bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial Metabolites Determine Host Health and the Status of Some Diseases
Authors: Sittipo Panida , Shim Jae-won , Lee Yun
Published: October 2019

The gastrointestinal (GI) tract is a highly complex organ composed of the intestinal epithelium layer, intestinal microbiota, and local immune system. Intestinal microbiota residing in the GI tract engages in a mutualistic relationship with the host. Different sections of the GI tract contain distinct proportions of the intestinal microbiota, resulting in the presence of unique bacterial products in each GI section. The intestinal microbiota converts ingested nutrients into metabolites that target either the intestinal microbiota population or host cells. Metabolites act as messengers of information between the intestinal microbiota and host cells. The intestinal microbiota composition and resulting metabolites thus impact host development, health, and pathogenesis. Many recent studies have focused on modulation of the gut microbiota and their metabolites to improve host health and prevent or treat diseases. In this review, we focus on the production of microbial metabolites, their biological impact on the intestinal microbiota composition and host cells, and the effect of microbial metabolites that contribute to improvements in inflammatory bowel diseases and metabolic diseases. Understanding the role of microbial metabolites in protection against disease might offer an intriguing approach to regulate disease.
USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro
Authors: Han Kyung Ho , Kwak Minseok , Lee Tae Hyeong , Park Min-soo , Jeong In-ho , Kim Min Ji , Jin Jun-O , Lee Peter Chang-Whan
Published: October 2019

The ubiquitin–proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment.
The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease
Authors: Hsu Chien-Ning , Lu Pei-Chen , Lo Mao-Hung , Lin I-Chun , Tain You-Lin
Published: October 2019

Cardiovascular disease (CVD) is common in chronic kidney disease (CKD), while major CV events are rare in young CKD patients. In addition to nitric oxide (NO)-related biomarkers, several surrogate markers have been assessed to stratify CV risk in youth with CKD, including 24-h ambulatory blood pressure monitoring (ABPM), carotid artery intima-media thickness (cIMT), pulse wave velocity (PWV), ABPM-derived arterial stiffness index (AASI), flow-mediated dilatation (FMD), and left ventricular mass index (LVMI). The aim of this study was to identify subclinical CVD through the analysis of indices of CV risk in children and adolescents with CKD. Between 2016 and 2018, the prospective observational study enrolled 125 patients aged 3 to 18 years with G1–G4 CKD stages. Close to two-thirds of young patients with CKD exhibited blood pressure (BP) abnormalities on ABPM. CKD children with abnormal office BP showed lower plasma arginine levels and arginine-to-asymmetric dimethylarginine (ADMA) ratio, but higher ratios of ADMA-to-symmetric dimethylarginine (SDMA) and citrulline-to-arginine. High PWV and AASI, indices of arterial stiffness, both strongly correlated with high BP load. Additionally, LV mass and LVMI exhibited strong correlations with high BP load. Using an adjusted regression model, we observed the citrulline-to-arginine ratio was associated with 24-h systolic and diastolic BP, systolic blood pressure (SBP) load, and diastolic blood pressure (DBP) load. Early assessments of NO-related parameters, BP load abnormalities, arterial stiffness indices, and LV mass will aid in early preventative care toward decreasing CV risk later in life for children and adolescents with CKD.
The Positive Effects of Grifola frondosa Heteropolysaccharide on NAFLD and Regulation of the Gut Microbiota
Authors: Li Xin , Zeng Feng , Huang Yifan , Liu Bin
Published: October 2019

: Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. In this study, the ability of Grifola frondosa heteropolysaccharide (GFP) to ameliorate NAFLD was investigated in rats fed a high-fat diet (HFD). The molecular mechanisms modulating the expression of specific gene members related to lipid synthesis and conversion, cholesterol metabolism, and inflammation pathways were determined. The components of the intestinal microflora in rats were analyzed by high-throughput next-generation 16S rRNA gene sequencing. Supplementation with GFP significantly increased the proportions of Allobaculum, Bacteroides, and Bifidobacterium and decreased the proportions of Acetatifactor, Alistipes, Flavonifractor, Paraprevotella, and Oscillibacter. In addition, Alistipes, Flavonifractor, and Oscillibacter were shown to be significant cecal microbiota according to the Spearman’s correlation test between the gut microbiota and biomedical assays (|r| > 0.7). Histological analysis and biomedical assays showed that GFP treatments could significantly protect against NAFLD. In addition, Alistipes, Flavonifractor, and Oscillibacter may play vital roles in the prevention of NAFLD. These results suggest that GFP could be used as a functional material to regulate the gut microbiota of NAFLD individuals.
Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys
Authors: Oswald Stefan , Müller Janett , Neugebauer Ute , Schröter Rita , Herrmann Edwin , Pavenstädt Hermann , Ciarimboli Giuliano
Published: October 2019

Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct protein abundance of these transporters in human kidneys, and about the impact of age and gender as potential factors of inter-subject variability in their expression and function. The aim of this study was to determine the protein abundance of MDR1, MRP1-4, BCRP, OAT1-3, OCT2-3, MATE1, PEPT1/2, and ORCTL2 by liquid chromatography-tandem mass spectrometry-based targeted proteomics in a set of 36 human cortex kidney samples (20 males, 16 females; median age 53 and 55 years, respectively). OAT1 and 3, OCT2 and ORCTL2 were found to be most abundant renal SLC transporters while MDR1, MRP1 and MRP4 were the dominating ABC transporters. Only the expression levels of MDR1 and ORCTL2 were significantly higher abundant in older donors. Moreover, we found several significant correlations between different transporters, which may indicate their functional interplay in renal vectorial transport processes. Our data may contribute to a better understanding of the molecular processes determining renal excretion of drugs.
Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy
Authors: Paar Vera , Jirak Peter , Larbig Robert , Zagidullin Naufal Shamilevich , Brandt Mathias C. , Lichtenauer Michael , Hoppe Uta C. , Motloch Lukas J.
Published: October 2019

Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling in action potential generation and cardiac contraction, Ca2+ channels and Ca2+ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca2+-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation.
Which Low-Abundance Proteins are Present in the Human Milieu of Gamete/Embryo Maternal Interaction?
Authors: Canha-Gouveia Analuce , Paradela A. , Ramos-Fernández António , Prieto-Sánchez Maria Teresa , Sánchez-Ferrer Maria Luisa , Corrales Fernando , Coy Pilar
Published: October 2019

The improvement of the embryo culture media is of high relevance due to its influence on successful implantation rates, pregnancy, neonatal outcomes, and potential effects in adult life. The ideal conditions for embryo development are those naturally occurring in the female reproductive tract, i.e., the oviductal and uterine fluids. To shed light on the differences between chemical and natural media, we performed the first comparative study of the low abundance proteins in plasma, uterine, and oviductal fluid collected, simultaneously, from healthy and fertile women that underwent a salpingectomy. The rationale for this design derives from the fact that high-abundant proteins in these fluids are usually those coming from blood serum and frequently mask the detection of low abundant proteins with a potentially significant role in specific processes related to the embryo–maternal interaction. The proteomic analysis by 1D-nano LC ESI-MSMS detected several proteins in higher amounts in oviductal fluid when compared to uterine and plasma samples (RL3, GSTA1, EZRI, DPYSL3, GARS, HSP90A). Such oviductal fluid proteins could be a target to improve fertilization rates and early embryo development if used in the culture media. In conclusion, this study presents a high-throughput analysis of female reproductive tract fluids and contributes to the knowledge of oviductal and uterine secretome.
The Overcrowded Crossroads: Mitochondria, Alpha-Synuclein, and the Endo-Lysosomal System Interaction in Parkinson’s Disease
Authors: Lin Kai-Jung , Lin Kai-Lieh , Chen Shang-Der , Liou Chia-Wei , Chuang Yao-Chung , Lin Hung-Yu , Lin Tsu-Kung
Published: October 2019

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, mainly affecting the elderly. The disease progresses gradually, with core motor presentations and a multitude of non-motor manifestations. There are two neuropathological hallmarks of PD, the dopaminergic neuronal loss and the alpha-synuclein-containing Lewy body inclusions in the substantia nigra. While the exact pathomechanisms of PD remain unclear, genetic investigations have revealed evidence of the involvement of mitochondrial function, alpha-synuclein (α-syn) aggregation, and the endo-lysosomal system, in disease pathogenesis. Due to the high energy demand of dopaminergic neurons, mitochondria are of special importance acting as the cellular powerhouse. Mitochondrial dynamic fusion and fission, and autophagy quality control keep the mitochondrial network in a healthy state. Should defects of the organelle occur, a variety of reactions would ensue at the cellular level, including disrupted mitochondrial respiratory network and perturbed calcium homeostasis, possibly resulting in cellular death. Meanwhile, α-syn is a presynaptic protein that helps regulate synaptic vesicle transportation and endocytosis. Its misfolding into oligomeric sheets and fibrillation is toxic to the mitochondria and neurons. Increased cellular oxidative stress leads to α-syn accumulation, causing mitochondrial dysfunction. The proteasome and endo-lysosomal systems function to regulate damage and unwanted waste management within the cell while facilitating the quality control of mitochondria and α-syn. This review will analyze the biological functions and interactions between mitochondria, α-syn, and the endo-lysosomal system in the pathogenesis of PD.
Tackling Acute Lymphoblastic Leukemia—One Fish at a Time
Authors: Sinha Arpan A. , Park Gilseung , Frazer J. Kimble
Published: October 2019

Despite advancements in the diagnosis and treatment of acute lymphoblastic leukemia (ALL), a need for improved strategies to decrease morbidity and improve cure rates in relapsed/refractory ALL still exists. Such approaches include the identification and implementation of novel targeted combination regimens, and more precise upfront patient risk stratification to guide therapy. New curative strategies rely on an understanding of the pathobiology that derives from systematically dissecting each cancer’s genetic and molecular landscape. Zebrafish models provide a powerful system to simulate human diseases, including leukemias and ALL specifically. They are also an invaluable tool for genetic manipulation, in vivo studies, and drug discovery. Here, we highlight and summarize contributions made by several zebrafish T-ALL models and newer zebrafish B-ALL models in translating the underlying genetic and molecular mechanisms operative in ALL, and also highlight their potential utility for drug discovery. These models have laid the groundwork for increasing our understanding of the molecular basis of ALL to further translational and clinical research endeavors that seek to improve outcomes in this important cancer.
Role of High-Mobility Group Box-1 in Liver Pathogenesis
Authors: Khambu Bilon , Yan Shengmin , Huda Nazmul , Yin Xiao-Ming
Published: October 2019

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.
Emerging Anticancer Potentials of Selenium on Osteosarcoma
Authors: Pang Kok-Lun , Chin Kok-Yong
Published: October 2019

Selenium is a trace element essential to humans and forms complexes with proteins, which exert physiological functions in the body. In vitro studies suggested that selenium possesses anticancer effects and may be effective against osteosarcoma. This review aims to summarise current evidence on the anticancer activity of inorganic and organic selenium on osteosarcoma. Cellular studies revealed that inorganic and organic selenium shows cytotoxicity, anti-proliferative and pro-apoptotic effects on various osteosarcoma cell lines. These actions may be mediated by oxidative stress induced by selenium compounds, leading to the activation of p53, proapoptotic proteins and caspases. Inorganic selenium is selective towards cancer cells, but can cause non-selective cell death at a high dose. This condition challenges the controlled release of selenium from biomaterials. Selenium treatment in animals inoculated with osteosarcoma reduced the tumour size, but did not eliminate the incidence of osteosarcoma. Only one study investigated the relationship between selenium and osteosarcoma in humans, but the results were inconclusive. In summary, although selenium may exert anticancer properties on osteosarcoma in experimental model systems, its effects in humans require further investigation.
The Landscape of Actionable Gene Fusions in Colorectal Cancer
Authors: Pagani Filippo , Randon Giovanni , Guarini Vincenzo , Raimondi Alessandra , Prisciandaro Michele , Lobefaro Riccardo , Di Bartolomeo Maria , Sozzi Gabriella , de Braud Filippo , Gasparini Patrizia , Pietrantonio Filippo
Published: October 2019

The treatment scenario of metastatic colorectal cancer (mCRC) has been rapidly enriched with new chemotherapy combinations and biological agents that lead to a remarkable improvement in patients’ outcome. Kinase gene fusions account for less than 1% of mCRC overall but are enriched in patients with high microsatellite instability, RAS/BRAF wild-type colorectal cancer. mCRC patients harboring such alterations show a poor prognosis with standard treatments that could be reversed by adopting novel therapeutic strategies. Moving forward to a positive selection of mCRC patients suitable for targeted therapy in the era of personalized medicine, actionable gene fusions, although rare, represent a peculiar opportunity to disrupt a tumor alteration to achieve therapeutic goal. Here we summarize the current knowledge on potentially actionable gene fusions in colorectal cancer available from retrospective experiences and promising preliminary results of new basket trials.
Interplay Between MicroRNAs and Oxidative Stress in Ovarian Conditions with a Focus on Ovarian Cancer and Endometriosis
Authors: Marí-Alexandre Josep , Carcelén Antonio Pellín , Agababyan Cristina , Moreno-Manuel Andrea , García-Oms Javier , Calabuig-Fariñas Silvia , Gilabert-Estellés Juan
Published: October 2019

Ovarian cancer and endometriosis are two distinct gynaecological conditions that share many biological aspects incuding proliferation, invasion of surrounding tissue, inflammation, inhibition of apoptosis, deregulation of angiogenesis and the ability to spread at a distance. miRNAs are small non-coding RNAs (19–22 nt) that act as post-transcriptional modulators of gene expression and are involved in several of the aforementioned processes. In addition, a growing body of evidence supports the contribution of oxidative stress (OS) to these gynaecological diseases: increased peritoneal OS due to the decomposition of retrograde menstruation blood facilitates both endometriotic lesion development and fallopian tube malignant transformation leading to high-grade serous ovarian cancer (HGSOC). Furthermore, as HGSOC develops, increased OS levels are associated with chemoresistance. Finally, continued bleeding within ovarian endometrioma raises OS levels and contributes to the development of endometriosis-associated ovarian cancer (EAOC). Therefore, this review aims to address the need for a better understanding of the dialogue between miRNAs and oxidative stress in the pathophysiology of ovarian conditions: endometriosis, EAOC and HGSOC.
CpWRKY71, a WRKY Transcription Factor Gene of Wintersweet (Chimonanthus praecox), Promotes Flowering and Leaf Senescence in Arabidopsis
Authors: Huang Renwei , Liu Daofeng , Huang Min , Ma Jing , Li Zhineng , Li Mingyang , Sui Shunzhao
Published: October 2019

The WRKY transcription factors are one of the most important plant-specific transcription factors and play vital roles in various biological processes. However, the functions of WRKY genes in wintersweet (Chimonanthus praecox) are still unknown. In this report, a group IIc WRKY gene, CpWRKY71, was isolated from wintersweet. CpWRKY71 was localized to the nucleus and possessed transcriptional activation activity. qRT-PCR (quantitative real-time PCR) analysis showed that CpWRKY71 was expressed in all tissues tested, with higher expression in flowers and senescing leaves. During the flower development, the highest expression was detected in the early-withering stage, an obvious expression of CpWRKY71 was also observed in the flower primordia differentiation and the bloom stage. Meanwhile, the expression of CpWRKY71 was influenced by various abiotic stress and hormone treatments. The expression patterns of the CpWRKY71 gene were further confirmed in CpWRKY71pro:GUS (β-glucuronidase) plants. Heterologous overexpression of CpWRKY71 in Arabidopsis caused early flowering. Consistent with the early flowering phenotype, the expression of floral pathway integrators and floral meristem identity (FMI) genes were significantly up-regulated in transgenic plants. In addition, we also observed that the transgenic plants of CpWRKY71 exhibited precocious leaf senescence. In conclusion, our results suggested that CpWRKY71 may be involved in the regulation of flowering and leaf senescence in Arabidopsis. Our study provides a foundation for further characterization of CpWRKY genes function in wintersweet, and also enrich our knowledge of molecular mechanism about flowering and senescence in wintersweet.
Wounding and UVB Light Synergistically Induce the Biosynthesis of Phenolic Compounds and Ascorbic Acid in Red Prickly Pears (Opuntia ficus-indica cv. Rojo Vigor)
Authors: Ortega-Hernández Erika , Nair Vimal , Welti-Chanes Jorge , Cisneros-Zevallos Luis , Jacobo-Velázquez Daniel A.
Published: October 2019

The present study evaluated the effects of ultraviolet B (UVB) radiation and wounding stress, applied alone or combined, on the biosynthesis of phenolic compounds and ascorbic acid in the peel and pulp of red prickly pear (Opuntia ficus-indica cv. Rojo Vigor). Whole and wounded-fruit samples were treated with UVB radiation (6.4 W·m−2) for 0 and 15 min, and stored for 24 h at 16 °C. Phytochemical analyses were performed separately in the peel and pulp. The highest phenolic accumulation occurred after storage of the whole tissue treated with UVB, where the main phenolic compounds accumulated in the peel and pulp were quercetin, sinapic acid, kaempferol, rosmarinic acid, and sinapoyl malate, showing increases of 709.8%, 570.2%, 442.8%, 439.9%, and 186.2%, respectively, as compared with the control before storage. Phenylalanine ammonia-lyase (PAL) activity was increased after storage of the whole and wounded tissue treated with UVB light, and this increase in PAL activity was associated to phenolic accumulation. On the other hand, l-galactono-γ-lactone dehydrogenase (GalLDH) activity and ascorbic acid biosynthesis was enhanced due to UVB radiation, and the effect was increased when UVB was applied in the wounded tissue showing 125.1% and 94.1% higher vitamin C content after storage when compared with the control. Respiration rate was increased due to wounding stress, whereas ethylene production was increased by wounding and UVB radiation in prickly pears. Results allowed the generation of a physiological model explaining the UVB and wound-induced accumulation of phenolic compounds and ascorbic acid in prickly pears, where wounding facilitates UVB to access the underlying tissue and enhances an apparent synergistic response.
Expression of Adenosine Receptors in Rodent Pancreas
Authors: Hayashi Mikio
Published: October 2019

Adenosine regulates exocrine and endocrine secretions in the pancreas. Adenosine is considered to play a role in acini-to-duct signaling in the exocrine pancreas. To identify the molecular basis of functional adenosine receptors in the exocrine pancreas, immunohistochemical analysis was performed in the rat, mouse, and guinea pig pancreas, and the secretory rate and concentration of HCO3− in pancreatic juice from the rat pancreas were measured. The A2A adenosine receptor colocalized with ezrin, an A-kinase anchoring protein, in the luminal membrane of duct cells in the mouse and guinea pig pancreas. However, a strong signal ascribed to A2B adenosine receptors was detected in insulin-positive β cells in islets of Langerhans. The A2A adenosine receptor agonist 4-[2-[[6-Amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid (CGS 21680) stimulated HCO3−-rich fluid secretion from the rat pancreas. These results indicate that A2A adenosine receptors may be, at least in part, involved in the exocrine secretion of pancreatic duct cells via acini-to-duct signaling. The adenosine receptors may be a potential therapeutic target for cancer as well as exocrine dysfunctions of the pancreas.
From Theory to Field Evidence: Observations on the Evolution of the Settlements of an Earthfill Dam, over Long Time Scales
Authors: Pytharouli Stella , Michalis Panagiotis , Raftopoulos Spyridon
Published: October 2019

Unprecedented flooding events put dams and downstream communities at risk, as evidenced by the recent cases of the Oroville and Whaley bridge dams. Empirical models may describe expected ‘normal’ dam behaviour, but they do not account for changes due to recurring extreme weather events. Numerical modelling provides insights into this, but results are affected by the chosen material properties. Long-term field monitoring data can help with understanding the mechanical behaviour of earthfill dams and how this is affected by the environment over decades. We analyse the recorded settlements for one of the largest earthfill dams in Europe. We compare the evolution of these settlements to the reservoir level, rainfall, and the occurrence of earthquakes for a period of 31 years after first impoundment. We find that the clay core responds to the reservoir fluctuations with an increasing (from 0 to 6 months) time delay. This is the first time that a change in the behaviour of a central clay core dam, as observed from field data, is reported in the international literature. Seepage rates, as recorded within the drainage galleries, are directly affected by cumulative rainfall depths exceeding 67 mm per fortnight.
High Expression of TTYH3 Is Related to Poor Clinical Outcomes in Human Gastric Cancer
Authors: Saha Subbroto Kumar , Biswas Polash Kumar , Gil Minchan , Cho Ssang-Goo
Published: October 2019

Ion channels play important roles in regulating various cellular processes and malignant transformation. Expressions of some chloride channels have been suggested to be associated with patient survival in gastric cancer (GC). However, little is known about the expression and function of TTYH3, a gene encoding a chloride ion channel, in cancer progression. Here, we comprehensively analyzed the expression of TTYH3 and its clinical outcome in GC using publicly available cancer gene expression and patient survival data through various databases. We examined the differences of TTYH3 expression between cancers and their normal tissues using the Oncomine, UALCAN, and GEO (Gene Expression Omnibus) databases. TTYH3 expression was investigated from immunohistochemistry images using the Human Protein Atlas database. Copy number alterations and mutations of TTYH3 were analyzed using cBioPortal. The co-expression profile of TTYH3 in GC was revealed using Oncomine. The gene ontology and pathway analyses were done using those co-expressed genes via the Enrichr tool to explore the predicted signaling pathways in GC. TTYH3 mRNA and protein levels in GC were significantly greater than those in normal tissue. Kaplan–Meier analysis revealed the upregulation of TTYH3 expression, which was significantly correlated with worse patient survival. Collectively, our data suggest that TTYH3 might be a potential prognostic marker for GC patients.
IL-1β and Statin Treatment in Patients with Myocardial Infarction and Diabetic Cardiomyopathy
Authors: Liberale Luca , Carbone Federico , Camici Giovanni G. , Montecucco Fabrizio
Published: October 2019

Statins are effective lipid-lowering drugs with a good safety profile that have become, over the years, the first-line therapy for patients with dyslipidemia and a real cornerstone of cardiovascular (CV) preventive therapy. Thanks to both cholesterol-related and “pleiotropic” effects, statins have a beneficial impact against CV diseases. In particular, by reducing lipids and inflammation statins, they can influence the pathogenesis of both myocardial infarction and diabetic cardiomyopathy. Among inflammatory mediators involved in these diseases, interleukin (IL)-1β is a pro-inflammatory cytokine that recently been shown to be an effective target in secondary prevention of CV events. Statins are largely prescribed to patients with myocardial infarction and diabetes, but their effects on IL-1β synthesis and release remain to be fully characterized. Of interest, preliminary studies even report IL-1β secretion to rise after treatment with statins, with a potential impact on the inflammatory microenvironment and glycemic control. Here, we will summarize evidence of the role of statins in the prevention and treatment of myocardial infarction and diabetic cardiomyopathy. In accordance with the dual lipid-lowering and anti-inflammatory effect of these drugs and in light of the important results achieved by IL-1β inhibition through canakinumab in CV secondary prevention, we will dissect the current evidence linking statins with IL-1β and outline the possible benefits of a potential double treatment with statins and canakinumab.
Less Is More: Ulnar Lengthening Alone without Radial Corrective Osteotomy in Forearm Deformity Secondary to Hereditary Multiple Exostoses
Authors: Hsu Po-Jen , Wu Kuan-Wen , Lee Chia-Che , Kuo Ken N. , Chang Jia-Feng , Wang Ting-Ming
Published: October 2019

Ulnar lengthening has gained popularity in treating forearm deformity due to hereditary multiple exostoses (HME). Whether a simultaneous radius angular correction is necessary for bowing deformity remains debatable. We aimed to evaluate effectiveness and safety of ulnar lengthening alone in HME children. HME patients with forearm deformity who underwent ulnar lengthening between 2011 and 2016 were included. Patients were divided into two groups: eight juniors (age ≤ 10 years) and six seniors (>10 years). The mean age of two groups was 8.1 ± 2.5 and 16.7 ± 4.4 years, respectively. The juniors underwent ulnar lengthening alone, and the seniors received an additional radial corrective osteotomy. Pre-operative and post-operative parameters of supination, pronation, ulnar variance (UV), radial articular angles (RAA), and carpal slip (CS) were assessed. The juniors rather the seniors had an improvement in supination (p < 0.05 and p = 0.109, respectively). The juniors and seniors improved in pronation (p < 0.05). UV, RAA, and CS were corrected in the seniors (p < 0.05). In the juniors, parameters improved in UV, RAA, and CS (p < 0.05). For HME children, ulnar lengthening alone can restore radiologic anatomy and functions, providing comparable surgical outcomes in cosmetic results and clinical parameters.
Factors Associated with Successful Response to Balloon Decompressive Adhesiolysis Neuroplasty in Patients with Chronic Lumbar Foraminal Stenosis
Authors: Oh Yul , Kim Doo-Hwan , Park Jun-Young , Ji Gyu Yeul , Shin Dong Ah , Lee Sang Won , Park Jin Kyu , Shin Jin-Woo , Choi Seong-Soo
Published: October 2019

Epidural neuroplasty, often called percutaneous epidural adhesiolysis, is often performed in refractory patients with chronic lumbar radiculopathy or neurogenic claudication. Recent studies have showed that decompressive adhesiolysis with an inflatable balloon catheter (balloon neuroplasty) is efficient in patients who experience refractory pain from epidural steroid injection or even epidural neuroplasty with a balloon-less catheter. However, exact indications or predictive factors for epidural balloon neuroplasty have not been fully evaluated. Therefore, to assess associated factors that could affect a favorable outcome, we analyzed a prospectively collected multicenter cohort of patients with chronic refractory lumbar foraminal stenosis after balloon neuroplasty. At the 6-month point in follow-up, 92 (44.4%) patients among 207 subjects were classified as successful responders according to a robust combination of outcome measures. Multivariate logistic regression analysis also showed that mild grade lumbar foraminal stenosis may be an independent factor associated with a successful response 6 months after balloon neuroplasty (odds ratio = 2.829; 95% confidence interval = 1.351–5.923; p = 0.006). However, we found that there were 29.4% and 24.6% successful responders with moderate and severe foraminal stenosis, respectively. Attempting balloon neuroplasty in refractory lumbar foraminal stenosis, especially mild grade, may be worthwhile.
Texture Analysis of Multi-Shot Echo-Planar Diffusion-Weighted Imaging in Head and Neck Squamous Cell Carcinoma: The Diagnostic Value for Nodal Metastasis
Authors: Park Jung Hyun , Bae Yun Jung , Choi Byung Se , Jung Young Ho , Jeong Woo-Jin , Kim Hyojin , Sunwoo Leonard , Jung Cheolkyu , Kim Jae Hyoung
Published: October 2019

Accurate assessment of nodal metastasis in head and neck squamous cell carcinoma (SCC) is important, and diffusion-weighted imaging (DWI) has emerged as a potential technique in differentiating benign from malignant lymph nodes (LNs). This study aims to evaluate the diagnostic performance of texture analysis using apparent diffusion coefficient (ADC) data of multi-shot echo-planar imaging-based DWI (msEPI-DWI) in predicting metastatic LNs of head and neck SCC. 36 patients with pathologically proven head and neck SCC were included in this study. A total of 204 MRI-detected LNs, including 176 subcentimeter-sized LNs, were assigned to metastatic or benign groups. Texture features of LNs were compared using independent t-test. Hierarchical cluster analysis was performed to exclude redundant features. Multivariate logistic regression and receiver operating characteristic analysis were performed to assess the diagnostic performance. The discriminative texture features for predicting metastatic LNs were complexity, energy and roundness. Areas under the curves (AUCs) for diagnosing metastasis in all/subcentimeter-sized LNs were 0.829/0.767 using complexity, 0.699/0.685 using energy and 0.671/0.638 using roundness, respectively. The combination of three features resulted in higher AUC values of 0.836/0.781. In conclusion, texture analysis of ADC data using msEPI-DWI could be a useful tool for nodal staging in head and neck SCC.
A CTC-Cluster-Specific Signature Derived from OMICS Analysis of Patient-Derived Xenograft Tumors Predicts Outcomes in Basal-Like Breast Cancer
Authors: Thangavel Hariprasad , Angelis Carmine De , Vasaikar Suhas , Bhat Raksha , Jolly Mohit Kumar , Nagi Chandandeep , Creighton Chad J. , Chen Fengju , Dobrolecki Lacey E. , George Jason T. , Kumar Tanya , Abdulkareem Noor Mazin , Mao Sufeng , Nardone Agostina , Rimawi Mothaffar , Osborne C. Kent , Lewis Michael T. , Levine Herbert , Zhang Bing , Schiff Rachel , Giuliano Mario , Trivedi Meghana V.
Published: October 2019

Circulating tumor cell clusters (CTCcl) have a higher metastatic potential compared to single CTCs and predict long-term outcomes in breast cancer (BC) patients. Because of the rarity of CTCcls, molecular characterization of primary tumors that give rise to CTCcl hold significant promise for better diagnosis and target discovery to combat metastatic BC. In our study, we utilized the reverse-phase protein array (RPPA) and transcriptomic (RNA-Seq) data of 10 triple-negative BC patient-derived xenograft (TNBC PDX) transplantable models with CTCs and evaluated expression of upregulated candidate protein Bcl2 (B-cell lymphoma 2) by immunohistochemistry (IHC). The sample-set consisted of six CTCcl-negative (CTCcl−) and four CTCcl-positive (CTCcl+) models. We analyzed the RPPA and transcriptomic profiles of CTCcl− and CTCcl+ TNBC PDX models. In addition, we derived a CTCcl-specific gene signature for testing if it predicted outcomes using a publicly available dataset from 360 patients with basal-like BC. The RPPA analysis of CTCcl+ vs. CTCcl− TNBC PDX tumors revealed elevated expression of Bcl2 (false discovery rate (FDR) < 0.0001, fold change (FC) = 3.5) and reduced acetyl coenzyme A carboxylase-1 (ACC1) (FDR = 0.0005, FC = 0.3) in CTCcl+ compared to CTCcl− tumors. Genome-wide transcriptomic analysis of CTCcl+ vs. CTCcl− tumors revealed 549 differentially expressed genes associated with the presence of CTCcls. Apoptosis was one of the significantly downregulated pathways (normalized enrichment score (NES) = −1.69; FDR < 0.05) in TNBC PDX tumors associated with CTCcl positivity. Two out of four CTCcl+ TNBC PDX primary tumors had high Bcl2 expression by IHC (H-score > 34); whereas, only one of six CTCcl− TNBC PDX primary tumors met this criterion. Evaluation of epithelial-mesenchymal transition (EMT)-specific signature did not show significant differences between CTCcl+ and CTCcl− tumors. However, a gene signature associated with the presence of CTCcls in TNBC PDX models was associated with worse relapse-free survival in the publicly available dataset from 360 patients with basal-like BC. In summary, we identified the multigene signature of primary PDX tumors associated with the presence of CTCcls. Evaluation of additional TNBC PDX models and patients can further illuminate cellular and molecular pathways facilitating CTCcl formation.
Analysis of Pulse Arrival Time as an Indicator of Blood Pressure in a Large Surgical Biosignal Database: Recommendations for Developing Ubiquitous Blood Pressure Monitoring Methods
Authors: Lee Joonnyong , Yang Seungman , Lee Saram , Kim Hee Chan
Published: October 2019

As non-invasive continuous blood pressure monitoring (NCBPM) has gained wide attraction in the recent decades, many pulse arrival time (PAT) or pulse transit time (PTT) based blood pressure (BP) estimation studies have been conducted. However, most of the studies have used small homogeneous subject pools to generate models of BP based on particular interventions for induced hemodynamic change. In this study, a large open biosignal database from a diverse group of 2309 surgical patients was analyzed to assess the efficacy of PAT, PTT, and confounding factors on the estimation of BP. After pre-processing the dataset, a total of 6,777,308 data pairs of BP and temporal features between electrocardiogram (ECG) and photoplethysmogram (PPG) were extracted and analyzed. Correlation analysis revealed that PAT or PTT extracted from the intersecting-tangent (IT) point of PPG showed the highest mean correlation to BP. The mean correlation between PAT and systolic blood pressure (SBP) was −0.37 and the mean correlation between PAT and diastolic blood pressure (DBP) was −0.30, outperforming the correlation between BP and PTT at −0.12 for SBP and −0.11 for DBP. A linear model of BP with a simple calibration method using PAT as a predictor was developed which satisfied international standards for automatic oscillometric BP monitors in the case of DBP, however, SBP could not be predicted to a satisfactory level due to higher errors. Furthermore, multivariate regression analyses showed that many confounding factors considered in previous studies had inconsistent effects on the degree of correlation between PAT and BP.
Noninvasive and Convenient Screening of Metabolic Syndrome Using the Controlled Attenuation Parameter Technology: An Evaluation Based on Self-Paid Health Examination Participants
Authors: Lin Yu-Jiun , Lin Chang-Hsien , Wang Sen-Te , Lin Shiyng-Yu , Chang Shy-Shin
Published: October 2019

Background: There is a medical need for an easy, fast, and non-invasive method for metabolic syndrome (MetS) screening. This study aimed to assess the ability of FibroScan to detect MetS, in participants who underwent a self-paid health examination. Methods: A retrospective cohort study was conducted on all adults who underwent a self-paid health examination comprising of an abdominal transient elastography inspection using FibroScan 502 Touch from March 2015 to February 2019. FibroScan can assess the level of liver fibrosis by using a liver stiffness score, and the level of liver steatosis by using the controlled attenuation parameter (CAP) score. The logistic regression analysis and receiver operating characteristic curve were applied to select significant predictors and assess their predictability. A final model that included all significant predictors that are found by univariate analysis, and a convenient model that excluded all invasive parameters were created. Results: Of 1983 participants, 13.6% had a physical status that fulfilled MetS criteria. The results showed that the CAP score solely could achieve an area under the curve (AUC) of 0.79 (0.76–0.82) in predicting MetS, and the AUC can be improved to 0.88 (0.85–0.90) in the final model. An AUC of 0.85 (0.83–0.88) in predicting MetS was obtained in the convenient model, which includes only 4 parameters (CAP score, gender, age, and BMI). A panel of predictability indices (the ranges of sensitivity, specificity, positive and negative likelihood ratio: 0.78–0.89, 0.66–0.82, 2.64–4.47, and 0.17–0.26) concerning gender- and BMI-specific CAP cut-off values (range: 191.65–564.95) were presented for practical reference. Conclusions: Two prediction systems were proposed for identifying individuals with a physical status that fulfilled the MetS criteria, and a panel of predictability indices was presented for practical reference. Both systems had moderate predictive performance. The findings suggested that FibroScan evaluation is appropriate as a first-line MetS screening; however, the variation in prediction performance of such systems among groups with varying metabolic derangements warrants further studies in the future.
Decontamination of Intravaginal Probes Infected by Human Papillomavirus (HPV) Using UV-C Decontamination System
Authors: Pichon Maxime , Lebail-Carval Karine , Billaud Geneviève , Lina Bruno , Gaucherand Pascal , Mekki Yahia
Published: October 2019

Background: This three-step study evaluated ultraviolet-C (UV-C) efficacy against human papillomavirus (HPV) found on vaginal ultrasound probes. Methods: The first two steps evaluated UV-C disinfection of vaginal ultrasound probes in routine condition. During the first phase, the probe (n = 100) was sampled after a complete cleaning and disinfection protocol, i.e., cleaning with chemically impregnated wipes, followed by UV-C. During the second phase, the probe (n = 47) was sampled after cleaning and UV-C. The final step consisted of applying mixes of HPV on a dedicated, covered probe (n = 15) then sampling the cover, the probe after removal of the cover, after cleaning, and after UV-C. HPV detection was performed using CLART® HPV2 PCR (Genomica, Madrid, Spain). Results: In the first phase, no probes were found to be positive for both DNA after UV-C. In the second phase, eight probes were found to be positive after cleaning (seven with human DNA and one with HPV) and negative after UV-C. In the final phase, one probe was found to be positive for HPV for each sample except after UV-C. Conclusions: Covers followed by a chemically impregnated wipe are not sufficient to ensure patient safety during vaginal ultrasound examinations. UV-C is effective in routine conditions against contaminations found on vaginal ultrasound probes, especially HPV.
Neurological Immune Related Adverse Events Associated with Nivolumab, Ipilimumab, and Pembrolizumab Therapy—Review of the Literature and Future Outlook
Authors: Möhn Nora , Beutel Gernot , Gutzmer Ralf , Ivanyi Philipp , Satzger Imke , Skripuletz Thomas
Published: October 2019

Immune checkpoint inhibitor (ICI) therapy has revolutionized the management of various cancers with previously poor prognosis. Despite its great efficacy, the therapy is associated with a wide spectrum of immune-related adverse events (irAE) including neurological symptoms which can affect all parts of the central and peripheral nervous system. Even though these events are rare, they are of high relevance as the rate of residual symptoms or even fatal outcomes is remarkable. To provide a detailed overview of neurological adverse events associated with immune checkpoint-inhibitor therapy we conducted a literature search. While focusing on ipilimumab, nivolumab, and pembrolizumab therapy, all available case reports as well as larger case series and clinical trials have been considered. Eighty-two case reports about checkpoint-inhibitor therapy induced symptoms of the peripheral nervous system have been published, while only 43 case reports addressed central nervous system abnormalities. The frequency of immune checkpoint-inhibitor therapy inducing neurological adverse events is about 1% in larger studies. Especially neuromuscular adverse events exhibit distinct clinical and diagnostic characteristics. Additionally, several affected patients presented with overlap-syndromes, which means that symptoms and diagnostic findings indicating myositis, myasthenia gravis, and neuropathy were present in one individual patient at the same time. Thus, neurological and particularly neuromuscular adverse events of immune checkpoint-inhibitor therapy may constitute a new disease entity.
Induced Pluripotent Stem Cells as Vasculature Forming Entities
Authors: Palladino Antonio , Mavaro Isabella , Pizzoleo Carmela , De Felice Elena , Lucini Carla , de Girolamo Paolo , Netti Paolo A. , Attanasio Chiara
Published: October 2019

Tissue engineering (TE) pursues the ambitious goal to heal damaged tissues. One of the most successful TE approaches relies on the use of scaffolds specifically designed and fabricated to promote tissue growth. During regeneration the guidance of biological events may be essential to sustain vasculature neoformation inside the engineered scaffold. In this context, one of the most effective strategies includes the incorporation of vasculature forming cells, namely endothelial cells (EC), into engineered constructs. However, the most common EC sources currently available, intended as primary cells, are affected by several limitations that make them inappropriate to personalized medicine. Human induced Pluripotent Stem Cells (hiPSC), since the time of their discovery, represent an unprecedented opportunity for regenerative medicine applications. Unfortunately, human induced Pluripotent Stem Cells-Endothelial Cells (hiPSC-ECs) still display significant safety issues. In this work, we reviewed the most effective protocols to induce pluripotency, to generate cells displaying the endothelial phenotype and to perform an efficient and safe cell selection. We also provide noteworthy examples of both in vitro and in vivo applications of hiPSC-ECs in order to highlight their ability to form functional blood vessels. In conclusion, we propose hiPSC-ECs as the preferred source of endothelial cells currently available in the field of personalized regenerative medicine.