bluuebunny/crossref_metadata_2025 huggingface dataset:
Analog Ensemble Methods for Improving Satellite-Based Intensity Estimates of Tropical Cyclones
Authors: Lewis William E. , Olander Timothy L. , Velden Christopher S. , Rozoff Christopher , Alessandrini Stefano
Published: June 2021

Accurate, reliable estimates of tropical cyclone (TC) intensity are a crucial element in the warning and forecast process worldwide, and for the better part of 50 years, estimates made from geostationary satellite observations have been indispensable to forecasters for this purpose. One such method, the Advanced Dvorak Technique (ADT), was used to develop analog ensemble (AnEn) techniques that provide more precise estimates of TC intensity with instant access to information on the reliability of the estimate. The resulting methods, ADT-AnEn and ADT-based Error Analog Ensemble (ADTE-AnEn), were trained and tested using seventeen years of historical ADT intensity estimates using k-fold cross-validation with 10 folds. Using only two predictors, ADT-estimated current intensity (maximum wind speed) and TC center latitude, both AnEn techniques produced significant reductions in mean absolute error and bias for all TC intensity classes in the North Atlantic and for most intensity classes in the Eastern Pacific. The ADTE-AnEn performed better for extreme intensities in both basins (significantly so in the Eastern Pacific) and will be incorporated in the University of Wisconsin’s Cooperative Institute for Meteorological Satellite Studies (UW-CIMSS) workflow for further testing during operations in 2021.
Different Characteristics of PM2.5 Measured in Downtown and Suburban Areas of a Medium-Sized City in South Korea
Authors: Park Sung-Won , Choi Su-Yeon , Byun Jin-Yeo , Kim Hekap , Kim Woo-Jin , Kim Pyung-Rae , Han Young-Ji
Published: June 2021

Chuncheon, a medium-sized city in South Korea, frequently shows high PM2.5 concentrations despite scarce anthropogenic emission sources. To identify factors increasing PM2.5 concentrations, PM2.5 and its major chemical components were concurrently measured at two different sites, namely, downtown and suburban areas. The average PM2.5 concentrations at the two sites were similar, but the daily and monthly variations in PM2.5 and its components were significantly larger at the suburban site. NH4+ was significantly higher at the suburban site than at the downtown site, whereas organic carbon (OC) showed the opposite trend. Several PM2.5 samples showed an abrupt increase during winter at the suburban site, along with an increase in the amount of OC, NH4+, and K+, and the correlations between water-soluble OC, K+, and NH4+ were considerably strong, implying that local biomass burning in the suburban site was an important source of high PM2.5 episodes. Secondary OC (SOC) concentration was generally lower at the suburban site than at the downtown site, but its contribution to OC increased during winter with an increase in relative humidity, indicating the significance of heterogeneous SOC formation reactions at the suburban site. These results indicate that relevant local measures can be put into place to alleviate the occurrence of high PM2.5 concentration episodes even in medium-sized residential cities where medium-and long-range transport is anticipated to be significant.
Cut-Off Lows and Extreme Precipitation in Eastern Spain: Current and Future Climate
Authors: Ferreira Rosana Nieto
Published: June 2021

This study presents a seasonal synoptic climatology of cut-off lows (COLs) that produced extreme precipitation in the Valencia region of Spain during 1998–2018 and uses simulations with the Weather Research and Forecasting (WRF) model to study how extreme COL precipitation may change in a future warmer climate. COLs were shown to be the main producer of extreme precipitation in the Valencia region, especially during the transition seasons. The strongest raining COL events occurred during September–November. Six-day composites of thermodynamic and dynamic fields and precipitation show that COLs that produce extreme precipitation in this region remain stationary over Spain for 2–3 days and tend to produce precipitation over the Valencia region for at least two consecutive days. In the low levels these COLs are characterized by low pressure over the Mediterranean sea and winds with an easterly, onshore component thus fueling precipitation. Comparison of current and future climate ensembles of WRF simulations of 14 September–November extreme precipitation producing COL events suggest that in a warmer climate extreme COL precipitation may increase by as much as 88% in northeastern Spain and 61% in the adjoining Mediterranean Sea. These projected increases in extreme COL precipitation in the northeast of Spain present additional challenges to a region where COL flooding already has significant socio-economic impacts. Additionally, about half of the future climate COL event simulations showed increases in precipitation in the Valencian region of eastern Spain. These results provide important nuance to projections of a decreasing trend of total precipitation in the Iberian Peninsula as the climate warms.
Generalizations of Hermite–Hadamard Type Integral Inequalities for Convex Functions
Authors: Wu Ying , Yin Hong-Ping , Guo Bai-Ni
Published: June 2021

In the paper, with the help of two known integral identities and by virtue of the classical Hölder integral inequality, the authors establish several new integral inequalities of the Hermite–Hadamard type for convex functions. These newly established inequalities generalize some known results.
Combined Effect of Laboratory-Simulated Fire and Chromium Pollution on Microbial Communities in an Agricultural Soil
Authors: Rascio Ida , Curci Maddalena , Gattullo Concetta Eliana , Lavecchia Anna , Yaghoubi Khanghahi Mohammad , Terzano Roberto , Crecchio Carmine
Published: June 2021

Fire events in agricultural soils can modify not only soil properties but also the structure of soil microbial communities, especially in soils containing high concentrations of potentially toxic elements (PTEs). The recolonization of burned soils can in fact favor the proliferation of certain microorganisms, more adaptable to post-fire soil conditions and higher PTE availability, over others. In this study, we simulated with laboratory experiments the microbial recolonization of an agricultural soil containing high Cr concentrations after heating at 500 °C for 30 min, to mimic the burning of crop residues. Changes in soil properties and Cr speciation were assessed, as well as soil microbial structure by means of 16S rRNA gene sequencing. Both altered soil conditions and increased Cr availability, especially Cr(VI), appeared to be responsible for the reduction in species diversity in heated soils and the proliferation of Firmicutes. Indeed, already after 3 days from the heat treatment, Firmicutes increased from 14% to 60% relative abundance. In particular, Paenibacillus was the most abundant genus identified after the simulation, with an average relative abundance of 40%. These bacteria are known to be good fire-responders and Cr-tolerant. These results could be useful to identify bacterial strains to be used as bioindicators of altered environments and for the recovery of fire-impacted polluted sites.
Genetic Polymorphisms of NLRP3 (rs4612666) and CARD8 (rs2043211) in Periodontitis and Cardiovascular Diseases
Authors: Mahendra Jaideep , Rao Abirami Nayaki , Mahendra Little , Fageeh Hytham N. , Fageeh Hammam Ibrahim , Balaji Thodur Madapusi , Varadarajan Saranya , Jagannathan Raghunathan , Mehta Deepak , Suresh Venkata V. , Raj A. Thirumal , Patil Shankargouda
Published: June 2021

Background: The existing data show that inflammasomes play a role in periodontal disease pathogenesis. However, their role in the pathogenesis of periodontitis and coronary heart disease remains unclear. This study had the objective of assessing NLRP3 (rs4612666) and CARD8 (rs2043211) gene polymorphisms in dental plaque and blood of generalized chronic periodontitis (CP) patients in the presence and absence of coronary heart disease (CHD). Methods: A total of 70 subjects were divided into two groups, including CP and CP + CHD subjects. Demographic variables, periodontal, and cardiac parameters were recorded from both groups. Subgingival plaque and blood samples were obtained from both groups and were subjected to further molecular analysis for NLRP3 (rs4612666) and CARD8 (rs2043211) expression and allele change using conventional polymerase chain reaction (PCR) and gene sequencing (Sanger’s method). Results: Amongst the demographic variables, age, and monthly income were statistically significant between the two groups. Plaque index (PI), clinical attachment level (CAL), high-density lipoprotein (HDL), and low density-lipoprotein (LDL) exhibited statistically significant levels between the two groups. NLRP3 (rs4612666) and CARD8 (rs2043211) genes showed a statistically significant association of allele change (frequency) among the groups. In general, when all of the parameters were compared to the allele change of the genes, statistically significant relationships were found between the two groups. Conclusions: The present study expressed an allele change of the investigated genes which could profoundly affect the pathobiology of the two diseases under investigation.
TGF-β1 Facilitates TAp63α Protein Lysosomal Degradation to Promote Pancreatic Cancer Cell Migration
Authors: Gao Guohui , Chen Jie , Wang Dongbo , Li Qiao , Yang Xiaojiao , Wang Jindan , Pan Zhiyong , Xiao Zhi-Xiong Jim , Yi Yong
Published: June 2021

TGF-β signaling plays a pivotal role in promoting tumor cell migration and cancer metastasis. ΔNp63α and TAp63α are two major isoforms of p53-related p63 protein. Our recent study has shown that TGF-β1 promotes ΔNp63α protein degradation to facilitate cancer metastasis. However, whether TAp63α is involved in TGF-β1-induced cancer metastasis remains unclear. In this study, we show that, in human pancreatic cancer MIA PaCa-2 cells harboring p53-R248W allele, TGF-β1 can significantly inhibit TAp63α protein stability in a Smad pathway-independent manner. Lysosome inhibitor, chloroquine, but not proteasome inhibitor MG132, can rescue TGF-β1-induced downregulation of TAp63α protein. In addition, we show that either TGF-β1 treatment or silencing of TAp63α can dramatically increase migration of MIA PaCa-2 cells. Importantly, the restored expression of TAp63α can effectively block TGF-β1-induced migration of MIA PaCa-2 cells. Mechanistically, we show that TGF-β1 promotes TAp63α protein degradation, leading to upregulation of p53-R248W protein expression, and consequently resulting in elevated MIA PaCa-2 cell migration. Together, this study indicates that lysosomal degradation is an important way for regulating TAp63α protein fate and highlights that TGF-β1-TAp63α-mutant p53 axis is critically important in pancreatic cancer metastasis.
Pathogenesis of Anorectal Malformations in Retinoic Acid Receptor Knockout Mice Studied by HREM
Authors: Mark Manuel , Teletin Marius , Wendling Olivia , Vonesch Jean-Luc , Féret Betty , Hérault Yann , Ghyselinck Norbert B.
Published: June 2021

Anorectal malformations (ARMs) are relatively common congenital abnormalities, but their pathogenesis is poorly understood. Previous gene knockout studies indicated that the signalling pathway mediated by the retinoic acid receptors (RAR) is instrumental to the formation of the anorectal canal and of various urogenital structures. Here, we show that simultaneous ablation of the three RARs in the mouse embryo results in a spectrum of malformations of the pelvic organs in which anorectal and urinary bladder ageneses are consistently associated. We found that these ageneses could be accounted for by defects in the processes of growth and migration of the cloaca, the embryonic structure from which the anorectal canal and urinary bladder originate. We further show that these defects are preceded by a failure of the lateral shift of the umbilical arteries and propose vascular abnormalities as a possible cause of ARM. Through the comparisons of these phenotypes with those of other mutant mice and of human patients, we would like to suggest that morphological data may provide a solid base to test molecular as well as clinical hypotheses.
Comparison of Single- and Mixed-Sized Gold Nanoparticles on Lateral Flow Assay for Albumin Detection
Authors: Chotithammakul Sasima , Cortie Michael B. , Pissuwan Dakrong
Published: June 2021

The sensitivity and reproducibility of the lateral flow assay can be influenced by multiple factors, such as the size of gold nanoparticles (GNPs) employed. Here, we evaluated the analytical performance of single-sized and mixed-sized GNPs using a simple lateral flow assay (LFA) platform. This platform was used as a model assay to diagnose albumin levels and demonstrate the analytical performance of single-sized and mixed-sized GNPs in LFA tests. Two sizes of GNPs@anti-bovine serum albumin (BSA) conjugate proteins were mixed at different ratios. The unique optical properties of the GNPs induced a distinguishing color-shedding effect on the single- and mixed-sized GNPs@anti-BSA conjugates interacting with the target analyte BSA spotted on the test line. The use of mixed-sized GNPs@anti-BSA conjugates enhanced signal relative to the 20 nm GNPs, and provided superior stability compared with solely employing the large GNPs (50 nm). The proposed platform in this study could provide an efficient BSA detection mechanism that can be utilized as a model biomarker for confronting chronic kidney disease.
Development of an Electrochemical Immunosensor for Detection of Cardiac Troponin I at the Point-of-Care
Authors: Lee Tsung-Han , Chen Lung-Chieh , Wang Erick , Wang Chin-Cheng , Lin Yan-Ren , Chen Wen-Liang
Published: June 2021

Cardiac troponin I (cTnI) plays an important role in the assessment of various cardiac diseases. However, accurate detection of cTnI at the point-of-care (POC) remains unfeasible. In this study, we report the development of an electrochemical immunosensor designed for rapid and accurate cTnI detection in pre-hospital settings. Rapid cTnI analysis of whole blood samples was then performed. cTnI measurements were highly correlated with the results of the standard clinical laboratory method for cTnI detection. The results of this study suggest that the proposed POC immunosensor can deliver fast and accurate cTnI analysis in pre-hospital settings to achieve rapid diagnosis and guide patient management.
IQVision: An Image-Based Evaluation Tool for Quantitative Lateral Flow Immunoassay Kits
Authors: Bheemavarapu Lalitha Pratyusha , Shah Malay Ilesh , Joseph Jayaraj , Sivaprakasam Mohanasankar
Published: June 2021

The development of quantitative lateral flow immunoassay test strips involves a lot of research from kit manufacturers’ standpoint. Kit providers need to evaluate multiple parameters, including the location of test regions, sample flow speed, required sample volumes, reaction stability time, etc. A practical visualization tool assisting manufacturers in this process is very much required for the design of more sensitive and reliable quantitative LFIA test strips. In this paper, we present an image-based quantitative evaluation tool determining the practical functionality of fluorescence-labelled LFIA test cartridges. Image processing-based algorithms developed and presented in this paper provide a practical analysis of sample flow rates, reaction stability times of samples under test, and detect any abnormalities in test strips. Evaluation of the algorithm is done with Glycated Hemoglobin (HbA1C) and Vitamin D test cartridges. Practical sample flow progress for HbA1C test cartridges is demonstrated. The reaction stability time of HbA1C test samples is measured to be 12 min, while that of Vitamin D test samples is 24 min. Experimental evaluation of the abnormality detection algorithm is carried out, and sample flow abnormalities are detected with 100% accuracy while membrane irregularities are detected with 96% accuracy.
Using System Identification to Construct an Inherent Model of Pupillary Light Reflex to Explore Diabetic Neuropathy
Authors: Yan Yung-Jhe , Chen Chien-Nan , Ou-Yang Mang
Published: June 2021

This study proposed a pupillary light reflex (PLR) inherent model based on the system identification method to demonstrate the dynamic physiological mechanism of the PLR, in which pupillary constriction and dilation are controlled by the sympathetic and parasympathetic nervous system. This model was constructed and verified by comparing the simulated and predicted PLR response with that of healthy participants. The least root-mean-square error (RMSE) of simulated PLR response was less than 0.7% when stimulus duration was under 3 ms. The RMSE of predicted PLR response increased by approximately 6.76%/s from the stimulus duration of 1 ms to 3 s, when the model directly used the parameters extracted from the PLR at the stimulus duration of 10 ms. When model parameters were derived from the regression by the measured PLR response, the RMSE kept under 8.5%. The model was applied to explore the PLR abnormalities of the people with Diabetic Mellitus (DM) by extracting the model parameters from 42 people with DM and comparing these parameters with those of 42 healthy participants. The parameter in the first-order term of the elastic force of the participants with DM was significantly lower than that of the healthy participants (p < 0.05). The sympathetic force and sympathetic action delay of the participants with DM were significantly larger (p < 0.05) and longer (p < 0.0001) than that of the healthy ones, respectively. The reason might be that the sympathetic nervous system, which controls the dilator muscle, degenerated in diabetic patients.
Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature
Authors: Martinotti Giovanni , Chiappini Stefania , Pettorruso Mauro , Mosca Alessio , Miuli Andrea , Di Carlo Francesco , D’Andrea Giacomo , Collevecchio Roberta , Di Muzio Ilenia , Sensi Stefano L. , Di Giannantonio Massimo
Published: June 2021

The obsessive–compulsive spectrum refers to disorders drawn from several diagnostic categories that share core features related to obsessive–compulsive disorder (OCD), such as obsessive thoughts, compulsive behaviors and anxiety. Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily preoccupation (i.e., eating disorders, ED) or impulse control (i.e., substance use disorders, SUD), and they exhibit intriguing similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes. The non-competitive N-methyl-D-aspartate receptor (NMDAr) antagonist ketamine has been indicated to produce remarkable results in patients with treatment-resistant depression, post-traumatic stress disorder and OCD in dozens of small studies accrued over the past decade, and it appears to be promising in the treatment of SUD and ED. However, despite many small studies, solid evidence for the benefits of its use in the treatment of OCD spectrum and addiction is still lacking. Thus, the aim of this perspective article is to examine the potential for ketamine and esketamine in treating OCD, ED and SUD, which all involve recurring and intrusive thoughts and generate associated compulsive behavior. A comprehensive and updated overview of the literature regarding the pharmacological mechanisms of action of both ketamine and esketamine, as well as their therapeutic advantages over current treatments, are provided in this paper. An electronic search was performed, including all papers published up to April 2021, using the following keywords (“ketamine” or “esketamine”) AND (“obsessive” OR “compulsive” OR “OCD” OR “SUD” OR “substance use disorder” OR “addiction” OR “craving” OR “eating” OR “anorexia”) NOT review NOT animal NOT “in vitro”, on the PubMed, Cochrane Library and Web of Science online databases. The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The use and efficacy of ketamine in SUD, ED and OCD is supported by glutamatergic neurotransmission dysregulation, which plays an important role in these conditions. Ketamine’s use is increasing, and preliminary data are optimistic. Further studies are needed in order to better clarify the many unknowns related to the use of both ketamine and esketamine in SUD, ED and OCD, and to understand their long-term effectiveness.
A Pilot Study on Covid and Autism: Prevalence, Clinical Presentation and Vaccine Side Effects
Authors: Brondino Natascia , Bertoglio Federico , Forneris Federico , Faravelli Silvia , Borghesi Alessandro , Damiani Stefano , Provenzani Umberto , Nola Marta , Olivola Miriam , Caviglia Monica , Politi Pierluigi , Fusar-Poli Laura , Fusar-Poli Paolo
Published: June 2021

Background: Several neurobiological mechanisms have been proposed to support the hypothesis of a higher COVID-19 risk in individuals with autism spectrum disorder (ASD). However, no real-world data are available on this population. Methods: We compared the period prevalence (March–May 2020) and symptom presentation of COVID-19 infections between a sample of individuals with severe ASD (n = 36) and the staff personnel (n = 35) of two specialized centers. Anti-SARS-Cov-2 antibody positivity was used as a proxy of infection. Additionally, we evaluated vaccine side effects in the same groups. Results: No significant difference was found between the prevalence of COVID-19 positivity between autistic participants and staff personnel. Levels of antibodies against the spike protein and the receptor binding domain were not significantly different between autistic and staff participants. The level of antibodies against the N-terminal domain were higher in autistic individuals. There was a significant difference between the prevalence of symptomatic COVID-19 in autistic participants (9.1%) compared to staff personnel (92.3%). The most frequent side effect among autistic participants was light fever. Conclusions: The present study provides preliminary data on COVID-19 transmission and presentation in ASD. Our data do not support the hypothesis of a higher susceptibility and severity of COVID-19 in people with ASD.
A Study on the Trends for Expression in Korean Contemporary Architectural Facade Design: Focusing on Large Buildings in the City Center
Authors: Lee Sungkyun
Published: June 2021

Various facade designs in modern architecture have expanded the limits of materials and construction methods. In this study, I explored and analyzed structural, decorative, media, and adaptive as representative case studies of facade expression. This study identified the following modern architectural trends for new facade construction methods in South Korea. First, efforts to improve the function of spaces by integrating interior and exterior spaces. Second, attempts for creating decorative facade expressions that stimulate human senses, or expand perceptions and increase aesthetic sense. Third, forming complementary relationships with the city by demonstrating regionality. Fourth, enhancing the performance of facades with adaptive facades. Fifth, helping to expand publicness, such as strengthening and combining the relationships between city, building, and person. Changes and advances in architectural facades will ultimately enhance fundamental aspects of architecture, enriching our daily living through harmony between the traditional and the modern, buildings and humans, and buildings and the environment.
Detection of District Heating Pipe Network Leakage Fault Using UCB Arm Selection Method
Authors: Shen Yachen , Chen Jianping , Fu Qiming , Wu Hongjie , Wang Yunzhe , Lu You
Published: June 2021

District heating networks make up an important public energy service, in which leakage is the main problem affecting the safety of pipeline network operation. This paper proposes a Leakage Fault Detection (LFD) method based on the Linear Upper Confidence Bound (LinUCB) which is used for arm selection in the Contextual Bandit (CB) algorithm. With data collected from end-users’ pressure and flow information in the simulation model, the LinUCB method is adopted to locate the leakage faults. Firstly, we use a hydraulic simulation model to simulate all failure conditions that can occur in the network, and these change rate vectors of observed data form a dataset. Secondly, the LinUCB method is used to train an agent for the arm selection, and the outcome of arm selection is the leaking pipe label. Thirdly, the experiment results show that this method can detect the leaking pipe accurately and effectively. Furthermore, it allows operators to evaluate the system performance, supports troubleshooting of decision mechanisms, and provides guidance in the arrangement of maintenance.
Multicenter Propensity Score-Based Study of Laparoscopic Repeat Liver Resection for Hepatocellular Carcinoma: A Subgroup Analysis of Cases with Tumors Far from Major Vessels
Authors: Miyama Arimasa , Morise Zenichi , Aldrighetti Luca , Belli Giulio , Ratti Francesca , Cheung Tan-To , Lo Chung-Mau , Tanaka Shogo , Kubo Shoji , Okamura Yukiyasu , Uesaka Katsuhiko , Monden Kazuteru , Sadamori Hiroshi , Hashida Kazuki , Kawamoto Kazuyuki , Gotohda Naoto , Chen KuoHsin , Kanazawa Akishige , Takeda Yutaka , Ohmura Yoshiaki , Ueno Masaki , Ogura Toshiro , Suh Kyung-Suk , Kato Yutaro , Sugioka Atsushi , Belli Andrea , Nitta Hiroyuki , Yasunaga Masafumi , Cherqui Daniel , Halim Nasser Abdul , Laurent Alexis , Kaneko Hironori , Otsuka Yuichiro , Kim Ki-Hun , Cho Hwui-Dong , Lin Charles Chung-Wei , Ome Yusuke , Seyama Yasuji , Troisi Roberto I. , Berardi Giammauro , Rotellar Fernando , Wilson Gregory C. , Geller David A. , Soubrane Olivier , Yoh Tomoaki , Kaizu Takashi , Kumamoto Yusuke , Han Ho-Seong , Ekmekcigil Ela , Dagher Ibrahim , Fuks David , Gayet Brice , Buell Joseph F. , Ciria Ruben , Briceno Javier , O’Rourke Nicholas , Lewin Joel , Edwin Bjorn , Shinoda Masahiro , Abe Yuta , Hilal Mohammed Abu , Alzoubi Mohammad , Tanabe Minoru , Wakabayashi Go
Published: June 2021

Less morbidity is considered among the advantages of laparoscopic liver resection (LLR) for HCC patients. However, our previous international, multi-institutional, propensity score-based study of emerging laparoscopic repeat liver resection (LRLR) failed to prove this advantage. We hypothesize that these results may be since the study included complex LRLR cases performed during the procedure’s developing stage. To examine it, subgroup analysis based on propensity score were performed, defining the proximity of the tumors to major vessels as the indicator of complex cases. Among 1582 LRLR cases from 42 international high-volume liver surgery centers, 620 cases without the proximity to major vessels (more than 1 cm far from both first–second branches of Glissonian pedicles and major hepatic veins) were selected for this subgroup analysis. A propensity score matching (PSM) analysis was performed based on their patient characteristics, preoperative liver function, tumor characteristics and surgical procedures. One hundred and fifteen of each patient groups of LRLR and open repeat liver resection (ORLR) were earned, and the outcomes were compared. Backgrounds were well-balanced between LRLR and ORLR groups after matching. With comparable operation time and long-term outcome, less blood loss (283.3±823.0 vs. 603.5±664.9 mL, p = 0.001) and less morbidity (8.7 vs. 18.3 %, p = 0.034) were shown in LRLR group than ORLR. Even in its worldwide developing stage, LRLR for HCC patients could be beneficial in blood loss and morbidity for the patients with less complexity in surgery.
Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma
Authors: Ruiz-Heredia Yanira , Ortiz-Ruiz Alejandra , Samur Mehmet K. , Garrido Vanesa , Rufian Laura , Sanchez Ricardo , Aguilar-Garrido Pedro , Barrio Santiago , Martín Miguel A. , Bolli Niccolò , Tai Yu-Tzu , Szalat Raphaël , Fulciniti Mariateresa , Munshi Nikhil , Martínez-López Joaquín , Linares María , Gallardo Miguel
Published: June 2021

Many studies over the last 20 years have investigated the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis. However, the status of the mtDNACN in MM and its implication in the pathogenesis of the disease remains unclear. We examined changes in plasma cell mtDNACN across different stages of MM by applying RT-PCR and high-throughput sequencing analysis. We observed a significant increase in the average mtDNACN in myeloma cells compared with healthy plasma cells (157 vs. 40 copies; p = 0.02). We also found an increase in mtDNACN in SMM and newly diagnosed MM (NDMM) paired samples and in consecutive relapses in the same patient. Survival analysis revealed the negative impact of a high mtDNACN in progression-free survival in NDMM (p = 0.005). Additionally, we confirmed the higher expression of mitochondrial biogenesis regulator genes in myeloma cells than in healthy plasma cells and we detected single nucleotide variants in several genes involved in mtDNA replication. Finally, we found that there was molecular similarity between “rapidly-progressing SMM” and MM regarding mtDNACN. Our data provide evidence that malignant transformation of myeloma cells involves the activation of mitochondrial biogenesis, resulting in increased mtDNA levels, and highlights vulnerabilities and potential therapeutic targets in the treatment of MM. Accordingly, mtDNACN tracking might guide clinical decision-making and management of complex entities such as high-risk SMM.
Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?
Authors: Pfab Christina , Schnobrich Luisa , Eldnasoury Samir , Gessner André , El-Najjar Nahed
Published: June 2021

The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.
Maximum Tolerated Dose and Anti-Tumor Activity of Intraperitoneal Cantrixil (TRX-E-002-1) in Patients with Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer: Phase I Study Results
Authors: Coward Jermaine I. , Barve Minal A. , Kichenadasse Ganessan , Moore Kathleen N. , Harnett Paul R. , Berg Daniel , Garner James S. , Dizon Don S.
Published: June 2021

Survival outcomes in ovarian cancer are poor. The aims of this Phase I progressive design study (NCT02903771) were to evaluate the maximum tolerated dose (MTD), tolerability, and antitumor activity of Cantrixil—a novel third-generation benzopyran molecule—in patients (n = 25) with advanced, recurrent/persistent epithelial ovarian, primary peritoneal, or fallopian tube cancer. All had completed ≥ 2 prior regimens; 3 (12%) had platinum-refractory disease, and 17 (68%) had platinum-resistant disease. Following intraperitoneal (IP) port placement, patients received weekly IP Cantrixil in 3-week cycles as monotherapy (Cycles 1–2), and then in combination with intravenous (IV) chemotherapy (Cycles 3–8). Part A (dose escalation) enrolled 11 patients in 6 dose-level cohorts. An MTD of 5 mg/kg was established with dose-limiting toxicity of ileus. Most treatment-related adverse events were gastrointestinal. Across Parts A and B (dose expansion), 16 (64%) patients received ≥ 1 3-week Cantrixil cycle, and had ≥ 1 post-baseline efficacy measurement available. The results show promising anti-tumor activity in monotherapy (stable disease rate of 56%) and in combination with IV chemotherapy (objective response rate of 19%, disease control rate of 56%, and median progression-free survival of 13.1 weeks). The molecular target and mechanism of action of Cantrixil are yet to be confirmed. Preliminary analysis of stem cell markers suggests that IP Cantrixil might induce ovarian cancer stem cell death and sensitize cells to standard chemotherapy, warranting further evaluation.
High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas
Authors: Willscher Edith , Hopp Lydia , Kreuz Markus , Schmidt Maria , Hakobyan Siras , Arakelyan Arsen , Hentschel Bettina , Jones David T. W. , Pfister Stefan M. , Loeffler Markus , Loeffler-Wirth Henry , Binder Hans
Published: June 2021

Molecular mechanisms of lower-grade (II–III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.
Serine-Threonine Kinase Receptor-Associated Protein (STRAP) Knockout Decreases the Malignant Phenotype in Neuroblastoma Cell Lines
Authors: Bownes Laura V , Williams Adele P , Marayati Raoud , Quinn Colin H , Hutchins Sara C , Stewart Jerry E , Vu Trung , Easlick Juliet L , Mroczek-Musulman Elizabeth , Crossman David K , Anderson Joshua C , Willey Christopher D , Datta Pran K , Beierle Elizabeth A
Published: June 2021

Background: Serine-threonine kinase receptor-associated protein (STRAP) plays an important role in neural development but also in tumor growth. Neuroblastoma, a tumor of neural crest origin, is the most common extracranial solid malignancy of childhood and it continues to carry a poor prognosis. The recent discovery of the role of STRAP in another pediatric solid tumor, osteosarcoma, and the known function of STRAP in neural development, led us to investigate the role of STRAP in neuroblastoma tumorigenesis. Methods: STRAP protein expression was abrogated in two human neuroblastoma cell lines, SK-N-AS and SK-N-BE(2), using transient knockdown with siRNA, stable knockdown with shRNA lentiviral transfection, and CRISPR-Cas9 genetic knockout. STRAP knockdown and knockout cells were examined for phenotypic alterations in vitro and tumor growth in vivo. Results: Cell proliferation, motility, and growth were significantly decreased in STRAP knockout compared to wild-type cells. Indicators of stemness, including mRNA abundance of common stem cell markers Oct4, Nanog, and Nestin, the percentage of cells expressing CD133 on their surface, and the ability to form tumorspheres were significantly decreased in the STRAP KO cells. In vivo, STRAP knockout cells formed tumors less readily than wild-type tumor cells. Conclusion: These novel findings demonstrated that STRAP plays a role in tumorigenesis and maintenance of neuroblastoma stemness.
Loss of CENP-I Impairs Homologous Recombination and Sensitizes Cells to PARP1 Inhibition
Authors: Dang Tuyen T. , Morales Julio C.
Published: June 2021

Centromere Protein I (CENP-I) is a member of the CENP-H/I/K complex. CENP-H/I/K is a major component of the inner kinetochore and aids in ensuring proper chromosomal segregation during mitosis. In addition to this chromosomal segregation function, CENP-I also plays a role in DNA double-strand break (DSB) repair. Loss of CENP-I leads to increased endogenous 53BP1 foci and R-loop formation, while reducing cellular survival after ionizing radiation and Niraparib, a PARP1 small molecule inhibitor, exposures. Cells lacking CENP-I display delayed 53BP1 foci regression, an indication that DSB repair is impaired. Additionally, loss of CENP-I impairs the homologous recombination DSB repair pathway, while having no effect on the non-homologous end-joining pathway. Interestingly, we find that RNaseH1 expression restores HR capacity in CENP-I deficient cells. Importantly, CENP-I expression is elevated in glioma tissue as compared to normal brain tissue. This elevated expression also correlates with poor overall patient survival. These data highlight the multi-functional role CENP-I plays in maintaining genetic, as well as chromosomal, stability and tumor survival.
MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer
Authors: Hermanowicz Justyna Magdalena , Pawlak Krystyna , Sieklucka Beata , Czarnomysy Robert , Kwiatkowska Iwona , Kazberuk Adam , Surazynski Arkadiusz , Mojzych Mariusz , Pawlak Dariusz
Published: June 2021

Background and aims: The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer. Methods: MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice. The mechanistic studies investigated cellular affinity of a new 1,2,4-triazine derivative by measuring levels of intracellular/extracellular signal molecules participating in tumorigenesis. Results: The results revealed that MM-129 significantly reduced tumor growth in mice challenged with DLD-1 and HT-29 cells. It exerted the ability to inhibit intracellular molecules promoting tumorigenesis and inducing cell cycle arrest, like Akt, mTOR, and CDK2. Simultaneously, it was able to downregulate PD-L1 expression, which involves immunological self-tolerance. Combined administration of MM-129 and 5-fluorouracil (5-FU) additionally amplified these effects, which were manifest as an increase population of cells in the G0/G1 phase. Conclusions: A novel 1,2,4-triazine derivative with a dual mechanism of antitumor activity—MM-129, may act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemotherapy of colon cancer.
The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review
Authors: Désage Anne-Laure , Karpathiou Georgia , Peoc’h Michel , Froudarakis Marios E.
Published: June 2021

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.
Novel Insights for Patients with Multiple Basal Cell Carcinomas and Tumors at High-Risk for Recurrence: Risk Factors, Clinical Morphology, and Dermatoscopy
Authors: Sgouros Dimitrios , Rigopoulos Dimitrios , Panayiotides Ioannis , Apalla Zoe , Arvanitis Dimitrios K. , Theofili Melpomeni , Theotokoglou Sofia , Syrmali Anna , Theodoropoulos Konstantinos , Pappa Georgia , Damaskou Vasileia , Stratigos Alexander , Katoulis Alexander
Published: June 2021

Introduction: Basal cell carcinoma (BCC) quite frequently presents as multiple tumors in individual patients. Neoplasm’s risk factors for local recurrence have a critical impact on therapeutic management. Objective: To detect risk factors for multiple BCCs (mBCC) in individual patients and to describe clinical and dermatoscopic features of low- and high-risk tumors. Materials & Methods: Our study included 225 patients with 304 surgically excised primary BCCs. All patients’ medical history and demographics were recorded. Clinical and dermatoscopic images of BCCs were evaluated for predefined criteria and statistical analyses were performed. Results: Grade II-III sunburns before adulthood (OR 2.146, p = 0.031) and a personal history of BCC (OR 3.403, p < 0.001) were the major predisposing factors for mBCC. Clinically obvious white color (OR 3.168, p < 0.001) and dermatoscopic detection of white shiny lines (OR 2.085, p = 0.025) represented strongly prognostic variables of high-risk BCC. Similarly, extensive clinico-dermatoscopic ulceration (up to 9.2-fold) and nodular morphology (3.6-fold) raise the possibility for high-risk BCC. On the contrary, dermatoscopic evidence of blue-black coloration had a negative prognostic value for high-risk neoplasms (light OR 0.269, p < 0.001/partial OR 0.198, p = 0.001). Conclusions: Profiling of mBCC patients and a thorough knowledge of high-risk tumors’ clinico-dermatoscopic morphology could provide physicians with important information towards prevention of this neoplasm.
Epigenetic Deregulation of Apoptosis in Cancers
Authors: Ozyerli-Goknar Ezgi , Bagci-Onder Tugba
Published: June 2021

Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death.
Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma
Authors: Brossel Hélène , Fontaine Alexis , Hoyos Clotilde , Jamakhani Majeed , Willems Mégane , Hamaidia Malik , Willems Luc
Published: June 2021

Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.
Margin Accentuation Irreversible Electroporation in Stage III Pancreatic Cancer: A Systematic Review
Authors: Ratnayake Bathiya , Al-Leswas Dhya , Mohammadi-Zaniani Ghazaleh , Littler Peter , Sen Gourab , Manas Derek , Pandanaboyana Sanjay
Published: June 2021

The present systematic review aimed to summarise the available evidence on indications and oncological outcomes after MA IRE for stage III pancreatic cancer (PC). A literature search was performed in the Pubmed, MEDLINE, EMBASE, SCOPUS databases using the PRISMA framework to identify all MA IRE studies. Nine studies with 235 locally advanced (LA) (82%, 192/235) or Borderline resectable (BR) PC (18%, 43/235) patients undergoing MA IRE pancreatic resection were included. Patients were mostly male (56%) with a weighted-mean age of 61 years (95% CI: 58–64). Pancreatoduodenectomy was performed in 51% (120/235) and distal pancreatectomy in 49% (115/235). R0 resection rate was 73% (77/105). Clavien Dindo grade 3–5 postoperative complications occurred in 19% (36/187). Follow-up intervals ranged from 3 to 29 months. Local and systematic recurrences were noted in 8 and 43 patients, respectively. The weighted-mean progression free survival was 11 months (95% CI: 7–15). The weighted-mean overall survival was 22 months (95% CI 20–23 months) and 8 months (95% CI 1–32 months) for MA IRE and IRE alone, respectively. Early non-randomised data suggest MA IRE during pancreatic surgery for stage III pancreatic cancer may result in increased R0 resection rates and improved OS with acceptable postoperative morbidity. Further, larger studies are warranted to corroborate this evidence.