation of carbon steel due to the action of chlorides, thus preventing pitting initiation due to the competitive adsorption on metal surface.
Tailored Functionalized Magnetic Nanoparticles to Target Breast Cancer Cells Including Cancer Stem-Like Cells
Authors: Lazaro-Carrillo Ana , Calero Macarena , Aires Antonio , L. Cortajarena Aitziber , Simões Bruno M. , Latorre Alfonso , Somoza Álvaro , Clarke Robert B. , Miranda Rodolfo , Villanueva Angeles
Published: June 2020

Nanotechnology-based approaches hold substantial potential to avoid chemoresistance and minimize side effects. In this work, we have used biocompatible iron oxide magnetic nanoparticles (MNPs) called MF66 and functionalized with the antineoplastic drug doxorubicin (DOX) against MDA-MB-231 cells. Electrostatically functionalized MNPs showed effective uptake and DOX linked to MNPs was more efficiently retained inside the cells than free DOX, leading to cell inactivation by mitotic catastrophe, senescence and apoptosis. Both effects, uptake and cytotoxicity, were demonstrated by different assays and videomicroscopy techniques. Likewise, covalently functionalized MNPs using three different linkers—disulfide (DOX-S-S-Pyr, called MF66-S-S-DOX), imine (DOX-I-Mal, called MF66-I-DOX) or both (DOX-I-S-S-Pyr, called MF66-S-S-I-DOX)—were also analysed. The highest cell death was detected using a linker sensitive to both pH and reducing environment (DOX-I-S-S-Pyr). The greatest success of this study was to detect also their activity against breast cancer stem-like cells (CSC) from MDA-MB-231 and primary breast cancer cells derived from a patient with a similar genetic profile (triple-negative breast cancer). In summary, these nanoformulations are promising tools as therapeutic agent vehicles, due to their ability to produce efficient internalization, drug delivery, and cancer cell inactivation, even in cancer stem-like cells (CSCs) from patients.
Neuronal Repressor REST Controls Ewing Sarcoma Growth and Metastasis by Affecting Vascular Pericyte Coverage and Vessel Perfusion
Authors: Zhou Zhichao , Yang Yuanzheng , Wang Fei , Kleinerman Eugenie S.
Published: June 2020

Survival rates for Ewing sarcoma (ES) patients with metastatic disease have not improved in over 20 years. Tumor growth and metastasis are dependent on tumor vasculature expansion; therefore, identifying the regulators that control this process in ES may provide new therapeutic opportunities. ES expresses high levels of repressor element 1 silencing transcription factor (REST), which is regulated by the EWS-FLI-1 fusion gene. However, the role of REST in ES growth and the regulation of the tumor vasculature have not been elucidated. To study this role, we established REST-knockout human TC71 ES cell lines through CRISPR/Cas9 recombination. While knockout of REST did not alter tumor cell proliferation in vitro, REST knockout reduced tumor growth and metastasis to the lung in vivo and altered tumor vascular morphology and function. Tumor vessels in the REST-knockout tumors had a punctate appearance with significantly decreased tumor vascular pericytes, decreased perfusion, and increased permeability. REST-knockout tumors also showed increased apoptosis and hypoxia. These results indicate that REST plays a critical role in ES vascular function, which in turn impacts the ability of ES tumors to grow and metastasize. These findings therefore provide a basis for the targeting of REST as a novel therapeutic approach in ES.
The Role of the Gut Microbiome in Colorectal Cancer Development and Therapy Response
Authors: Sánchez-Alcoholado Lidia , Ramos-Molina Bruno , Otero Ana , Laborda-Illanes Aurora , Ordóñez Rafael , Medina José Antonio , Gómez-Millán Jaime , Queipo-Ortuño María Isabel
Published: June 2020

Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer-related deaths. Recently, several studies have demonstrated that gut microbiota can alter CRC susceptibility and progression by modulating mechanisms such as inflammation and DNA damage, and by producing metabolites involved in tumor progression or suppression. Dysbiosis of gut microbiota has been observed in patients with CRC, with a decrease in commensal bacterial species (butyrate-producing bacteria) and an enrichment of detrimental bacterial populations (pro-inflammatory opportunistic pathogens). CRC is characterized by altered production of bacterial metabolites directly involved in cancer metabolism including short-chain fatty acids and polyamines. Emerging evidence suggests that diet has an important impact on the risk of CRC development. The intake of high-fiber diets and the supplementation of diet with polyunsaturated fatty acids, polyphenols and probiotics, which are known to regulate gut microbiota, could be not only a potential mechanism for the reduction of CRC risk in a primary prevention setting, but may also be important to enhance the response to cancer therapy when used as adjuvant to conventional treatment for CRC. Therefore, a personalized modulation of the pattern of gut microbiome by diet may be a promising approach to prevent the development and progression of CRC and to improve the efficacy of antitumoral therapy.
Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice
Authors: Guarino Maria , Kumar Pavitra , Felser Andrea , Terracciano Luigi M. , Guixé-Muntet Sergi , Humar Bostjan , Foti Michelangelo , Nuoffer Jean-Marc , St-Pierre Marie V. , Dufour Jean-François
Published: June 2020

Non-alcoholic fatty liver disease (NAFLD) leads to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. For sedentary patients, lifestyle interventions combining exercise and dietary changes are a cornerstone of treatment. However, the benefit of exercise alone when dietary changes have failed is uncertain. We query whether exercise alone arrests the progression of NASH and tumorigenesis in a choline-deficient, high-fat diet (CD-HFD) murine model. Male C57Bl/6N mice received a control diet or CD-HFD for 12 weeks. CD-HFD mice were randomized further for 8 weeks of sedentariness (SED) or treadmill exercise (EXE). CD-HFD for 12 weeks produced NAFL. After 20 weeks, SED mice developed NASH and hepatic adenomas. Exercise attenuated the progression to NASH. EXE livers showed lower triglycerides and tumor necrosis factor-α expression, less fibrosis, less ballooning, and a lower NAFLD activity score than did SED livers. Plasma transaminases and triglycerides were lower. Exercise activated AMP-activated protein kinase (AMPK) with inhibition of mTORC1 and decreased S6 phosphorylation, reducing hepatocellular adenoma. Exercise activated autophagy with increased LC3-II/LC3-I and mitochondrial recruitment of phosphorylated PTEN-induced kinase. Therefore, exercise attenuates the transition from NAFL to NASH, improves biochemical and histological parameters of NAFLD, and impedes the progression of fibrosis and tumorigenesis associated with enhanced activation of AMPK signaling and favors liver autophagy. Our work supports the benefits of exercise independently of dietary changes.
Current Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor
Authors: Filippi Luca , Bruno Gennaro , Domazetovic Vladana , Favre Claudio , Calvani Maura
Published: June 2020

Melanoma is one of the most aggressive types of cancer and the most deadly skin cancer. According to World Health Organization, about 132,000 melanoma skin cancers occur globally each year. Thanks to the efficacy of new therapies, life expectation has been improved over the last years. However, some malignant melanomas still remain unresponsive to these therapies. The β-adrenergic system, among its many physiological roles, has been recognized as the main mediator of stress-related tumorigenic events. In particular, catecholamine activation of β-adrenergic receptors (β-ARs) affects several processes that sustain cancer progression. Among the β-AR subtypes, the β3-AR is emerging as an important regulator of tumorigenesis. In this review, we summarize data of different experimental studies focused on β3-AR involvement in tumor development in various types of cancer and, particularly, in melanoma. Taken together, the preclinical evidences reported in this review demonstrate the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression. Therefore, a need exists to further disseminate this new concept and to investigate more deeply the role of β3-AR as a possible therapeutic target for counteracting melanoma progression at clinical level.
Efficacy and Safety of Oncolytic Viruses in Randomized Controlled Trials: A Systematic Review and Meta-Analysis
Authors: Li Zengbin , Jiang Zeju , Zhang Yingxuan , Huang Xiaotian , Liu Qiong
Published: June 2020

Oncolytic virotherapy is a promising antitumor therapeutic strategy. It is based on the ability of viruses to selectively kill cancer cells and induce host antitumor immune responses. However, the clinical outcomes of oncolytic viruses (OVs) vary widely. Therefore, we performed a meta-analysis to illustrate the efficacy and safety of oncolytic viruses. The Cochrane Library, PubMed, and EMBASE databases were searched for randomized controlled trials (RCTs) published up to 31 January 2020. The data for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were independently extracted by two investigators from 11 studies that met the inclusion criteria. In subgroup analyses, the objective response rate benefit was observed in patients treated with oncolytic DNA viruses (odds ratio (OR) = 4.05; 95% confidence interval (CI): 1.96–8.33; p = 0.0002), but not in those treated with oncolytic RNA viruses (OR = 1.00, 95% CI: 0.66–1.52, p = 0.99). Moreover, the intratumoral injection arm yielded a statistically significant improvement (OR = 4.05, 95% CI: 1.96–8.33, p = 0.0002), but no such improvement was observed for the intravenous injection arm (OR = 1.00, 95% CI: 0.66–1.52, p = 0.99). Among the five OVs investigated in RCTs, only talimogene laherparepvec (T-VEC) effectively prolonged the OS of patients (hazard ratio (HR), 0.79; 95% CI: 0.63–0.99; p = 0.04). None of the oncolytic virotherapies improved the PFS (HR = 1.00, 95% CI: 0.85–1.19, p = 0.96). Notably, the pooled rate of severe AEs (grade ≥3) was higher for the oncolytic virotherapy group (39%) compared with the control group (27%) (risk difference (RD), 12%; risk ratio (RR), 1.44; 95% CI: 1.17–1.78; p = 0.0006). This review offers a reference for fundamental research and clinical treatment of oncolytic viruses. Further randomized controlled trials are needed to verify these results.
Fanconi Anemia Pathway Activation by FOXM1 is Critical to Bladder Cancer Recurrence and Anticancer Drug Resistance
Authors: Roh Yun-Gil , Mun Jeong-Yeon , Kim Seon-Kyu , Park Won Young , Jeong Mi-So , Kim Tae Nam , Kim Won-Tae , Choi Yung Hyun , Chu In-Sun , Leem Sun-Hee
Published: June 2020

Although the 5-year survival rate of patients diagnosed with nonmuscle invasive bladder cancer (NMIBC) has reached 85%, more than 50% of patients suffer from frequent recurrences. To identify molecular targets associated with recurrence of NMIBC, we analyzed gene expression data and found that FOXM1 and FANCD2 were involved in recurrence. Therefore, we investigated how these genes were involved in the mechanism of recurrence and confirmed their usefulness as biomarkers. Investigation have shown that FOXM1 directly regulated the transcription of FANCD2, which is the key gene of the Fanconi anemia (FA) pathway. Depletion of FOXM1 resulted in DNA repair defects in the FA pathway and in decreased resistance to chemotherapy. Thus, the FANCD2-associated FA pathway activated by FOXM1 is an important mechanism involved in chemotherapy-related recurrence. In conclusion, FOXM1 and FANCD2 can be used as prognostic factors that are associated with high risk of recurrence and with anticancer drug resistance properties in NMIBC patients.
Targeted Osmotic Lysis of Highly Invasive Breast Carcinomas Using Pulsed Magnetic Field Stimulation of Voltage-Gated Sodium Channels and Pharmacological Blockade of Sodium Pumps
Authors: Paul Dennis , Maggi Paul , Piero Fabio Del , Scahill Steven D. , Sherman Kelly Jean , Edenfield Samantha , Gould Harry J.
Published: June 2020

Concurrent activation of voltage-gated sodium channels (VGSCs) and blockade of Na+ pumps causes a targeted osmotic lysis (TOL) of carcinomas that over-express the VGSCs. Unfortunately, electrical current bypasses tumors or tumor sections because of the variable resistance of the extracellular microenvironment. This study assesses pulsed magnetic fields (PMFs) as a potential source for activating VGSCs to initiate TOL in vitro and in vivo as PMFs are unaffected by nonconductive tissues. In vitro, PMFs (0–80 mT, 10 msec pulses, 15 pps for 10 min) combined with digoxin-lysed (500 nM) MDA-MB-231 breast cancer cells stimulus-dependently. Untreated, stimulation-only, and digoxin-only control cells did not lyse. MCF-10a normal breast cells were also unaffected. MDA-MB-231 cells did not lyse in a Na+-free buffer. In vivo, 30 min of PMF stimulation of MDA-MB-231 xenografts in J/Nu mice or 4T1 homografts in BALB/c mice, concurrently treated with 7 mg/kg digoxin reduced tumor size by 60–100%. Kidney, spleen, skin and muscle from these animals were unaffected. Stimulation-only and digoxin-only controls were similar to untreated tumors. BALB/C mice with 4T1 homografts survived significantly longer than mice in the three control groups. The data presented is evidence that the PMFs to activate VGSCs in TOL provide sufficient energy to lyse highly malignant cells in vitro and to reduce tumor growth of highly malignant grafts and improve host survival in vivo, thus supporting targeted osmotic lysis of cancer as a possible method for treating late-stage carcinomas without compromising noncancerous tissues.
Patient-Derived In Vitro Models for Drug Discovery in Colorectal Carcinoma
Authors: Ramzy George M. , Koessler Thibaud , Ducrey Eloise , McKee Thomas , Ris Frédéric , Buchs Nicolas , Rubbia-Brandt Laura , Dietrich Pierre-Yves , Nowak-Sliwinska Patrycja
Published: June 2020

Lack of relevant preclinical models that reliably recapitulate the complexity and heterogeneity of human cancer has slowed down the development and approval of new anti-cancer therapies. Even though two-dimensional in vitro culture models remain widely used, they allow only partial cell-to-cell and cell-to-matrix interactions and therefore do not represent the complex nature of the tumor microenvironment. Therefore, better models reflecting intra-tumor heterogeneity need to be incorporated in the drug screening process to more reliably predict the efficacy of drug candidates. Classic methods of modelling colorectal carcinoma (CRC), while useful for many applications, carry numerous limitations. In this review, we address the recent advances in in vitro CRC model systems, ranging from conventional CRC patient-derived models, such as conditional reprogramming-based cell cultures, to more experimental and state-of-the-art models, such as cancer-on-chip platforms or liquid biopsy.
Long Noncoding RNAs Involved in the Endocrine Therapy Resistance of Breast Cancer
Authors: Takeiwa Toshihiko , Ikeda Kazuhiro , Mitobe Yuichi , Horie-Inoue Kuniko , Inoue Satoshi
Published: June 2020

Long noncoding RNAs (lncRNAs) are defined as RNAs longer than 200 nucleotides that do not encode proteins. Recent studies have demonstrated that numerous lncRNAs are expressed in humans and play key roles in the development of various types of cancers. Intriguingly, some lncRNAs have been demonstrated to be involved in endocrine therapy resistance for breast cancer through their own mechanisms, suggesting that lncRNAs could be promising new biomarkers and therapeutic targets of breast cancer. Here, we summarize the functions and mechanisms of lncRNAs related to the endocrine therapy resistance of breast cancer.
A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors
Authors: de Braud Filippo , Machiels Jean-Pascal H. , Boggiani Daniela , Rottey Sylvie W.H. , Duca Matteo , Laruelle Marie , Salvagni Stefania , Damian Silvia , Lapeire Lore D.F. , Tiseo Marcello , Dermine Alexandre , Ould-Kaci Mahmoud , Braunger Juergen , Rascher Juliane , Fischer Daniela , Hoefler Josef , Mariani Gabriella L. , Cresta Sara
Published: June 2020

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.
The Recombinant Fragment of Human κ-Casein Induces Cell Death by Targeting the Proteins of Mitochondrial Import in Breast Cancer Cells
Authors: Richter Max , Wohlfromm Fabian , Kähne Thilo , Bongartz Hannes , Seyrek Kamil , Kit Yuriy , Chinak Olga , Richter Vladimir A. , Koval Olga A. , Lavrik Inna N.
Published: June 2020

Breast cancer is still one of the most common cancers for women. Specified therapeutics are indispensable for optimal treatment. In previous studies, it has been shown that RL2, the recombinant fragment of human κ-Casein, induces cell death in breast cancer cells. However, the molecular mechanisms of RL2-induced cell death remain largely unknown. In this study, mechanisms of RL2-induced cell death in breast cancer cells were systematically investigated. In particular, we demonstrate that RL2 induces loss of mitochondrial membrane potential and cellular ATP loss followed by cell death in breast cancer cells. The mass spectrometry-based screen for RL2 interaction partners identified mitochondrial import protein TOM70 as a target of RL2, which was subsequently validated. Further to this, we show that RL2 is targeted to mitochondria after internalization into the cells, where it can also be found in the dimeric form. The importance of TOM70 and RL2 interaction in RL2-induced reduction in ATP levels was validated by siRNA-induced downregulation of TOM70, resulting in the partial rescue of ATP production. Taken together, this study demonstrates that RL2–TOM70 interaction plays a key role in RL2-mediated cell death and targeting this pathway may provide new therapeutic options for treating breast cancer.
Benefits of Conversion Surgery after Multimodal Treatment for Unresectable Pancreatic Ductal Adenocarcinoma
Authors: Yanagimoto Hiroaki , Satoi Sohei , Yamamoto Tomohisa , Yamaki So , Hirooka Satoshi , Kotsuka Masaya , Ryota Hironori , Ishida Mitsuaki , Matsui Yoichi , Sekimoto Mitsugu
Published: June 2020

Background: Traditionally, the treatment options for unresectable locally advanced (UR-LA) and metastatic (UR-M) pancreatic ductal adenocarcinoma (PDAC) are palliative chemotherapy or chemoradiotherapy. The benefits of surgery for such patients remains unknown. The present study investigated clinical outcomes of patients undergoing conversion surgery (CS) after chemo(radiation)therapy for initially UR-PDAC. Methods: We recruited patients with UR-PDAC who underwent chemo(radiation)therapy for initially UR-PDAC between April 2006 and September 2017. We analyzed resectability of CS, predictive parameters for overall survival, and early recurrence (within six months). Results: A total of 468 patients (108 with UR-LA and 360 with UR-M PDAC) were enrolled in this study, of whom, 17 (15.7%) with UR-LA and 15 (4.2%) with UR-M underwent CS. The median survival time (MST) and five-year survival of patients who underwent CS was 37.2 months and 34%, respectively; significantly better than non-resected patients (nine months and 1%, respectively, p < 0.0001). MST did not differ according to UR-LA or UR-M (50.5 vs. 29.0 months, respectively, p = 0.53). Early recurrence after CS occurred in eight patients (18.8%). Lymph node metastasis, positive washing cytology, large tumor size (>35 mm), and lack of postoperative adjuvant chemotherapy were statistically significant predictive factors for early recurrence. Moreover, the site of pancreatic lesion and administration of postoperative adjuvant chemotherapy were statistically significant prognostic factors for overall survival in the patients undergoing CS. Conclusion: Conversion surgery offers benefits in terms of increase survival for initially UR-PDAC for patients who responded favorably to chemo(radiation)therapy when combined with postoperative adjuvant chemotherapy.
Characterization of a Myeloid Activation Signature That Correlates with Survival in Melanoma Patients
Authors: Kremenovic Mirela , Rombini Nives , Chan Alfred A. , Gruber Thomas , Bäriswyl Lukas , Lee Delphine J. , Schenk Mirjam
Published: June 2020

Understanding the cellular interactions within the tumor microenvironment (TME) of melanoma paved the way for novel therapeutic modalities, such as T cell-targeted immune checkpoint inhibitors (ICI). However, only a limited fraction of patients benefits from such therapeutic modalities, highlighting the need for novel predictive and prognostic biomarkers. As myeloid cells orchestrate the tumor-specific immune response and influence the efficacy of ICI, assessing their activation state within the TME is of clinical relevance. Here, we characterized a myeloid activation (MA) signature, comprising the three genes Cxcl11, Gbp1, and Ido1, from gene expression data of human myeloid cells stimulated with poly(I:C) or cGAMP. This MA signature positively correlated to overall survival in melanoma. In addition, increased expression of the MA signature was observed in melanoma patients responding to ICI (anti-PD-1), as compared to non-responders. Furthermore, the MA signature was validated in the murine B16F10 melanoma model where it was induced and associated with decreased tumor growth upon intratumoral administration of poly(I:C) and cGAMP. Finally, we were able to visualize co-expression of the MA signature genes in myeloid cells of human melanoma tissues using RNAscope in situ hybridization. In conclusion, the MA signature indicates the activation state of myeloid cells and represents a prognostic biomarker for the overall survival in melanoma patients.
The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling
Authors: Tran Bang Manh , Flanagan Dustin James , Ebert Gregor , Warner Nadia , Tran Hoanh , Fifis Theodora , Kastrappis Georgios , Christophi Christopher , Pellegrini Marc , Torresi Joseph , Phesse Toby James , Vincan Elizabeth
Published: June 2020

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription. The effect of p22 on TCF/β-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/β-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or β-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/β-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer.
Impact of CD56 Continuously Recognizable as Prognostic Value of Acute Promyelocytic Leukemia: Results of Multivariate Analyses in the Japan Adult Leukemia Study Group (JALSG)-APL204 Study and a Review of the Literature
Authors: Takeshita Akihiro , Asou Norio , Atsuta Yoshiko , Furumaki Hiroaki , Sakura Toru , Ueda Yasunori , Sawa Masashi , Dobashi Nobuaki , Taniguchi Yasuhiro , Suzuki Rikio , Nakagawa Masaru , Tamaki Shigehisa , Hagihara Maki , Fujimaki Katsumichi , Minamiguchi Hitoshi , Fujita Hiroyuki , Yanada Masamitsu , Maeda Yoshinobu , Usui Noriko , Kobayashi Yukio , Kiyoi Hitoshi , Ohtake Shigeki , Matsumura Itaru , Naoe Tomoki , Miyazaki Yasushi ,   the Japan Adult Leukemia Study Group
Published: June 2020

Background: After long-term analysis of the JALSG-APL204 study we recently reported that maintenance therapy with tamibarotene was more effective than all-trans retinoic acid (ATRA) by reducing relapse in APL patients. Here, the clinical significance of other important prognostic factors was evaluated with multivariate analyses. Patients and Methods: Newly diagnosed acute promyelocytic leukemia (APL) patients were registered with the study. Induction was composed of ATRA and chemotherapy. Patients who achieved molecular remission after consolidation were randomly assigned to maintenance with tamibarotene or ATRA. Results: Of the 344 eligible patients, 319 (93%) achieved complete remission (CR). After completing consolidation, 269 patients underwent maintenance random assignment—135 to ATRA, and 134 to tamibarotene. By multivariate analysis, overexpression of CD56 in blast was an independent unfavorable prognostic factor for relapse-free survival (RFS) (p = 0.006) together with more than 10.0 × 109/L WBC counts (p = 0.001) and the ATRA arm in maintenance (p = 0.028). Of all phenotypes, CD56 was related most clearly to an unfavorable prognosis. The CR rate, mortality rate during induction and overall survival of CD56+ APL were not significantly different compared with CD56− APL. CD56 is continuously an independent unfavorable prognostic factor for RFS in APL patients treated with ATRA and chemotherapy followed by ATRA or tamibarotene maintenance therapy.
The Long and Short of It: The Emerging Roles of Non-Coding RNA in Small Extracellular Vesicles
Authors: Abramowicz Agata , Story Michael D
Published: June 2020

Small extracellular vesicles (EVs) play a significant role in intercellular communication through their non-coding RNA (ncRNA) cargo. While the initial examination of EV cargo identified both mRNA and miRNA, later studies revealed a wealth of other types of EV-related non-randomly packed ncRNAs, including tRNA and tRNA fragments, Y RNA, piRNA, rRNA, and lncRNA. A number of potential roles for these ncRNA species were suggested, with strong evidence provided in some cases, whereas the role for other ncRNA is more speculative. For example, long non-coding RNA might be used as a potential diagnostic tool but might also mediate resistance to certain cancer-specific chemotherapy agents. piRNAs, on the other hand, have a significant role in genome integrity, however, no role has yet been defined for the piRNAs found in EVs. While our knowledgebase for the function of ncRNA-containing EVs is still modest, the potential role that these EV-ensconced ncRNA might play is promising. This review summarizes the ncRNA content of EVs and describes the function where known, or the potential utility of EVs that harbor specific types of ncRNA.
Highly Active Transition Metal-Promoted CuCeMgAlO Mixed Oxide Catalysts Obtained from Multicationic LDH Precursors for the Total Oxidation of Methane
Authors: Al-Aani Hussein Mahdi S. , Trandafir Mihaela M. , Fechete Ioana , Leonat Lucia N. , Badea Mihaela , Negrilă Cătălin , Popescu Ionel , Florea Mihaela , Marcu Ioan-Cezar
Published: June 2020

To improve the catalytic performance of an active layered double hydroxide (LDH)-derived CuCeMgAlO mixed oxide catalyst in the total oxidation of methane, it was promoted with different transition-metal cations. Thus, two series of multicationic mixed oxides were prepared by the thermal decomposition at 750 °C of their corresponding LDH precursors synthesized by coprecipitation at constant pH of 10 under ambient atmosphere. The first series of catalysts consisted of four M(3)CuCeMgAlO mixed oxides containing 3 at.% M (M = Mn, Fe, Co, Ni), 15 at.% Cu, 10 at.% Ce (at.% with respect to cations), and with Mg/Al atomic ratio fixed to 3. The second series consisted of four Co(x)CuCeMgAlO mixed oxides with x = 1, 3, 6, and 9 at.% Co, while keeping constant the Cu and Ce contents and the Mg/Al atomic ratio. All the mixed oxides were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM) coupled with X-ray energy dispersion analysis (EDX), X-ray photoelectron spectroscopy (XPS), nitrogen adsorption-desorption at −196 °C, temperature-programmed reduction under hydrogen (H2-TPR), and diffuse reflectance UV-VIS spectroscopy (DR UV-VIS), while thermogravimetric and differential thermal analyses (TG-DTG-DTA) together with XRD were used for the LDH precursors. The catalysts were evaluated in the total oxidation of methane, a test reaction for volatile organic compounds (VOC) abatement. Their catalytic performance was explained in correlation with their physicochemical properties and was compared with that of a reference Pd/Al2O3 catalyst. Among the mixed oxides studied, Co(3)CuCeMgAlO was found to be the most active catalyst, with a temperature corresponding to 50% methane conversion (T50) of 438 °C, which was only 19 °C higher than that of a reference Pd/Al2O3 catalyst. On the other hand, this T50 value was ca. 25 °C lower than that observed for the unpromoted CuCeMgAlO system, accounting for the improved performance of the Co-promoted catalyst, which also showed a good stability on stream.
Effect of Ultrasound-Assisted Blanching on Myrosinase Activity and Sulforaphane Content in Broccoli Florets
Authors: Mahn Andrea , Quintero Julián , Castillo Noelia , Comett Raidel
Published: June 2020

Sulforaphane (SFN) is a health-promoting compound occurring in broccoli. It is formed by action of myrosinase in a two-step reaction that also yields undesirable compounds such as nitriles and isothionitriles. Different techniques affecting enzyme activity and tissue integrity were proposed to increase SFN content in the edible parts and discards of broccoli. Ultrasound processing is an emerging technology that produces these effects in foods, but has been poorly explored in broccoli so far. The aim of this work was to study the effect of ultrasound-assisted blanching on myrosinase activity and SFN content in broccoli florets. Myrosinase showed first-order inactivation kinetics in blanching at different temperatures with and without ultrasound processing. The inactivation rate was faster using ultrasound, with kinetic constants two orders of magnitude higher than without ultrasound. The activation energy (Ea) in traditional blanching (57.3 kJ mol−1) was higher than in ultrasound-assisted blanching (15.8 kJ mol−1). Accordingly, ultrasound accelerates myrosinase inactivation. The blanching time and temperature significantly affected myrosinase activity and SFN content. At 60 °C and 4 min of ultrasound-assisted blanching, myrosinase activity was minimum and SFN content was the highest. These findings may help to design SFN enrichment processes and will contribute to the valorization of agro-industrial wastes.
XPS Studies of the Initial Oxidation of Polycrystalline Rh Surface
Authors: Trzcinski Marek , Balcerowska-Czerniak Grażyna , Bukaluk Antoni
Published: June 2020

Increased interest in the oxidation process of polycrystalline rhodium, observed in recent years, is the result of its application in exhaust catalytic converters. However, most studies have involved sample surfaces with low Miller indices. In our research, we investigated polycrystalline rhodium foil containing crystallographically different, highly stepped, µm-sized crystallites. These crystallites were exposed to identical oxidizing conditions. To determine crystallographic orientation, the electron backscattering diffraction (EBSD) method was used. To investigate the initial stages of oxidation on the individual crystallites of Rh, X-ray photoelectron spectroscopy (XPS) studies were performed. The results obtained for the individual crystallites were compared and analyzed using chemical state quantification of XPS data and multivariate statistical analysis (MVA).
miR-23a-3p is a Key Regulator of IL-17C-Induced Tumor Angiogenesis in Colorectal Cancer
Authors: Lee Yunna , Kim Su Jin , Choo Jieun , Heo Gwangbeom , Yoo Jin-Wook , Jung Yunjin , Rhee Sang Hoon , Im Eunok
Published: June 2020

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy.