bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?
Authors: Hofmann Julia , Otarashvili Giorgi , Meszaros Andras , Ebner Susanne , Weissenbacher Annemarie , Cardini Benno , Oberhuber Rupert , Resch Thomas , Öfner Dietmar , Schneeberger Stefan , Troppmair Jakob , Hautz Theresa
Published: April 2020

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.
What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?
Authors: Amaral Margarida D. , Quaresma Margarida C. , Pankonien Ines
Published: April 2020

One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial–mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.
High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia
Authors: Unachukwu Uchenna , Chada Kiran , D’Armiento Jeanine
Published: April 2020

High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.
Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications
Authors: Tarozzi Andrea
Published: April 2020

Oxidative stress plays an important role in the pathogenesis of several different neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) [...]
Safety Profile of Biologics Used in Rheumatology: An Italian Prospective Pharmacovigilance Study
Authors: Barbieri Maria Antonietta , Cicala Giuseppe , Cutroneo Paola Maria , Gerratana Elisabetta , Palleria Caterina , De Sarro Caterina , Vero Ada , Iannone Luigi , Manti Antonia , Russo Emilio , De Sarro Giovambattista , Atzeni Fabiola , Spina Edoardo
Published: April 2020

Post-marketing surveillance activities are essential to detect the risk/benefit profile of biologic disease-modifying antirheumatic drugs (bDMARDs) in inflammatory arthritis. The aim of this study was to evaluate adverse events (AEs) in patients treated with bDMARDs in rheumatology during a prospective pharmacovigilance study from 2016 to 2018. Descriptive statistical analyses were performed to evaluate bDMARDs-related variables of patients without AEs/failures vs patients with AEs and failures. The risk profile among biologics was assessed by comparing patients treated with each bDMARD to patients treated with etanercept. A total of 1155 patients were enrolled, mostly affected by rheumatoid arthritis (46.0%). AEs and failures were experienced by 8.7% and 23.3%, respectively. The number of comorbidities significantly influenced the onset of AEs, while anxiety-depressive, gastrointestinal disease, and fibromyalgia influenced onset of failures. The probability of developing an AE was significantly lower in patients treated with secukinumab, while the probability of developing treatment failure was significantly lower in patients treated with golimumab, secukinumab and tocilizumab. A total of 216 AEs were reported (25.5% serious), mostly regarding infections (21.8%), musculoskeletal (17.6%) and skin (16.2%) disorders. Serious AEs included neutropenia (12.7%), lymphocytosis (9.1%) and uveitis (7.3%). The obtained results revealed known AEs but real-world data should be endorsed for undetected safety concerns.
The Association between Serum Levels of 25[OH]D, Body Weight Changes and Body Composition Indices in Patients with Heart Failure
Authors: Stefaniak Apolonia , Partyka Robert , Duda Sylwia , Ostręga Weronika , Niedziela Jacek , Nowak Jolanta , Malinowska-Borowska Jolanta , Rywik Tomasz , Leszek Przemysław , Hudzik Bartosz , Zubelewicz-Szkodzińska Barbara , Rozentryt Piotr
Published: April 2020

We try to determine the association between weight changes (WC), both loss or gain, body composition indices (BCI) and serum levels of 25[OH]D during heart failure (HF). WC was determined in 412 patients (14.3% female, aged: 53.6 ± 10.0 years, NYHA class: 2.5 ± 0.8). Body fat, fat percentage and fat-free mass determined by dual energy X-rays absorptiometry (DEXA) and serum levels of 25[OH]D were analyzed. Logistic regression was used to calculate odds ratios for 25[OH]D insufficiency (<30 ng/mL) or deficiency (<20 ng/mL) by quintiles of WC, in comparison to weight-stable subgroup. The serum 25[OH]D was lower in weight loosing than weight stable subgroup. In fully adjusted models the risk of either insufficient or deficient 25[OH]D levels was independent of BCI and HF severity markers. The risk was elevated in higher weight loss subgroups but also in weight gain subgroup. In full adjustment, the odds for 25[OH]D deficiency in the top weight loss and weight gain subgroups were 3.30; 95%CI: 1.37–7.93, p = 0.008 and 2.41; 95%CI: 0.91–6.38, p = 0.08, respectively. The risk of 25[OH]D deficiency/insufficiency was also independently associated with potential UVB exposure, but not with nutritional status and BCI. Metabolic instability in HF was reflected by edema-free WC, but not nutritional status. BCI is independently associated with deficiency/insufficiency of serum 25[OH]D.
Changes in Iris Perfusion Following Scleral Buckle Surgery for Rhegmatogenous Retinal Detachment: An Anterior Segment Optical Coherence Tomography Angiography (AS-OCTA) Study
Authors: D’Aloisio Rossella , Viggiano Pasquale , Borrelli Enrico , Parravano Mariacristina , Agbèanda Aharrh-Gnama , Evangelista Federica , Ferro Giada , Toto Lisa , Mastropasqua Rodolfo
Published: April 2020

Purpose: To investigate iris vasculature changes following scleral buckling (SB) surgery in eyes with rhegmatogenous retinal detachment (RRD) with anterior-segment (AS) optical coherence tomography angiography (OCTA). Methods: In this prospective study, enrolled subjects were imaged with an SS-OCTA system (PLEX Elite 9000, Carl Zeiss Meditec Inc., Dublin, CA, USA). Image acquisition of the iris was obtained using an AS lens and a manual focusing adjustment in the iris using the retina imaging software. The quantitative analysis was performed in eight different iris regions: (i) superior, (ii) supero-temporal, (iii) supero-nasal, (iv) nasal, (v) temporal, (vi) inferior, (vii) infero-temporal, (viii) infero nasal which, were defined as squares with area of 1.5 mm2. Results: Fifteen eyes of 15 patients (six females; nine males) were included. Anterior segment optical coherence tomography angiography (AS-OCTA) parameters of the iris were statistically compared at baseline (preoperatively), 1 week, 1 month and 6 months after SB. At post-operative 1 week, perfusion density (PD) showed a significant decrease from 66.8 ± 13.2% to 58.55 ± 12.0% in the iris supero-nasal region (p = 0.016). However, at the 1-month follow-up visit, iris PD was significantly lower in all the analyzed iris regions, apart from the superior one. Conclusions: This study is the first description of AS-OCTA in patients undergoing SB. Our results showed a uniform reduction of the iris vessel network at 1 month after surgery, supporting the clinical use of AS-OCTA to identify early iris perfusion changes as potential predictive biomarkers of vascular disorders.
A Meta-Analysis on the Effect of Dexamethasone on the Sugammadex Reversal of Rocuronium-Induced Neuromuscular Block
Authors: Koo Chang-Hoon , Hwang Jin-Young , Min Seong-Won , Ryu Jung-Hee
Published: April 2020

Sugammadex reverses the rocuronium-induced neuromuscular block by trapping the cyclopentanoperhydrophenanthrene ring of rocuronium. Dexamethasone shares the same steroidal structure with rocuronium. The purpose of this study was to evaluate the influence of dexamethasone on neuromuscular reversal of sugammadex after general anesthesia. Electronic databases were searched to identify all trials investigating the effect of dexamethasone on neuromuscular reversal of sugammadex after general anesthesia. The primary outcome was time for neuromuscular reversal, defined as the time to reach a Train-of-Four (TOF) ratio of 0.9 after sugammadex administration. The secondary outcome was the time to extubation after sugammadex administration. The mean difference (MD) and 95% CI were used for these continuous variables. Six trials were identified; a total of 329 patients were included. The analyses indicated that dexamethasone did not influence the time for neuromuscular reversal of sugammadex (MD −3.28, 95% CI −36.56 to 29.99, p = 0.847) and time to extubation (MD 25.99, 95% CI −4.32 to 56.31, p = 0.093) after general anesthesia. The results indicate that dexamethasone did not influence the neuromuscular reversal of sugammadex in patients after general anesthesia. Therefore, the dexamethasone does not appear to interfere with reversal of neuromuscular blockade with sugammadex in patients undergoing general anesthesia for elective surgery.
Prevalence and Associated Factors of Nocturnal Eating Behavior and Sleep-Related Eating Disorder-Like Behavior in Japanese Young Adults: Results of an Internet Survey Using Munich Parasomnia Screening
Authors: Matsui Kentaro , Komada Yoko , Nishimura Katsuji , Kuriyama Kenichi , Inoue Yuichi
Published: April 2020

Nocturnal (night) eating syndrome and sleep-related eating disorder have common characteristics, but are considered to differ in their level of consciousness during eating behavior and recallability. To date, there have been no large population-based studies determining their similarities and differences. We conducted a cross-sectional web-based survey for Japanese young adults aged 19–25 years to identify factors associated with nocturnal eating behavior and sleep-related eating disorder-like behavior using Munich Parasomnia Screening and logistic regression. Of the 3347 participants, 160 (4.8%) reported experiencing nocturnal eating behavior and 73 (2.2%) reported experiencing sleep-related eating disorder-like behavior. Smoking (p < 0.05), use of hypnotic medications (p < 0.01), and previous and/or current sleepwalking (p < 0.001) were associated with both nocturnal eating behavior and sleep-related eating disorder-like behavior. A delayed sleep-wake schedule (p < 0.05) and sleep disturbance (p < 0.01) were associated with nocturnal eating behavior but not with sleep-related eating disorder-like behavior. Both nocturnal eating behavior and sleep-related eating disorder-like behavior had features consistent with eating disorders or parasomnias. Nocturnal eating behavior but not sleep-related eating disorder-like behavior was characterized by a sleep-awake phase delay, perhaps representing an underlying pathophysiology of nocturnal eating syndrome.
Breakpoint Mapping of Symptomatic Balanced Translocations Links the EPHA6, KLF13 and UBR3 Genes to Novel Disease Phenotype
Authors: Murcia Pienkowski Victor , Kucharczyk Marzena , Rydzanicz Małgorzata , Poszewiecka Barbara , Pachota Katarzyna , Młynek Marlena , Stawiński Piotr , Pollak Agnieszka , Kosińska Joanna , Wojciechowska Katarzyna , Lejman Monika , Cieślikowska Agata , Wicher Dorota , Stembalska Agnieszka , Matuszewska Karolina , Materna-Kiryluk Anna , Gambin Anna , Chrzanowska Krystyna , Krajewska-Walasek Małgorzata , Płoski Rafał
Published: April 2020

De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing. In all seven cases, a disruption of at least one gene was found. In two patients, the phenotypic impact of the disrupted genes is well known (NFIA, ATP7A). In five patients, the aberration damaged genes: PARD3, EPHA6, KLF13, STK24, UBR3, MLLT10 and TLE3, whose influence on the human phenotype is poorly understood. In particular, our results suggest novel candidate genes for retinal degeneration with anophthalmia (EPHA6), developmental delay with speech impairment (KLF13), and developmental delay with brain dysembryoplastic neuroepithelial tumor (UBR3). In conclusion, identification of the exact structure of symptomatic BCTs using next generation sequencing is a viable method for both diagnosis and finding novel disease candidate genes in humans.
Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension
Authors: Cai Zongye , Klein Theo , Geenen Laurie W. , Tu Ly , Tian Siyu , van den Bosch Annemien E. , de Rijke Yolanda B. , Reiss Irwin K. M. , Boersma Eric , Duncker Dirk J. , Boomars Karin A. , Guignabert Christophe , Merkus Daphne
Published: April 2020

Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2–139.9), 118.9 (109.3–147.7), 118.3 (106.8–130.1) versus 108.0 (102.3–115.2) pM, respectively, p all <0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32–58) months. Kaplan–Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2–4 (Mean survival times were 46 (95% CI: 30–65) versus 68 (58–77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1–11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.
Dysregulations of MicroRNA and Gene Expression in Chronic Venous Disease
Authors: Zalewski Daniel P. , Ruszel Karol P. , Stępniewski Andrzej , Gałkowski Dariusz , Bogucki Jacek , Komsta Łukasz , Kołodziej Przemysław , Chmiel Paulina , Zubilewicz Tomasz , Feldo Marcin , Kocki Janusz , Bogucka-Kocka Anna
Published: April 2020

Chronic venous disease (CVD) is a vascular disease of lower limbs with high prevalence worldwide. Pathologic features include varicose veins, venous valves dysfunction and skin ulceration resulting from dysfunction of cell proliferation, apoptosis and angiogenesis. These processes are partly regulated by microRNA (miRNA)-dependent modulation of gene expression, pointing to miRNA as a potentially important target in diagnosis and therapy of CVD progression. The aim of the study was to analyze alterations of miRNA and gene expression in CVD, as well as to identify miRNA-mediated changes in gene expression and their potential link to CVD development. Using next generation sequencing, miRNA and gene expression profiles in peripheral blood mononuclear cells of subjects with CVD in relation to healthy controls were studied. Thirty-one miRNAs and 62 genes were recognized as potential biomarkers of CVD using DESeq2, Uninformative Variable Elimination by Partial Least Squares (UVE-PLS) and ROC (Receiver Operating Characteristics) methods. Regulatory interactions between potential biomarker miRNAs and genes were projected. Functional analysis of microRNA-regulated genes revealed terms closely related to cardiovascular diseases and risk factors. The study shed new light on miRNA-dependent regulatory mechanisms involved in the pathology of CVD. MicroRNAs and genes proposed as CVD biomarkers may be used to develop new diagnostic and therapeutic methods.
Bibliometric Analysis of Moxibustion Research Trends Over the Past 20 Years
Authors: Park Hyejin , Lee In-Seon , Lee Hyangsook , Chae Younbyoung
Published: April 2020

Objectives: A bibliometric approach using network analysis was applied to identify the development and research trends for moxibustion. This study also examined the network hub of moxibustion research by investigating the collaborative work of organizations and authors. Methods: Academic articles on moxibustion research published from 2000 to 2019 were retrieved from the Web of Science database. Extracted records were analyzed according to publication year, research area, journal title, country, organization, and authors. The VOSviewer program was utilized to visualize the trends in moxibustion research and to explore the influential organizations and authors. Results: Analyses of 1146 original and review articles written in English demonstrated that the number of publications related to moxibustion research has increased consistently over the last 20 years. China issued the most articles in this field, and the most represented research area was integrative complementary medicine. A network analysis based on the co-occurrence and publication year of keywords identified the relevant characteristics and trends of moxibustion research. By assessing the total link strength of organizations and authors, influential organizations and authors who have contributed to moxibustion research were identified. Conclusions: The current study examined research on moxibustion using bibliometric analysis and identified a time-based development of moxibustion research and a global network hub of moxibustion research.
Novel Insights into PARK7 (DJ-1), a Potential Anti-Cancer Therapeutic Target, and Implications for Cancer Progression
Authors: Jin Wook
Published: April 2020

The expression of PARK7 is upregulated in various types of cancer, suggesting its potential role as a critical regulator of the pathogenesis of cancer and in the treatment of cancer and neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington disease. PARK7 activates various intracellular signaling pathways that have been implicated in the induction of tumor progression, which subsequently enhances tumor initiation, continued proliferation, metastasis, recurrence, and resistance to chemotherapy. Additionally, secreted PARK7 has been identified as a high-risk factor for the pathogenesis and survival of various cancers. This review summarizes the current understanding of the correlation between the expression of PARK7 and tumor progression.
Enhanced Serum Levels of sFlt1: Impact on Materno–Fetal CMV Transmission
Authors: Penka Lukas , Kagan Karl-Oliver , Hamprecht Klaus
Published: April 2020

Background: Antenatal Cytomegalovirus infection (CMV) can be associated with severe fetal symptoms and newborn outcome. The current prenatal diagnosis is based on amniocentesis (AC). No reliable biomarker for fetal infection is available. Methods: We measured Placenta-derived growth factor (PlGF), and soluble fms-like tyrosine kinase 1 (sFlt1), concentrations in maternal serum and amniotic fluid (AF) in context of maternal CMV primary infection. Blood sampling was carried out at the time of AC for detection of fetal CMV infection. The study cohort was divided into four subcohorts according to the presence or absence of fetal infection and preemptive hyperimmunoglobulin (HIG) treatment during the time interval between diagnosis of the CMV primary infection and AC. Results: The study cohort involved 114 pregnancies. In the non-transmitting subcohorts (NT) with and without prior HIG treatment, the median sFlt1 concentrations were 1.5 ng/mL (NT, HIG+) and 1.4 ng/mL (NT, HIG−), respectively. In the two transmitting groups (T) the concentrations were 1.3 ng/mL (T, HIG+) and 2.3 ng/mL (T, HIG−), respectively (NT, HIG− vs. T, HIG−, p < 0.001). The corresponding PlGF levels and the sFlt1/PlGF ratios showed no significant differences between the cohorts. The empirical cut-off values <1504 pg/mL sFlt1 and <307 pg/mL PlGF, were associated with the exclusion of CMV transmission (p < 0.001). Conclusion: sFlt1 concentration in the maternal blood could be a predictive biomarker for maternofetal CMV transmission.
Complement Inhibition Therapy and Dialytic Strategies in Paroxysmal Nocturnal Hemoglobinuria: The Nephrologist’s Opinion
Authors: Gembillo Guido , Siligato Rossella , Cernaro Valeria , Santoro Domenico
Published: April 2020

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million. It is characterized by hemolysis, bone marrow dysfunction with peripheral blood cytopenia, hypercoagulability, thrombosis, renal impairment and arterial and pulmonary hypertension. Hemolysis and subsequent hemosiderin accumulation in tubular epithelium cells induce tubular atrophy and interstitial fibrosis. The origin of PNH is the somatic mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene located on Xp22: this condition leads to the production of clonal blood cells with a deficiency in those surface proteins that protect against the lytic action of the activated complement system. Despite the increased knowledge of this syndrome, therapies for PNH were still only experimental and symptomatic, until the introduction of the C5 complement blockade agent Eculizumab. A second generation of anti-complement agents is currently under investigation, representing future promising therapeutic strategies for patients affected by PNH. In the case of chronic hemolysis and renal iron deposition, a multidisciplinary approach should be considered to avoid or treat acute tubular injury or acute kidney injury (AKI). New promising perspectives derive from complement inhibitors and iron chelators, as well as more invasive treatments such as immunoadsorption or the use of dedicated hemodialysis filters in the presence of AKI.
Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial
Authors: Dupuis-Girod Sophie , Fargeton Anne-Emmanuelle , Grobost Vincent , Rivière Sophie , Beaudoin Marjolaine , Decullier Evelyne , Bernard Lorraine , Bréant Valentine , Colombet Bettina , Philouze Pierre , Bailly Sabine , Faure Frédéric , Hermann Ruben
Published: April 2020

Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.
Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder
Authors: Kim Donghyun , Kim Jin Man , Kim Jun-Sang , Kim Sup , Kim Kyung-Hee
Published: April 2020

Purpose: Evasion of the immune system by cancer cells allows for the progression of tumors. Antitumor immunotherapy has shown remarkable effects in a diverse range of cancers. The aim of this study was to determine the clinicopathological significance of human epidermal growth factor receptor 2 (HER2), indoleamine 2,3-dioxygenase (IDO), and programmed death ligand-1 (PD-L1) expression in urothelial carcinoma of the bladder (UCB). Materials and Methods: We retrospectively studied 97 patients with UCB. We performed an immunohistochemical study to measure the expression levels of HER2, IDO, and PD-L1 in UCB tissue from these 97 patients. Results: In all 97 cases, the PD-L1 expression of tumor-infiltrating immune cells (ICs) was significantly correlated with higher pathologic tumor stage (pT). In pT2–pT4 cases (n = 69), higher levels of HER2 and IDO expression in invasive tumor cells (TCs) were associated with shorter periods of disease-free survival (DFS). Conclusion: These results imply that the expression of PD-L1 in ICs of the UCB microenvironment is associated with cancer invasion and the expression of HER2 or IDO in the invasive cancer cell and suggestive of the potential for cancer recurrence. We suggest that the expression levels of IDO, HER2, and PD-L1 could be useful as targets in the development of combined cancer immunotherapeutic strategies.
Outcome of Percutaneous Coronary Intervention in Relation to the Institutional Volume of Coronary Artery Bypass Surgery
Authors: Kohsaka Shun , Kumamaru Hiraku , Inohara Taku , Amano Tetsuya , Akasaka Takashi , Miyata Hiroaki , Motomura Noboru , Nakamura Masato
Published: April 2020

Background: Percutaneous coronary intervention (PCI) is performed in a wide range of institutions. We sought to assess the relationship between coronary artery bypass grafting (CABG) volume relative to PCI volume and clinical outcome using nationally representative PCI and CABG registries in Japan. Methods: This was a collaborative, registry-based cohort study enrolling patients undergoing percutaneous coronary intervention in 2013–2014 using Japanese nationwide registry (J-PCI) with follow up until discharge. The absolute volume of CABG for each hospital was calculated using additional data from Japan CardioVascular Surgery Database (JCVSD). Patients undergoing their first PCI registered in the registry (N = 220,934), at 943 facilities were studied. Main outcomes were in-hospital mortality, and incidence of composite of in-hospital death and postprocedural complications. Results: Among the 220,934 patients, 162,411 were men, with a mean age of 69.7 (SD 11.6) years. Patients underwent PCI at hospitals with varying CABG volume: The overall in-hospital mortality and composite event rate for PCI patients was 0.9% and 2.4%, respectively. CABG volume was associated with the in-hospital mortality of PCI at facilities performing less than 200 PCIs per year, but not at facilities performing 200 or more. Similarly, in-hospital mortality or complication was associated with PCI volume <200 only if no CABG is done at the facility. The result remained largely consistent in subgroup of patients presenting with acute coronary syndrome or even after excluding these institutions with extremely low number of PCI (<50 cases/year) or CABG (<15 cases / year). Conclusions: In a nationwide registry-based analysis, the surgical volume was associated with patients’ clinical outcome after PCI, when limited number of PCIs were performed at the facility.
Cardiovascular Complications of Systemic Therapy in Non-Small-Cell Lung Cancer
Authors: Zaborowska-Szmit Magdalena , Krzakowski Maciej , Kowalski Dariusz M. , Szmit Sebastian
Published: April 2020

Cardiovascular diseases may determine therapy outcomes of non-small-cell lung cancer (NSCLC). The evidence for how iatrogenic cardiovascular complications contribute to ceasing anticancer treatment, decreasing the quality of life or even premature death, is unclear. Older patients and smokers are at risk of atherosclerosis and arterial thromboembolic events (TE), such as myocardial infarction or stroke. Venous TE can be observed in up to 15% of NSCLC patients, but the risk increases three to five times in ALK (anaplastic lymphoma kinase)-rearranged NSCLC. ALK inhibitors are associated with electrophysiological disorders. Cytotoxic agents and anti-VEGF inhibitors mainly cause vascular complications, including venous or arterial TE. Cardiac dysfunction and arrhythmias seem to be less frequent. Chemotherapy is often administered in two-drug regimens. Clinical events can be triggered by different mechanisms. Among epidermal growth factor inhibitors, erlotinib and gefitinib can lead to coronary artery events; however, afatinib and osimertinib can be associated with the development of heart failure. During anti-PD1/anti-PDL1 therapy, myocarditis is possible, which must be differentiated from acute coronary syndrome and heart failure. Awareness of all possible cardiovascular complications in NSCLC encourages vigilance in early diagnostics and treatment.
Sarcopenia in Neurological Patients: Standard Values for Temporal Muscle Thickness and Muscle Strength Evaluation
Authors: Steindl Ariane , Leitner Johannes , Schwarz Matthias , Nenning Karl-Heinz , Asenbaum Ulrika , Mayer Sophie , Woitek Ramona , Weber Michael , Schöpf Veronika , Berghoff Anna S. , Berger Thomas , Widhalm Georg , Prayer Daniela , Preusser Matthias , Furtner Julia
Published: April 2020

Temporal muscle thickness (TMT) was investigated as a novel surrogate marker on MRI examinations of the brain, to detect patients who may be at risk for sarcopenia. TMT was analyzed in a retrospective, normal collective cohort (n = 624), to establish standard reference values. These reference values were correlated with grip strength measurements and body mass index (BMI) in 422 healthy volunteers and validated in a prospective cohort (n = 130) of patients with various neurological disorders. Pearson correlation revealed a strong association between TMT and grip strength (retrospective cohort, ρ = 0.746; p < 0.001; prospective cohort, ρ = 0.649; p < 0.001). A low or no association was found between TMT and age (retrospective cohort, R2 correlation coefficient 0.20; p < 0.001; prospective cohort, ρ = −0.199; p = 0.023), or BMI (retrospective cohort, ρ = 0.116; p = 0.042; prospective cohort, ρ = 0.227; p = 0.009), respectively. Male patients with temporal wasting and unintended weight loss, respectively, showed significantly lower TMT values (p = 0.04 and p = 0.015, unpaired t-test). TMT showed a high correlation with muscle strength in healthy individuals and in patients with various neurological disorders. Therefore, TMT should be integrated into the diagnostic workup of neurological patients, to prevent, delay, or treat sarcopenia.
Novel Treatment Strategy for Management of Traumatic Bulbar Urethral Rupture Using Temporary Urethral Stent after Primary Realignment; Retrospective Comparison between Thermo-Expandable Urethral Stent and Self-Expandable Polymer-Coated Urethral Stent
Authors: Ahn Sun Tae , Lee Dong Hyun , Kim Jong Wook , Moon Du Geon
Published: April 2020

A variety of retrievable and other types of temporarily placed stents are currently being used. However, only a few studies have considered primary endoscopic realignment with temporary urethral stent insertion in the event of traumatic bulbar urethral injury. We aimed to compare the clinical effectiveness and complications between thermo-expandable urethral stents and polymer-coated bulbar urethral stents (BUSs) for the treatment of traumatic bulbar urethral strictures. Between September 2011 and March 2018, 30 patients who had been diagnosed with complete bulbar urethral rupture following blunt trauma underwent temporary urethral stent placement after primary realignment. Thermo-expandable nickel-titanium alloy urethral stents were placed for 15 patients (group M), and retrievable self-expandable polymer-coated BUSs were placed for another 15 patients (group A). All stents were removed within 6 months after placement. The complications and maintained patency rates were compared between the two groups. The mean stent indwelling period was 5.0 ± 2.5 months in group M and 4.9 ± 4.0 months in group A. Both groups maintained high patency rates (Group M 12/15 (80.0%) and group A 13/15 (86.7%)). Five patients who developed urethral stricture underwent direct visual internal urethrotomy (DVIU), and no patients required repeat DVIU or open surgical urethroplasty. Both groups maintained the mean maximal urinary flow rate (Qmax) at 12 months after stent removal. Discomfort (46.7% vs. 6.7%), granulation tissue formation (73.3% vs. 26.7%) and post-void dribbling (80.0% vs. 20.0%) were more frequent in group M than in group A (p = 0.013, p = 0.011 and p = 0.001, respectively). In conclusion, both stents were effective for managing traumatic complete bulbar urethral rupture after primary realignment. However, the thermo-expandable urethral stents had a higher complication rate while the stent was in situ than the BUSs.
Lymphatic Invasion Might Be Considered as an Upstaging Factor in N0 and N1 Gastric Cancer
Authors: Choi Won Hyuk , Kim Min Jeong , Park Jun Ho , Kang Jin Gu , Seo Seung In , Kim Hak Yang , Shin Woon Geon
Published: April 2020

(Background) The aim of this study was to investigate the prognostic impact of lymphatic invasion in gastric cancer, focusing on survival differences between N stage groups. (Methods) A total of 398 consecutive patients who underwent curative gastrectomy for primary gastric adenocarcinoma from January 2006 to December 2015 were analyzed retrospectively using data from a prospectively collected registry database. We compared various clinicopathological features and survival differences between lymphatic invasion-positive and -negative groups. (Results) Of the 398 patients, 141 (35.4%) showed lymphatic invasion. The lymphatic invasion-positive subgroup had poorer prognosis than the lymphatic invasion-negative subgroup in N0 (five-year survival rate: 87.8% vs. 73.6%, p = 0.048) and N1 (87.2% vs. 50%, p = 0.007) stage patients. The odds ratio (OR) of lymphatic invasion to five-year survival rate was 2.078 (95% confidence interval (CI), 1.103–3.916; p = 0.024). The presence of lymphatic invasion had worse effect on survival than age (OR, 1.807; 95% CI, 1.024–2.242; p = 0.029) or tumor depth (OR, 1.286; 95% CI, 1.078–1.897; p = 0.013) in N0 and N1 stage patients. The overall survival of patients with lymphatic invasion was not different from that of patients at a one-higher N stage without lymphatic invasion at any N stage. (Conclusions) The presence of lymphatic invasion may be the most important independent prognostic factor in N0 and N1 gastric cancer and might be an upstaging factor of N stage at any N stage. Therefore, in addition to the number of metastasized lymph nodes, the presence of lymphatic invasion should be included in N stage determination.
Impact of Mononuclear Cell Infiltration on Chondrodestructive MMP/ADAMTS Production in Osteoarthritic Knee Joints—An Ex Vivo Study
Authors: Platzer Hadrian , Nees Timo A. , Reiner Tobias , Tripel Elena , Gantz Simone , Hagmann Sébastien , Moradi Babak , Rosshirt Nils
Published: April 2020

Progressive loss of joint function in osteoarthritis (OA) is driven by degenerative and inflammatory processes and their complex interaction. Decoding the link between degeneration and inflammation is one of the most exciting approaches in understanding OA pathophysiology and holds the promise to open new therapeutic avenues. The overarching goal of this project was to analyze the impact of mononuclear cells (MNC) on enzymatic chondrodestructive processes (MMP/ADAMTS) in OA. Synovial membrane (SM), articular cartilage (AC) and peripheral blood (PB) were obtained from a total of 21 patients with advanced knee OA who underwent arthroplastic surgery. In supernatants of native synovial cell cultures, T cell-depleted synovial cell cultures and macrophage-depleted synovial cell cultures, the concentrations of various metalloproteinases were examined by Enzyme Linked Immunosorbent Assay (ELISA). Furthermore, ELISA was used to analyze concentrations of metalloproteinases in supernatants of chondrocyte monocultures and chondrocyte co-cultures with CD4+CD127dim/- enriched peripheral blood mononuclear cells (PBMC), Treg depleted CD4+CD25-CD127dim/- enriched PBMC and CD4+CD25+CD127dim/- Treg. Compared to native synovial cell culture, T cell depletion led to significantly lower levels of MMP-1, MMP-3 and MMP-9 and macrophage depletion led to a significant decline of MMP-1, MMP-3, MMP-9 and ADAMTS-5 concentration. Compared to T cell depletion, macrophage depletion resulted in a significantly stronger reduction of MMP-1, MMP-3, MMP-9 and ADAMTS-5. In chondrocyte co-culture with CD4+CD127dim/- enriched PBMC the concentration of MMP-1 and ADAMTS-5 was significantly increased compared to chondrocyte monoculture. No significant differences were found between chondrocyte monoculture and chondrocyte co-culture with Treg as well as between co-culture with CD4+CD127dim/- enriched PBMC containing Treg and co-culture with Treg-depleted CD4+CD25-CD127dim/- enriched PBMC. In conclusion, our data suggests that both synovial macrophages and T cells have a catabolic potential by inducing the release of chondrodestructive metalloproteinases in OA synovium. This study also supports the hypothesis that MNC affect the release of metalloproteinases by chondrocytes and are hereby involved in the cartilage-induced chondrodestructive process. In this study no suppressive effect of Treg was shown.
Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival
Authors: Schönberg Alfrun , Hamdorf Matthias , Bock Felix
Published: April 2020

Even though the cornea is regarded as an immune-privileged tissue, transplantation always comes with the risk of rejection due to mismatches between donor and recipient. It is common sense that an alternative to corticosteroids as the current gold standard for treatment of corneal transplantation is needed. Since blood and lymphatic vessels have been identified as a severe risk factor for corneal allograft survival, much research has focused on vessel regression or inhibition of hem- and lymphangiogenesis in general. However, lymphatic vessels have been identified as required for the inflammation’s resolution. Therefore, targeting other players of corneal engraftment could reveal new therapeutic strategies. The establishment of a tolerogenic microenvironment at the graft site would leave the recipient with the ability to manage pathogenic conditions independent from transplantation. Dendritic cells (DCs) as the central player of the immune system represent a target that allows the induction of tolerogenic mechanisms by many different strategies. These strategies are reviewed in this article with regard to their success in corneal transplantation.
Luteinizing Hormone Levels Relate to the Unfavorable Pathology of Prostate Cancer
Authors: Choi Se Young , Chi Byung Hoon , Lee Wonchul , Lim Bumjin , You Dalsan , Kim Choung-Soo
Published: April 2020

Purpose: This study analyzed the association between sex hormone concentrations and stage/condition in patients with prostate cancer. Materials and methods: The concentrations of sex hormones, including testosterone (total, free, and bioavailable), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), were measured in 415 patients diagnosed with prostate cancer. Differences in serum hormone concentrations after receiving androgen deprivation therapy (ADT) and after withdrawal from ADT were evaluated. Pathologic characteristics were assessed in the 225 patients unexposed to ADT with a history of radical prostatectomy. Logistic regression analysis was performed to identify factors predictive of unfavorable pathology (Grade ≥3, ≥T3a, or N1). Results: Of the 415 prostate cancer patients, 130 (31.3%) were assessed before treatment, 171 (41.2%) after surgery, 35 (8.4%) after biochemical recurrence, and 59 (14.2%) during ADT, whereas 20 (4.8%) had castration-resistant prostate cancer. FSH was significantly lower after compared to before prostatectomy (3.229 ± 4.486 vs. 5.941 ± 7.044 mIU/mL, p < 0.001). LH, FSH, and testosterone decreased significantly 3 months after starting ADT, but increased 3 months after ADT withdrawal, whereas SHBG was unchanged. Multivariate analysis showed that high LH (odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.03–2.47, p = 0.0376) and prostate-specific antigen (PSA) (OR: 1.13, 95% CI: 1.03–1.24, p = 0.0133) concentrations were significantly associated with a high risk of unfavorable pathology. Conclusions: Sex hormones, including LH, FSH, and testosterone, were affected by ADT. The FSH level decreased after radical prostatectomy. High baseline LH concentration in patients unexposed to ADT was associated with an unfavorable pathology.
An In Vivo Study in Rat Femurs of Bioactive Silicate Coatings on Titanium Dental Implants
Authors: Brunello Giulia , Biasetto Lisa , Elsayed Hamada , Sbettega Elia , Gardin Chiara , Scanu Anna , Carmignato Simone , Zavan Barbara , Sivolella Stefano
Published: April 2020

Silica-based ceramics have been proposed for coating purposes to enhance dental and orthopedic titanium (Ti) implant bioactivity. The aim of this study was to investigate the influence of sphene-based bioceramic (CaO.TiO2.SiO2) coatings on implant osseointegration in vivo. Sphene coatings were obtained from preceramic polymers and nano-sized active precursors and deposited by an automatic airbrush. Twenty customized Ti implants, ten sphene-coated and ten uncoated rough implants were implanted into the proximal femurs of ten Sprague-Dawley rats. Overall, cortical and cancellous bone-to-implant contact (BIC) were determined using micro-computed tomography (micro-CT) at 14 and 28 days. Moreover, peri-implant bone healing was histologically and histomorphometrically evaluated. The white blood cell count in the synovial fluid of the knee joints, if present, was also assessed. No difference in the BIC values was observed between the sphene-coated and uncoated implants, overall and in the two bone compartments (p > 0.05). Delamination of the coating occurred in three cases. Consistently with micro-CT data, the histological evaluation revealed no differences between the two groups. In addition, no synovial fluid could be collected on the test side, thus confirming sphene biocompatibility. In conclusion, sphene coating was found to be a suitable material for biomedical applications. Further studies are needed to improve coating adhesion to the implants.
Current Trends in Dissimilar Diffusion Bonding of Titanium Alloys to Stainless Steels, Aluminium and Magnesium
Authors: Cooke Kavian O. , Atieh Anas M.
Published: April 2020

This article provides a comprehensive review of the advancements made in the diffusion bonding of titanium and its alloys to other advanced materials such as aluminium, stainless steel, and magnesium. This combination of advanced alloys has received considerable attention in different industries, including aerospace, petrochemical, and nuclear applications due to high specific strength, lightweight, corrosion resistance, and moderate to high mechanical properties. The mechanisms of bond formation are discussed based on the type of microstructures formed and the mechanical properties achieved. The scientific literature identifies various methods/processes for controlling the volume of intermetallic compounds formed within the joint regions, as well as ways of maximising the strength of the weld/joints. This paper discusses the relationship between weld/bond properties and bonding parameters such as time, temperature, surface roughness, pressures, interlayer composition, and thickness. The scientific literature also shows that the bonding mechanisms and microstructural evolution of the bond zone can be significantly affected by suitable optimization of the bonding parameters. Additionally, this is a method of maximising bond strength.