bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of High-Grade Clear Cell Renal Cell Carcinoma Based on Plasma mRNA Profiles in Patients with Localized Pathologic T1N0M0 Stage Disease
Authors: Park Jee Soo , Lee Hyo Jung , Almujalhem Ahmad , Althubiany Hatem Hamed , A Alqahatani Ali , Jang Won Sik , Kim Jongchan , Lee Seung Hwan , Rha Koon Ho , Ham Won Sik
Published: May 2020

A high nuclear grade is crucial to predicting tumor recurrence and metastasis in clear cell renal cell carcinomas (ccRCCs). We aimed to compare the mRNA profiles of tumor tissues and preoperative plasma in patients with localized T1 stage ccRCCs, and to evaluate the potential of the plasma mRNA profile for predicting high-grade ccRCCs. Data from a prospective cohort (n = 140) were collected between November 2018 and November 2019. Frozen tumor tissues and plasma were used to measure PBRM1, BAP1, SET domain-containing 2 (SETD2), KDM5C, FOXC2, CLIP4, AQP1, DDX11, BAIAP2L1, and TMEM38B mRNA levels, and correlation with the Fuhrman grade was investigated. Multivariate logistic regression analysis revealed significant association between high-grade ccRCC and SETD2 and DDX11 mRNA levels in tissues (odds ratio (β) = 0.021, 95% confidence interval (CI): 0.001–0.466, p = 0.014; β = 6.116, 95% CI: 1.729–21.631, p = 0.005, respectively) and plasma (β = 0.028, 95% CI 0.007–0.119, p < 0.001; β = 1.496, 95% CI: 1.187–1.885, p = 0.001, respectively). High-grade ccRCC prediction models revealed areas under the curve of 0.997 and 0.971 and diagnostic accuracies of 97.86% and 92.86% for the frozen tissue and plasma, respectively. SETD2 and DDX11 mRNA can serve as non-invasive plasma biomarkers for predicting high-grade ccRCCs. Studies with long follow-ups are needed to validate the prognostic value of these biomarkers in ccRCCs.
The Association between Selective Serotonin Reuptake Inhibitors (SSRIs) Use and the Risk of Bladder Cancer: A Nationwide Population-Based Cohort Study
Authors: Liu Yi-Chun , Chen Vincent Chin-Hung , Lu Mong-Liang , Lee Min-Jing , McIntyre Roger S. , Majeed Amna , Lee Yena , Chen Yi-Lung
Published: May 2020

Background: Past studies suggest mixed associations between selective serotonin reuptake inhibitor (SSRI) prescription and carcinogenic risk. There is no epidemiological study reporting on the association between SSRI use and the incidence of bladder cancer. The aim of this study is to determine whether SSRI use influences the risk of bladder cancer. Methods: We conducted a nationwide retrospective cohort study by Taiwan’s National Health Insurance Research Database from January 1, 1997 to December 31, 2013. 192,392 SSRI prescribed individuals were randomly matched 1 to 1 with 191,786 individuals who had never received any SSRIs by propensity scores match. The Cox Proportional Hazard models were conducted to examine the risk of bladder cancer between individuals prescribed SSRIs and individuals not prescribed SSRIs. Results: SSRIs were associated with significant reduced risk of bladder cancer with 0.5, 1, and 2 year induction periods (adjusted hazard ratio (aHR) = 0.86, 95% CI (confidence interval) = 0.76–0.98, aHR = 0.85, 95% CI = 0.75–0.97, and aHR = 0.77, 95% CI = 0.66–0.89). When examining the effect of specific SSRI, there was significantly lower risk of bladder cancer in individuals prescribed fluoxetine (6 month induction period: aHR = 0.78, 95% CI = 0.65–0.93; 1 year induction period: aHR = 0.78, 95% CI = 0.65–0.94; 2 year induction period: aHR = 0.73, 95% CI = 0.60–0.89), paroxetine (6 month induction period: aHR = 0.78, 95% CI = 0.61–0.99; 1 year induction period: aHR = 0.79, 95% CI = 0.61–1.01; 2 year induction period: aHR = 0.72, 95% CI = 0.54–0.95), and citalopram (6 month induction period: aHR = 0.74, 95% CI = 0.53–1.03; 1 year induction period: aHR = 0.70, 95% CI = 0.50–0.99; 2 year induction period: aHR = 0.60, 95% CI = 0.41–0.88). Conclusions: Individuals prescribed fluoxetine, paroxetine, or citalopram had a reduced risk of bladder cancer in this large, cross-national database.
Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge
Authors: Abbott David Michael , Bortolotto Chandra , Benvenuti Silvia , Lancia Andrea , Filippi Andrea Riccardo , Stella Giulia Maria
Published: May 2020

Mesothelioma is a malignancy of serosal membranes including the peritoneum, pleura, pericardium and the tunica vaginalis of the testes. Malignant mesothelioma (MM) is a rare disease with a global incidence in countries like Italy of about 1.15 per 100,000 inhabitants. Malignant Pleural Mesothelioma (MPM) is the most common form of mesothelioma, accounting for approximately 80% of disease. Although rare in the global population, mesothelioma is linked to industrial pollutants and mineral fiber exposure, with approximately 80% of cases linked to asbestos. Due to the persistent asbestos exposure in many countries, a worldwide progressive increase in MPM incidence is expected for the current and coming years. The tumor grows in a loco-regional pattern, spreading from the parietal to the visceral pleura and invading the surrounding structures that induce the clinical picture of pleural effusion, pain and dyspnea. Distant spreading and metastasis are rarely observed, and most patients die from the burden of the primary tumor. Currently, there are no effective treatments for MPM, and the prognosis is invariably poor. Some studies average the prognosis to be roughly one-year after diagnosis. The uniquely poor mutational landscape which characterizes MPM appears to derive from a selective pressure operated by the environment; thus, inflammation and immune response emerge as key players in driving MPM progression and represent promising therapeutic targets. Here we recapitulate current knowledge on MPM with focus on the emerging network between genetic asset and inflammatory microenvironment which characterize the disease as amenable target for novel therapeutic approaches.
Targeted Dual Intervention-Oriented Drug-Encapsulated (DIODE) Nanoformulations for Improved Treatment of Pancreatic Cancer
Authors: Madamsetty Vijay Sagar , Pal Krishnendu , Dutta Shamit Kumar , Wang Enfeng , Mukhopadhyay Debabrata
Published: May 2020

Despite recent advancements, effective treatment for pancreatic ductal adenocarcinoma (PDAC) has remained elusive. The overall survival rate in PDAC patients has been dismally low due to resistance to standard therapies. In fact, the failure of monotherapies to provide long-term survival benefits in patients led to ascension of several combination therapies for PDAC treatment. However, these combination therapies provided modest survival improvements while increasing treatment-related adverse side effects. Hence, recent developments in drug delivery methods hold the potential for enhancing therapeutic benefits by offering cocktail drug loading and minimizing chemotherapy-associated side effects. Nanoformulations-aided deliveries of anticancer agents have been a success in recent years. Yet, improving the tumor-targeted delivery of drugs to PDAC remains a major hurdle. In the present paper, we developed several new tumor-targeted dual intervention-oriented drug-encapsulated (DIODE) liposomes. We successfully formulated liposomes loaded with gemcitabine (G), paclitaxel (P), erlotinib (E), XL-184 (c-Met inhibitor, X), and their combinations (GP, GE, and GX) and evaluated their in vitro and in vivo efficacies. Our novel DIODE liposomal formulations improved median survival in comparison with gemcitabine-loaded liposomes or vehicle. Our findings are suggestive of the importance of the targeted delivery for combination therapies in improving pancreatic cancer treatment.
Added Value of Computed Tomography to Ultrasonography for Assessing LN Metastasis in Preoperative Patients with Thyroid Cancer: Node-by-Node Correlation
Authors: Yoo Roh-Eul , Kim Ji-hoon , Hwang Inpyeong , Kang Koung Mi , Yun Tae Jin , Choi Seung Hong , Sohn Chul-Ho , Park Sun-Won
Published: May 2020

Diagnostic accuracy of US in the evaluation of lymph node (LN) metastasis for thyroid cancer patients is limited. We investigated the value of CT added to US for characterizing LNs in preoperative thyroid cancer patients by node-by-node correlation. A total of 225 primary thyroid cancer patients who underwent LN biopsy were included. Based on node-by-node correlation, 274 LNs were classified into probably benign, indeterminate, and suspicious categories on US, CT, and combined US/CT. Malignancy risks were calculated for each category and were compared between US/CT concordant and discordant cases. On US, CT, and combined US/CT, malignancy risks were 1.7%, 8.7%, and 0% in the probably benign category, 22.4%, 5.9%, and 8.0% in the indeterminate category, and 77.2%, 82.0%, and 75.6% in the suspicious category, respectively. Malignancy risk of the concordant suspicious category was higher than that of the discordant suspicious category (84.7% vs. 43.2%, p < 0.001). The addition of CT helped correctly detect additional metastasis in 16.4% of the US indeterminate LNs and in 1.7% of the US probably benign LNs. CT may complement US for LN characterization in thyroid cancer patients by suggesting the diagnostic confidence level for the suspicious category and helping correctly detect metastasis in US indeterminate LNs.
The Role of HPV and Non-HPV Sexually Transmitted Infections in Patients with Oropharyngeal Carcinoma: A Case Control Study
Authors: Kofler Barbara , Laimer Johannes , Bruckmoser Emanuel , Steinbichler Teresa B. , Runge Annette , Schartinger Volker H. , von Laer Dorothee , Borena Wegene
Published: May 2020

Background: Certain high-risk (hr) types of human papillomavirus (HPV) can cause cervical cancer in women and penile cancer in men. Hr-HPV can also cause cancers of the oropharynx and anus in both sexes. In the anal and cervical region, a contribution of co-infections with Ureaplasma spp. on the persistence of the hr-HPV infection by a profound inflammatory state is suggested. Here, we investigated if non-HPV sexually transmitted infections are associated with oropharyngeal carcinoma (OPC). Materials and Methods: In this case-control study, a brush test directly from the tumor surface of OPC patients (study group) and from the oropharynx of healthy volunteers (control group), both groups matching in age and sex, was performed. HPV subtypes were detected using a commercially available test kit. For non-HPV sexually transmitted infections (Ureaplasma spp., Chlamydia trachomatis, Mycoplasma hominis, and Mycoplasma genitalium), a multiplex nucleic acid amplification approach was performed. Results: In the study group, 96 patients (23 female/73 male), with histologically confirmed OPC and in the control group 112 patients (19 female/93 male), were included. Oropharyngeal hr-HPV-positivity was detected in 68% (65/96 patients) of the study group and 1.8% (2/112 patients) of the control group (p < 0.001). In three patients in the study group, Ureaplasma spp. was detected, whereas no patient was Ureaplasma spp. positive in the control group (p = 0.097). Chlamydia trachomatis, Mycoplasma hominis, and Mycoplasma genitalium were negative in both groups. Conclusion: Based on the current study, the prevalence of oropharyngeal Ureaplasma spp. among patients with OPC is low and does not support a role in oropharyngeal cancer. However, the detection of the pathogen only among OPC patients but not in the healthy individuals might indicate a potential role and needs further elucidation.
Real-Time Visualization of the Mascagni-Sappey Pathway Utilizing ICG Lymphography
Authors: Johnson Anna Rose , Granoff Melisa D. , Suami Hiroo , Lee Bernard T. , Singhal Dhruv
Published: May 2020

Background: Anatomic variations in lymphatic drainage pathways of the upper arm may have an important role in the pathophysiology of lymphedema development. The Mascagni–Sappey (M–S) pathway, initially described in 1787 by Mascagni and then again in 1874 by Sappey, is a lymphatic drainage pathway of the upper arm that normally bypasses the axilla. Utilizing modern lymphatic imaging modalities, there is an opportunity to better visualize this pathway and its potential clinical implications. Methods: A retrospective review of preoperative indocyanine green (ICG) lymphangiograms of consecutive node-positive breast cancer patients undergoing nodal resection was performed. Lymphography targeted the M-S pathway with an ICG injection over the cephalic vein in the lateral upper arm. Results: In our experience, the M-S pathway was not visualized in 22% (n = 5) of patients. In the 78% (n = 18) of patients where the pathway was visualized, the most frequent anatomic destination of the channel was the deltopectoral groove in 83% of patients and the axilla in the remaining 17%. Conclusion: Our study supports that ICG injections over the cephalic vein reliably visualizes the M-S pathway when present. Further study to characterize this pathway may help elucidate its potential role in the prevention or development of upper extremity lymphedema.
Oncogene-Addicted Non-Small-Cell Lung Cancer: Treatment Opportunities and Future Perspectives
Authors: Ferrara Miriam Grazia , Di Noia Vincenzo , D’Argento Ettore , Vita Emanuele , Damiano Paola , Cannella Antonella , Ribelli Marta , Pilotto Sara , Milella Michele , Tortora Giampaolo , Bria Emilio
Published: May 2020

Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3–7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients.
Nano-Ru Supported on Ni Nanowires for Low-Temperature Carbon Dioxide Methanation
Authors: Siudyga Tomasz , Kapkowski Maciej , Janas Dawid , Wasiak Tomasz , Sitko Rafał , Zubko Maciej , Szade Jacek , Balin Katarzyna , Klimontko Joanna , Lach Daniel , Popiel Judyta , Smoliński Adam , Polanski Jaroslaw
Published: May 2020

In this study, we investigated the catalytic performance of Ru nanoparticles (NPs) supported on Ni-nanowires for the first time. This appears to be a highly efficient catalyst for low-temperature methanation, e.g., ca. 100% conversion and 100% of CH4 selectivity can be achieved at ca. 179 °C, while the turnover frequency (TOF) value was 2479.2 h−1. At the same time, the onset of a reaction was observed at a temperature as low as 130 °C. The comparison of nano-Pd and nano-Ru supported on Ni-nanowires enabled us to prove that oxidized surface metals are highly important for the high activity of the investigated nano-Ru@nanowired-Ni. Moreover, similar to the microscopic Sabatier rule, which indicates that some optimal reactivity level of a catalyst exists, we showed that Ni-nanowires (a higher specific surface area than a standard metal surface, e.g., in the form of a metal foam, but lower than nano-sized materials) significantly enhances the performance of the Ru-Ni catalytic system.
Facile Synthesis of Amorphous C3N4ZnxOy (x, y = 0.32–1.10) with High Photocatalytic Efficiency for Antibiotic Degradation
Authors: Zhang Ran , Dong Jing Xian , Gao Guo Liang , Wang Xue Lu , Yao Ye-Feng
Published: May 2020

The development of novel, noble metal-free semiconductor catalysts with high efficiency is of great importance for the degradation of organic compounds. Among them, amorphous materials have been extensively studied for their unique and commercially useful properties. Here, a completely amorphous, noble metal-free photocatalyst C3N4ZnxOy (x, y = 0.32–1.10) was successfully synthesized from urea and ZnO by a simple high-temperature polymerization method. As the Zn content increased, the short-range ordered structures of the amorphous samples were still retained, as revealed by XPS, FTIR, and ssNMR. Meanwhile, the -CN3 structures were observed to be gradually destroyed, which may make the amorphous state more favorable for photocatalytic reactions. Compared with g-C3N4, the amorphous samples showed significantly reduced intensities in the photoluminescence spectra, indicating that the recombination rate of the photo-generated charge carriers was greatly reduced. It was confirmed that the optimized sample (C3N4Zn0.61O0.61) achieved a photocatalytic efficiency of 86.1% in the degradation of tetracycline hydrochloride under visible light irradiation within 1 h. This is about 2 times higher than that of both g-C3N4 and ZnO. This study emphasizes the importance of the amorphous structure in photocatalytic reactions, and this synthetic strategy may provide an effective model for designing other novel catalysts.
Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection
Authors: Borger Pieter , Buzdin Anton , Sorokin Maksim , Kachaylo Ekaterina , Humar Bostjan , Graf Rolf , Clavien Pierre-Alien
Published: May 2020

Despite numerous studies addressing normal liver regeneration, we still lack comprehensive understanding of the biological processes underlying failed liver regeneration. Therefore, we analyzed the activity of 271 intracellular signaling pathways (ISPs) by genome wide profiling of differentially expressed RNAs in murine liver tissue biopsies after normal hepatectomy (nHx; 68% of liver removed) and extended hepatectomy (eHx; 86% of liver removed). Comprehensive, genome-wide transcriptome profiling using RNAseq was performed in liver tissue obtained from mice (sham, nHx, and eHx) harvested 1, 8, 16, 32, and 48 h after operation (n = 3 per group) and the OncoFinder toolkit was used for an unsupervised, unbiased identification of intracellular signaling pathways (ISP) activity. We observed that the normal regenerative process requires a transient activation and silencing of approximately two dozen of ISPs. After nHx, the Akt Pathway represented with 13 branches, the Chromatin Pathway and the DDR Pathways dominated. After eHx, the ATM main pathway and two of its branches (Cell Survival; G2_M Checkpoint Arrest) dominated, as well as the Hypoxia Pathways. Further, 14 ISPs demonstrated a strong inverse regulation, with the Hedgehog and the Brca1 Main Pathways as chief activators after nHx, and the ATM Pathway(G2_M Checkpoint Arrest) as the dominating constraining response after eHx.
Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells
Authors: Meneses-Salas Elsa , García-Melero Ana , Blanco-Muñoz Patricia , Jose Jaimy , Brenner Marie-Sophie , Lu Albert , Tebar Francesc , Grewal Thomas , Rentero Carles , Enrich Carlos
Published: May 2020

We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann–Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 inhibition, using U18666A, were not due to upregulated AnxA6 mRNA expression, but caused by defects in AnxA6 protein degradation. Two KFERQ-motifs are believed to target AnxA6 to lysosomes for chaperone-mediated autophagy (CMA), and we hypothesized that the cholesterol accumulation in endolysosomes (LE/Lys) triggered by the NPC1 inhibition could interfere with the CMA pathway. Therefore, AnxA6 protein amounts and cholesterol levels in the LE/Lys (LE-Chol) compartment were analyzed in NPC1 mutant cells ectopically expressing lysosome-associated membrane protein 2A (Lamp2A), which is well known to induce the CMA pathway. Strikingly, AnxA6 protein amounts were strongly decreased and coincided with significantly reduced LE-Chol levels in NPC1 mutant cells upon Lamp2A overexpression. Therefore, these findings suggest Lamp2A-mediated restoration of CMA in NPC1 mutant cells to lower LE-Chol levels with concomitant lysosomal AnxA6 degradation. Collectively, we propose CMA to permit a feedback loop between AnxA6 and cholesterol levels in LE/Lys, encompassing a novel mechanism for regulating cholesterol homeostasis in NPC1 disease.
How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter
Authors: Yukawa Masashi , Teratani Yasuhiro , Toda Takashi
Published: May 2020

The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. The roles of three mitotic kinesins (Kinesin-5, Kinesin-6 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborate with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated the remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges.
Yeast-Based Genetic Interaction Analysis of Human Kinome
Authors: Kim Jae-Hong , Seo Yeojin , Jo Myungjin , Jeon Hyejin , Lee Won-Ha , Yachie Nozomu , Zhong Quan , Vidal Marc , Roth Frederick P. , Suk Kyoungho
Published: May 2020

Kinases are critical intracellular signaling proteins. To better understand kinase-mediated signal transduction, a large-scale human–yeast genetic interaction screen was performed. Among 597 human kinase genes tested, 28 displayed strong toxicity in yeast when overexpressed. En masse transformation of these toxic kinase genes into 4653 homozygous diploid yeast deletion mutants followed by barcode sequencing identified yeast toxicity modifiers and thus their human orthologs. Subsequent network analyses and functional grouping revealed that the 28 kinases and their 676 interaction partners (corresponding to a total of 969 genetic interactions) are enriched in cell death and survival (34%), small-molecule biochemistry (18%) and molecular transport (11%), among others. In the subnetwork analyses, a few kinases were commonly associated with glioma, cell migration and cell death/survival. Our analysis enabled the creation of a first draft of the kinase genetic interactome network and identified multiple drug targets for inflammatory diseases and cancer, in which deregulated kinase signaling plays a pathogenic role.
BHRF1 Enhances EBV Mediated Nasopharyngeal Carcinoma Tumorigenesis through Modulating Mitophagy Associated with Mitochondrial Membrane Permeabilization Transition
Authors: Song Shujie , Jiang Zhiying , Spezia-Lindner David Ethan , Liang Ting , Xu Chang , Wang Haifeng , Tian Ye , Bai Yidong
Published: May 2020

Epstein–Barr virus (EBV) is a major contributor to nasopharyngeal carcinoma (NPC) tumorigenesis. Mitochondria have been shown to be a target for tumor viral invasion, and to mediate viral tumorigenesis. In this study, we detected that mitochondrial morphological changes in tumor tissues of NPC patients infected with EBV were accompanied by an elevated expression of BHRF1, an EBV encoded protein homologue to Bcl-2. High expression of BHRF1 in human NPC cell lines enhanced tumorigenesis and metastasis features. With BHRF1 localized to mitochondria, its expression induced cyclophlin D dependent mitochondrial membrane permeabilization transition (MMPT). The MMPT further modulated mitochondrial function, increased ROS production and activated mitophagy, leading to enhanced tumorigenesis. Altogether, our results indicated that EBV-encoded BHRF1 plays an important role in NPC tumorigenesis through regulating cyclophlin D dependent MMPT.
Homing and Engraftment of Intravenously Administered Equine Cord Blood-Derived Multipotent Mesenchymal Stromal Cells to Surgically Created Cutaneous Wound in Horses: A Pilot Project
Authors: Mund Suzanne J. K. , Kawamura Eiko , Awang-Junaidi Awang Hazmi , Campbell John , Wobeser Bruce , MacPhee Daniel J. , Honaramooz Ali , Barber Spencer
Published: May 2020

Limb wounds on horses are often slow to heal and are prone to developing exuberant granulation tissue (EGT) and close primarily through epithelialization, which results in a cosmetically inferior and non-durable repair. In contrast, wounds on the body heal rapidly and primarily through contraction and rarely develop EGT. Intravenous (IV) multipotent mesenchymal stromal cells (MSCs) are promising. They home and engraft to cutaneous wounds and promote healing in laboratory animals, but this has not been demonstrated in horses. Furthermore, the clinical safety of administering >1.00 × 108 allogeneic MSCs IV to a horse has not been determined. A proof-of-principle pilot project was performed with two horses that were administered 1.02 × 108 fluorescently labeled allogeneic cord blood-derived MSCs (CB-MSCs) following wound creation on the forelimb and thorax. Wounds and contralateral non-wounded skin were sequentially biopsied on days 0, 1, 2, 7, 14, and 33 and evaluated with confocal microscopy to determine presence of homing and engraftment. Results confirmed preferential homing and engraftment to wounds with persistence of CB-MSCs at 33 days following wound creation, without clinically adverse reactions to the infusion. The absence of overt adverse reactions allows further studies to determine effects of IV CB-MSCs on equine wound healing.
Alpha Radiation as a Way to Target Heterochromatic and Gamma Radiation-Exposed Breast Cancer Cells
Authors: Svetličič Maja , Bomhard Anton , Sterr Christoph , Brückner Fabian , Płódowska Magdalena , Lisowska Halina , Lundholm Lovisa
Published: May 2020

Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of chromatin structure for densely ionising alpha radiation as well as its therapeutic potential. Chromatin opening by histone deacetylase inhibitor trichostatin A (TSA) pretreatment reduced clonogenic survival and increased γH2AX foci in MDA-MB-231 cells, indicative of increased damage induction by free radicals using gamma radiation. In contrast, TSA pretreatment tended to improve survival after alpha radiation while γH2AX foci were similar or lower; therefore, an increased DNA repair is suggested due to increased access of repair proteins. MDA-MB-231 cells exposed to fractionated gamma radiation (2 Gy × 6) expressed high levels of stem cell markers, elevated heterochromatin H3K9me3 marker, and a trend towards reduced clonogenic survival in response to alpha radiation. There was a higher level of H3K9me3 at baseline, and the ratio of DNA damage induced by alpha vs. gamma radiation was higher in the aggressive MDA-MB-231 cells compared to hormone receptor-positive MCF7 cells. We demonstrate that heterochromatin structure and stemness properties are induced by fractionated radiation exposure. Gamma radiation-exposed cells may be targeted using alpha radiation, and we provide a mechanistic basis for the involvement of chromatin in these effects.
RIAM-VASP Module Relays Integrin Complement Receptors in Outside-In Signaling Driving Particle Engulfment
Authors: Torres-Gomez Alvaro , Sanchez-Trincado Jose Luis , Toribio Víctor , Torres-Ruiz Raul , Rodríguez-Perales Sandra , Yáñez-Mó María , Reche Pedro A. , Cabañas Carlos , Lafuente Esther M.
Published: May 2020

The phagocytic integrins and complement receptors αMβ2/CR3 and αXβ2/CR4 are classically associated with the phagocytosis of iC3b-opsonized particles. The activation of this receptor is dependent on signals derived from other receptors (inside-out signaling) with the crucial involvement of the Rap1-RIAM-Talin-1 pathway. Here, we analyze the implication of RIAM and its binding partner VASP in the signaling events occurring downstream of β2 integrins (outside-in) during complement-mediated phagocytosis. To this end, we used HL-60 promyelocytic cell lines deficient in RIAM or VASP or overexpressing EGFP-tagged VASP to determine VASP dynamics at phagocytic cups. Our results indicate that RIAM-deficient HL-60 cells presented impaired particle internalization and altered integrin downstream signaling during complement-dependent phagocytosis. Similarly, VASP deficiency completely blocked phagocytosis, while VASP overexpression increased the random movement of phagocytic particles at the cell surface, with reduced internalization. Moreover, the recruitment of VASP to particle contact sites, amount of pSer157-VASP and formation of actin-rich phagocytic cups were dependent on RIAM expression. Our results suggested that RIAM worked as a relay for integrin complement receptors in outside-in signaling, coordinating integrin activation and cytoskeletal rearrangements via its interaction with VASP.
Membrane Binding Promotes Annexin A2 Oligomerization
Authors: Matos Anna Lívia Linard , Kudruk Sergej , Moratz Johanna , Heflik Milena , Grill David , Ravoo Bart Jan , Gerke Volker
Published: May 2020

Annexin A2 (AnxA2) is a cytosolic Ca2+ regulated membrane binding protein that can induce lipid domain formation and plays a role in exocytosis and endocytosis. To better understand the mode of annexin-membrane interaction, we analyzed membrane-bound AnxA2 assemblies by employing a novel 3-armed chemical crosslinker and specific AnxA2 mutant proteins. Our data show that AnxA2 forms crosslinkable oligomers upon binding to membranes containing negatively charged phospholipids. AnxA2 mutants with amino acid substitutions in residues predicted to be involved in lateral protein–protein interaction show compromised oligomer formation, albeit still being capable of binding to negatively charged membranes in the presence of Ca2+. These results suggest that lateral protein–protein interactions are involved in the formation of AnxA2 clusters on a biological membrane.
Live-Cell Cardiac-Specific High-Throughput Screening Platform for Drug-Like Molecules That Enhance Ca2+ Transport
Authors: Schaaf Tory M. , Kleinboehl Evan , Yuen Samantha L. , Roelike Lauren N. , Svensson Bengt , Thompson Andrew R. , Cornea Razvan L. , Thomas David D.
Published: May 2020

We engineered a concatenated fluorescent biosensor and dual-wavelength fluorescence lifetime (FLT) detection, to perform high-throughput screening (HTS) in living cells for discovery of potential heart-failure drugs. Heart failure is correlated with insufficient activity of the sarcoplasmic reticulum Ca-pump (SERCA2a), often due to excessive inhibition by phospholamban (PLB), a small transmembrane protein. We sought to discover small molecules that restore SERCA2a activity by disrupting this inhibitory interaction between PLB and SERCA2a. Our approach was to fluorescently tag the two proteins and measure fluorescence resonance energy transfer (FRET) to detect changes in binding or structure of the complex. To optimize sensitivity to these changes, we engineered a biosensor that concatenates the two fluorescently labeled proteins on a single polypeptide chain. This SERCA2a-PLB FRET biosensor construct is functionally active and effective for HTS. By implementing 2-wavelength FLT detection at extremely high speed during primary HTS, we culled fluorescent compounds as false-positive Hits. In pilot screens, we identified Hits that alter the SERCA2a-PLB interaction, and a newly developed secondary calcium uptake assay revealed both activators and inhibitors of Ca-transport. We are implementing this approach for large-scale screens to discover new drug-like modulators of SERCA2a-PLB interactions for heart failure therapeutic development.
Adult Stem Cell-Derived Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges
Authors: Parfejevs Vadims , Sagini Krizia , Buss Arturs , Sobolevska Kristine , Llorente Alicia , Riekstina Una , Abols Arturs
Published: May 2020

Adult stem cells (SCs) participate in tissue repair and homeostasis regulation. The relative ease of SC handling and their therapeutic effect has made of these cell popular candidates for cellular therapy. However, several problems interfere with their clinical application in cancer treatment, like safety issues, unpredictable pro-tumour effects, and tissue entrapment. Therefore cell-free therapies that exhibit SC properties are being investigated. It is now well known that adult SCs exhibit their therapeutic effect via paracrine mechanisms. In addition to secretory proteins, SCs also release extracellular vesicles (EV) that deliver their contents to the target cells. Cancer treatment is one of the most promising applications of SC-EVs. Moreover, SC-EVs could be modified to improve targeted drug delivery. The aim of the review is to summarise current knowledge of adult SC-EV application in cancer treatment and to emphasise future opportunities and challenges in cancer treatment.
Transposon Reactivation in the Germline May Be Useful for Both Transposons and Their Host Genomes
Authors: Maupetit-Mehouas Stéphanie , Vaury Chantal
Published: May 2020

Transposable elements (TEs) are long-term residents of eukaryotic genomes that make up a large portion of these genomes. They can be considered as perfectly fine members of genomes replicating with resident genes and being transmitted vertically to the next generation. However, unlike regular genes, TEs have the ability to send new copies to new sites. As such, they have been considered as parasitic members ensuring their own replication. In another view, TEs may also be considered as symbiotic sequences providing shared benefits after mutualistic interactions with their host genome. In this review, we recall the relationship between TEs and their host genome and discuss why transient relaxation of TE silencing within specific developmental windows may be useful for both.
The Measurement of Asthma and Allergic Rhinitis Control in Children and Adolescents
Authors: Tosca Maria , Del Barba Paolo , Licari Amelia , Ciprandi Giorgio ,   Asthma and Rhinitis Control Study Group
Published: May 2020

Asthma and allergic rhinitis (AR) are frequently associated. The objective of the treatment of asthma and AR should be the control of symptoms and disease progression. Therefore, the combined measurement of disease control is desirable. In this regard, a questionnaire able to together assess asthma and AR control has been validated: the CARAT (Control of Allergic Rhinitis and Asthma Test). A further pediatric version (CARATkids) has been generated. The current real-world study used different disease control measures in children and adolescents with asthma and rhinitis. A total of 138 children and adolescents were recruited at three allergy centers. CARAT, CARATkids, ACT (Asthma Control Test), cACT (children ACT), GINA (Global Initiative for Asthma) disease control classification, VAS (Visual Analog Scale) for asthma and nasal symptoms, and lung function were used in all subjects. There was a predominance of males (67.4%) and asthma was well-controlled (according to GINA classification) in about half the subjects. In children, the median CARAT and cACT values were 5 and 22 respectively. In adolescents, the median CARAT and ACT values were 23 for both tests. There were significant differences between CARAT and ACT (p = 0.035) as well as between CARATkids and cACT (p = 0.0001). However, the tests’ outcomes were different as assessed in different domains. CARAT and CARATkids are disease-control measurements that give additional information to other tests, therefore, these different questionnaires to measure disease control complement each other.
Passivation of Carbon Steel Using Intelligent Epoxy Paint
Authors: Silva Rodrigo Sanchotene , Meneguzzi Álvaro
Published: May 2020

This paper presents the production of an epoxy paint associated with a determined concentration of PAni emeraldine base binder, in order to increase dispersion of PAni polymer chains in the paint allow physical contact between PAni chains, the electrolytic medium, and the metal of interest. The coating called Intelligent Epoxy Paint (IEP) seeks to potentialize the electrolytic capacity of PAni to produce passivation, differentiated research which uses PAni in oxidized and conductive form as paint pigment that needs high PAni concentrations. The physicochemical characterization and morphological presented results that indicate the preservation of the desirable properties of PAni in order to make the passivation process possible. The electrochemical tests showed the passivation and/or maintenance of the passivation of the metal of interest, without the need to apply an external current.
Friction Mechanism Features of the Nickel-Based Composite Antifriction Materials at High Temperatures
Authors: Kurzawa Adam , Roik Tetiana , Gavrysh Oleg , Vitsiuk Iuliia , Bocian Miroslaw , Pyka Dariusz , Zajac Pawel , Jamroziak Krzysztof
Published: May 2020

The friction behavior of the formed antifriction films and their effect on the functional properties of the composite based on the powder nickel alloy EI929 with solid lubricant CaF2 at high temperatures was investigated. An antifriction film was formed on the contact surfaces during the friction process. Such a film was the result of the interaction of the contact surfaces with atmospheric oxygen at high temperatures. It contains oxides of alloying elements from materials of the frictional contact and solid lubricant calcium fluoride. The quantitative ratio of formed oxides depends on the temperature operating conditions of material. The data of thermodynamic simulation of the high-temperature interaction of the composite with oxygen coincide with the experimental data obtained by studying the fine structure of surface antifriction films. Antifriction films consist of oxide phases in combination with solid CaF2 lubricant. Anti-friction films provide high wear resistance of the self-lubricating composite in the range of temperatures 1073–1173 K due to the balance between the rate of their formation and wear. When the temperature exceeds 1200 K, the film loses its lubricating properties and acts as an abrasive substance due to the intense oxidation. Abrasive surfaces of materials were subjected also to microscopic examination, in which the mechanically mixed layer (MML) was described. The study of the friction surface roughness parameters confirmed the presence of the formed friction self-lubricating film and allowed to determine its parameters. The friction mechanism was the formation of an oxide layer combined with a solid lubricant, which provides high antifriction properties in the range of 1073–1273 K.
Three-Dimensional Graphene Hybrid SiO2 Hierarchical Dual-Network Aerogel with Low Thermal Conductivity and High Elasticity
Authors: Zhang Liwei , He Peng , Song Kunkun , Zhang Jingxiang , Zhang Baoqiang , Huang Ruixian , Zhang Qiangqiang
Published: May 2020

We describe lightweight three-dimensional (3D) graphene hybrid SiO2 aerogels (GSAs) with hierarchically robust interconnected networks fabricated via an in situ deposition procedure after a hydrothermal assembling strategy with graphene oxide sheets. The nano-/micron-thick SiO2 coating conformably grew over porous graphene templates with two constituents (e.g., graphene and SiO2) and formed chemically bonded interfaces. In addition, it significantly refined the primary graphene pores by hundreds of microns into smaller porous patterns. Studies of its mechanical properties verified that the graphene interframework made the ceramic composites elastic, while SiO2 deposition enhanced the strength required it to resist deformation. The higher SiO2 contents resulted in lower elasticity but larger strength because of the apparent nanosize effect of SiO2 ceramic thickness; GSAs with a density of 82.3–250.3 mg/cm3 (corresponding to SiO2 sol with concentration ranging from 5 to 20 wt %) could reach a good balance of strength and elasticity. Benefiting from hierarchical micronetworks consisting of semiclosed or closed pores, GSAs offer excellent thermal-insulation performance, with thermal conductivity as low as 0.026 W/(m·K). GSAs offer improved fire-resistant capacity rather than that of pure carbon-based aerogels via the synergic protection of SiO2 ceramic accretion. This highlights the promising applications of GSAs as lightweight thermal-shielding candidates for industrial equipment, civil architectures, and defense transportation vehicles.
Performance and Energy Assessment of a Lattice Boltzmann Method Based Application on the Skylake Processor
Authors: Girotto Ivan , Schifano Sebastiano Fabio , Calore Enrico , Di Staso Gianluca , Toschi Federico
Published: May 2020

This paper presents the performance analysis for both the computing performance and the energy efficiency of a Lattice Boltzmann Method (LBM) based application, used to simulate three-dimensional multicomponent turbulent systems on massively parallel architectures for high-performance computing. Extending results reported in previous works, the analysis is meant to demonstrate the impact of using optimized data layouts designed for LBM based applications on high-end computer platforms. A particular focus is given to the Intel Skylake processor and to compare the target architecture with other models of the Intel processor family. We introduce the main motivations of the presented work as well as the relevance of its scientific application. We analyse the measured performances of the implemented data layouts on the Skylake processor while scaling the number of threads per socket. We compare the results obtained on several CPU generations of the Intel processor family and we make an analysis of energy efficiency on the Skylake processor compared with the Intel Xeon Phi processor, finally adding our interpretation of the presented results.
Synthesis and Characterization of Crown-Ether Appended Hexaazatrinaphthylene-Based Liquid-Crystalline Derivative
Authors: Isoda Kyosuke , Shimooka Keigo
Published: May 2020

In this article, we report on the synthesis and characterization of crown-ether appended hexaazatrinaphthylene derivatives with two alkoxy chains. The complexation of a derivative having shorter alkoxy chains with metal ions, such as NaI and KI, prompts remarkable changes in the electronic properties of sold states, because of changing intermolecular interactions. Polarized optical microscopic observation, X-ray diffraction pattern measurement and differential scanning calorimetry reveal that a compound with longer alkoxy chains self-assembles into the formation of the columnar liquid-crystalline phase. Moreover, the addition of benzenesulphonic acid influences the self-assembled liquid-crystalline structures, as well as the electronic properties. The complexation of the derivative having longer alkoxy chains with benzenesulphonic acid induces a larger dipole moment, compared to that before complexation, thereby leading to the enhancement of intermolecular interaction, such as dipole-dipole interaction. Also, peaks in UV-vis absorption and fluorescent spectra show a dramatically bathochromic shift, due to their intermolecular interaction, such as the π-π interaction.
Formation of Nanoclusters in Gold Nucleation
Authors: Schneider Cornelia M. , Cölfen Helmut
Published: May 2020

Gold nanoclusters consisting of a specific atom number have gained popularity in research in recent years due to their outstanding properties. Due to their molecule-like behavior, their properties depend strongly on their size. Although they represent the link species between atoms and nanoparticles and are the subject of current research, a high-resolution characterization is still missing. Here, we used the band forming experiment in analytical ultracentrifugation (AUC) to characterize the gold nanoclusters in the moment of their generation using thioglycerol as a stabilizer. The concentration variation of the gold precursor, reducing agent, and stabilizer was investigated. The formation of different cluster species from the smallest Au4 up to Au911 could be observed. Very stable clusters of Au55 appear in every experiment and other cluster sizes more rarely. The extracted UV/Vis spectra could additionally be correlated to every cluster. The variation in the concentration of sodium borohydride and the stabilizer did not lead to a clear trend, but the gold ion concentration directed the size of the formed clusters. A decrease seemed to promote the generation of a higher abundance of smaller clusters accompanied by less big clusters, and vice versa. These results present the characterization of the different nanocluster generations directly in the formation process of nanoparticles and therefore are a contribution to the understanding of their formation.