bluuebunny/crossref_metadata_2025 huggingface dataset:
The genome of the bowfin (Amia calva) illuminates the developmental evolution of ray-finned fishes
Authors: Thompson Andrew , Hawkins Michael , Parey Elise , Wcisel Dustin , Ota Tatsuya , Kawasaki Kazuhiko , Funk Emily , Losilla Mauricio , Fitch Olivia , Pan Qiaowei , Feron Romain , Milhes Marine , Racicot Brett , Childs Kevin , Fontenot Quenton , Ferrara Allyse , David Solomon , McCune Amy , Dornburg Alex , Yoder Jeffrey , Guiguen Yann , Crollius Hugues Roest , Berthelot Camille , Harris Matthew , Braasch Ingo
Published: October 2020

The bowfin fish (Amia calva) diverged before the genome duplication in teleost fishes, and its archetypical body plan and slow rate of molecular evolution make it a key species for genomic exploration as a basal representative of the neopterygian fishes. To investigate the evolution and development of ray-finned fishes, we generated a chromosome-level genome assembly for bowfin that enables gene-order analyses which settle its long-debated, phylogenetic relationship with gars. We analyze the genomic underpinnings of the bowfin’s unique combination of derived and ancestral phenotypes involving the immune system as well as scale, respiratory organ, and skeletal development. By detailing chromatin accessibility and gene expression through bowfin development, we connect developmental gene regulatory loci across vertebrates. We illustrate the utility of these genomic resources to connect developmental evolution across bony fishes, showing the importance of bowfin in understanding vertebrate biology and diversity.
Regulating Health Professional Scopes of Practice: Comparing Institutional Arrangements & Approaches in the US, Canada, Australia & the UK
Authors: Leslie Kathleen , Moore Jean , Robertson Chris , Bilton Douglas , Hirschkorn Kristine , Langelier Margaret H , Bourgeault Ivy Lynn
Published: October 2020

BackgroundFundamentally, the goal of health professional regulatory regimes is to ensure the highest quality of care to the public. Part of that task is to control what health professionals do, or their scope of practice. Ideally, this involves the application of evidence-based professional standards of practice to the tasks for which health professional have received training. There are different jurisdictional approaches to achieving these goals. MethodsUsing a comparative case study approach and similar systems policy analysis design, we present and discuss four different regulatory approaches from the US, Canada, Australia and the UK. For each case, we highlight the jurisdictional differences in how these countries regulate health professional scopes of practice in the interest of the public. Our comparative Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis is based on archival research carried out by the authors wherein we describe the evolution of the institutional arrangements for form of regulatory approach, with specific reference to scope of practice.Results/ConclusionsOur comparative examination finds that the different regulatory approaches in these countries have emerged in response to similar challenges. In some cases, ‘tasks’ or ‘activities’ are the basis of regulation, whereas in other contexts protected ‘titles’ are regulated, and in some cases both. We discuss the implications for how these different approaches achieve positive outcomes for the public but also for health professionals and the system more broadly in terms of workforce optimization.
Sequential Motor Learning Transfers from Real to Virtual Environment
Authors: Takeo Yuhi , Hara Masayuki , Shirakawa Yuna , Ikeda Takashi , Sugata Hisato
Published: October 2020

Background:Skill acquisition of motor learning between virtual environments (VEs) and real environments (REs) may be related. Although studies have previously examined the transfer of motor learning in VEs and REs through the same tasks, only a small number of studies have focused on studying the transfer of motor learning in VEs and REs by using different tasks. Thus, detailed effects of the transfer of motor skills between VEs and REs remain controversial. Here, we investigated the transfer of sequential motor learning between VEs and REs conditions.Methods:Twenty-seven healthy volunteers performed two types of sequential motor learning tasks; a visually cued button press task in RE (RE task) and a virtual reaching task in VE (VE task). Participants were randomly assigned to two groups in the task order; the first group was RE task followed by VE task and the second group was VE task followed by RE task. Subsequently, the response time in RE task and VE task was compared between the two groups respectively.Results:The results revealed that sequential motor learning was transferred when motor learning in VEs was performed after motor learning in REs, but not when motor learning in REs was performed after motor learning in VEs.Conclusions:These findings suggested that sequential motor learning in VEs can be facilitated by motor learning task consisting of the same sequence in REs even when different task is applied. These results may derive from the fact that motor learning in REs is more implicit than that in VEs.
Perioperative FLOT Chemotherapy Plus Surgery for Oligometastatic Esophagogastric Adenocarcinoma: Surgical Outcome and Overall Survival
Authors: Runkel Mira , Verst Rasmus , Spiegelberg Julia , Fichtner-Feigl Stefan , Hoeppner Jens , Glatz Torben
Published: October 2020

Background:Guidelines do not recommend surgery for patients with oligometastatic disease from esophagogastric adenocarcinoma (EGAC), although some studies suggest a more favourable survival. We analyzed the outcome of oligometastatic EGAC receiving FLOT chemotherapy followed by surgery. Methods:The data of patients with either pre-therapeutic, post-neoadjuvant or intraoperative clinical diagnosis of oligometastatic EGAC were extracted from a prospective database of the 2009-2018 treatment period. 48 consecutive patients were identified with oligometastatic disease, who underwent perioperative chemotherapy plus surgery. We retrospectively analyzed surgical outcome and overall survival. Results:The overall 5-year survival was 18 %. 12 patients with pre-therapeutic oligometastatic EGAC, who had no histologic vital tumor evidence of metastases after surgery had a survival rate of 48 % compared to an 11 % 5-year survival rate of 36 patients, who had histologic vital tumor metastatic evidence after FLOT chemotherapy and surgical resection (p=0.012). The survival rates after R0, R1 and R2 (non-resected metastases) resection were 21 % (n=33), 0 % (n=4) and 17 % (n=11), respectively (p=0.273).Conclusion:Oligometastatic EGAC is associated with poor overall survival even after complete resection of all tumor manifestations. The subgroup of patients with a complete pathohistologic response of metastatic lesions to neoadjuvant FLOT shows 5-year survival rates similar to non-metastatic EGAC. Trial registration: Not applicable
Macrophage activation in obese type 2 diabetes: an enhanced risk for COVID-19 and Acute Respiratory Distress Syndrome?
Authors: Moin Abu , Sathyapalan Thozhukat , Diboun Ilhame , Atkin Stephen , Butler Alexandra
Published: October 2020

Objective Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS), the hallmark of severe COVID-19 disease. Objectives: to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects.Methods A case-controlled interventional pilot study in OT2D (n=23) and control subjects (n=23). Subjects underwent hyperinsulinemic clamp normalizing serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-hour of insulin clamp (OT2D subjects only).Results. Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers CXCL9 and CXCL10 were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGβ-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia.Conclusion In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences may predispose the diabetic individuals to ARDS reflecting in increased COVID-19 disease severity.
Functional Melanocytes Obtained From Rabbit Hair Follicle Outer Root Sheath
Authors: Li Hanluo , Baumbach Christina-Marie , Schneider Marie , Schwalenberg Katrin , Kottek Tina , Bartella Alexander , Simon Jan-Christoph , Savkovic Vuk , Lethaus Bernd
Published: October 2020

BackgroundMelanocytes have been cultivated from the outer root sheath of hair follicles for two decades. So far, these isolation and culturing procedures have been carried out from human and mouse follicles. In this study, we have translated the established procedure for obtaining melanocytes from stem cells and precursors of human hair follicle to a rabbit species in order to isolate and cultivate rabbit melanocytes from whisker follicle outer root sheath (ORS), hereby named rMORS, and compare them to rabbit epidermal rabbit melanocytes (rEMs).ResultsThe rMORS were isolated and cultured by extracting whisker follicles from enzymatically digested skin and submitting them to the air-liquid interface hypoxic conditions. The cells were allowed to migrate from the follicle ORS onto the nylon mesh of Transwell inserts, collected and subcultured in melanocyte culture medium for 11 passages. From early passages on, the rMORS cells displayed typical melanocyte characteristics comparable to those of rEM used as experimental control. Melanocyte features were assessed on morphological level by the means of microscopy, functional and gene expression level. Functionality was qualitatively assessed by the Von Kossa and Nile Blue staining of melanin and by biochemically quantifying melanin content and Tyrosinase activity. Gene expression of neuroectodermal and melanocytic lineage markers NES, PAX3, MITF, TYR, CKIT and PMEL was determined by the means of qRT-PCR. ConclusionsWe concluded that the method of isolating and culturing rMORS efficiently and reproducibly corresponded to the prior art method established in human follicle, yielding melanocytes comparable to the rabbit epidermal melanocytes in all assessed features. This method is not crucial in terms of regenerative therapy, it rather paves way for a non-invasive ex vivo sampling of hair and it may give way to deeper insights into rabbit follicle biology or to postulating useful species-specific in vivo experimental models.
The Effect of Pre-analytical Handling on the Stability of Fractalkine, Monocyte Chemoattractant Protein 1 (MCP-1), Interleukin 6 and Interleukin 8 in Samples of Human Cerebrospinal Fluid: A Prospective Cohort Study.
Authors: Mortensen Winnie Charlotte , Bendix Laila , Jensen Hanne Irene , Varnum Claus , Rasmussen Lasse Enkebølle , Lauridsen Joergen , Borbye-Lorenzen Nis , Skogstrand Kristin , Toft Palle , Vaegter Henrik Bjarke , Blichfeldt-Eckhardt Morten Rune
Published: October 2020

BackgroundCytokine networks in cerebrospinal fluid (CSF) are important to our understanding of several neuroinflammatory diseases. Knowledge about optimal handling of samples is limited but important to minimize bias and reduce costs in CSF biomarker studies. The aim of this study was to examine the effect of storage temperature and time delay from CSF sample collection until freezing on the concentration levels of 11 different cytokines thought to be associated with chronic pain.MethodsCSF samples from 21 individuals undergoing hip or knee arthroplasty under spinal anesthesia were divided between two tubes. One tube was stored and centrifuged (within 30 minutes) at room temperature, and one tube was stored in ice water and centrifuged (within 30 minutes) at 4˚C. Each tube was split into six vials that were frozen at -80 ˚C, 0.5, 1, 2, 3, 4, or 5 hours after collection. Cytokines were analyzed using a multiplex panel. A random effect panel data regression was conducted for each biomarker including the variables of storage temperature until freezing and time delay. ResultsFour cytokines had detectable levels: Fractalkine, monocyte chemoattractant protein 1(MCP-1), interleukine 6 (IL-6), and interleukine 8 (IL-8). There was no significant effect of storage temperature and time delay on MCP-1, IL-6, or IL-8 levels. Fractalkine levels showed no clear trend. No concentration differences were observed between samples kept in ice water and those at room temperature except at the 3-hour time point, and there was no overall significant effect of time delay on fractalkine concentration.ConclusionsWe found no clear effect of storage temperature and time delay up to five hours from sample collection until freezing on the CSF concentrations of fractalkine, MCP-1, IL-6, or IL-8.Trial registrationNot applicable as the study was not an intervention study.
Roles of GABA Signaling in Directing Basket Cell Axonal Projections Toward Purkinje Cells in the Cerebellum
Authors: Miwa Hideki , Kobayashi Ken , Hirai Shinobu , Yamada Mitsuhiko , Watanabe Masahiko , Okado Haruo , Yanagawa Yuchio
Published: October 2020

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. GABA may act as a trophic factor during brain development, but its contribution to the development and maturation of cerebellar neural circuits is not known. To understand the roles of GABA in cerebellar development and associated functions in motor coordination and balance, we examined GAD65 conventional knock out (KO) mice and mice in which GAD67 was eliminated in parvalbumin-expressing neurons ( PV-Cre ; GAD67 flox/flox mice). We found aberrant subcellular localization of the Shaker-type K channel Kv1.1 in basket cell collaterals of PV-Cre ; GAD67 flox/flox mice and abnormal projections from basket cells to Purkinje cells in both mouse strains. Furthermore, PV-Cre ; GAD67 flox/flox mice exhibited abnormal motor coordination in the rotarod test. These results indicate that GABA signaling in the cerebellum during development is critical for establishing appropriate connections between basket cells and Purkinje cells and is associated with motor coordination in mice.
Age at Menarche, Age at Natural Menopause and Risk of Rheumatoid Arthritis – A Mendelian Randomization Study
Authors: Zhu Jingjing , Niu Zheng , Alfredsson Lars , Klareskog Lars , Padyukov Leonid , Jiang Xia
Published: October 2020

Background Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM) and age at first birth (AFB), with the risk of RA.Methods We collected summary statistics from the hitherto largest GWAS conducted in AAM (N=329,345), ANM (N=69,360), AFB (N=251,151) and RA (Ncase=14,361 and Ncontrol=43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted-median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.Results We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORAAM=1.06 [0.98-1.15], ORANM=1.05 [0.98-1.11], ORAFB=0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORAAM=1.06 [0.97-1.15], ORANM=1.05 [0.98-1.13], ORAFB=0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORAAM=1.03 [0.94-1.12], ORANM=1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.Conclusions Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.
Systemic Proteomic Analysis Reveals Distinct Exosomal Proteins Profiles in Rheumatoid Arthritis
Authors: Qin Qiu , SONG Ronghua , DU Peng , GAO Chaoqun , YAO Qiuming , ZHANG Jinan
Published: October 2020

BackgroundRheumatoid arthritis (RA) is a heterogeneous and complex disease characterized by autoantibodies production and inflammation of the synovium. Its underlying mechanisms remain elusive. In recent years, exosomes have emerged as non-invasive biomarkers in diverse diseases. Due to its various inflammatory and immunological functions, some studies highlighted abnormalities of exosomes in RA, but fewer have paid attention to the broad spectrum of potential systemic markers of RA. The aim of this study was to identify exosomal candidate proteins in the pathogenesis of RA using systemic proteomic method. MethodsTotally 12 specimens of plasma from 6 RA patients and 6 age-and gender-matched controls from the Chinese population were obtained for nanoscale liquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS) analysis to identify differentially expressed proteins (DEPs) in exosomes. Gene ontology (GO), protein interaction network (PPI) and KEGG pathway analyses were used in subcellular localization analysis. ResultsA total of 278 exosomal proteins were detected. Among them, 32 proteins were significantly upregulated (FC≥2.0 and P<0.05) and 5 proteins were downregulated (FC≤0.5 and P<0.05). Most of these DEPs were immunoglobullins (Igs). Bioinformatics analysis indicated that these Igs are involved in inflammatory response of RA through diverse immune regulatory pathways, such as NF-kappa B signaling pathway. PPI analysis revealed that transthyretin (TTR, P02766), angiotensinogen (AGT, P01019), lipopolysaccharide-binding protein (LBP, P18428), monocyte differentiation antigen CD14 (CD14, P08571), cartilage oligomeric matrix protein (COMP, P49747), serum amyloid P (SAP/APCS, P02743) and tenascin (TNC, P24821) can interact with each other or may form a regulatory networks. Subsequently, these cross-linked proteins may mainly involve in the NF-kappa B signaling pathway or inflammatory-related pathways to mediate the onset of RA. Noteworthy, among these exosomal DEPs, the complex composed of LBP and CD14 is involved in NF-kappa B signaling pathway, resulting in promoted expression of IL-8, TNF-α, and eventually leading to the development of RA.ConclusionsOur findings suggest distinct plasmic exosomal protein profiles in RA patients. These proteins not only take important parts in the vicious circle in the pathogenic process of RA, but also serve as novel biomarkers in RA diagnosis and prognosis.
Effects of Timing of Umbilical Cord Clamping on Preventing Early Infancy Anemia in Japanese Term Infants With Planned Breastfeeding: A Randomized Controlled Trial
Authors: Shinohara Eriko , Kataoka Yaeko , Yaju Yukari
Published: October 2020

BackgroundJapanese infants have relatively higher risk of anemia and neonatal jaundice. This study aimed to assess the effects of delayed cord clamping (DCC) on the prevention of anemia during early infancy in Japanese term infants with planned exclusive breastfeeding for 4 months. This study also aimed to explore the effects of DCC on neonatal jaundice.Methods We conducted an open-label, parallel-arm, multicenter randomized controlled trial of DCC (clamping the cord after more than a minute or pulsation stops) vs. early cord clamping (ECC; clamping the cord within 15 sec) at one birth center and two clinics in Japan. Pregnant women planning to have a vaginal birth and to exclusively breastfeed and term singleton infants delivered in cephalic presentation were included in this study. The primary outcome was spectrophotometric estimation of hemoglobin at 4 months. Secondary outcomes were anemia incidence at four months, four outcomes related to neonatal jaundice, hematocrit levels, and related outcomes. ResultsA total of 150 pregnant women were recruited. Participants (N = 138) were randomly allocated to two groups (DCC n= 68, ECC n = 70). There were no significant differences between the two groups in spectrophotometric estimation of hemoglobin at 4 months: mean difference = 0.1 g/dL, 95% confidence interval -0.14, 0.35, DCC 12.4 g/dL, ECC 12.3 g/dL. Only the hematocrit levels on days 3 to 5 were significantly higher in the DCC group than in the ECC group: DCC 57.0%, ECC 52.6%, mean difference = 4.4, 95% confidence interval 2.61, 6.20. There were no significant differences in other secondary outcomes, including outcomes related to neonatal jaundice.ConclusionAmong Japanese term infants with planned exclusive breastfeeding, DCC showed no significant effects on spectrophotometric hemoglobin levels at 4 months compared with ECC. We observed significantly higher hematocrit levels in infants who underwent DCC, while these levels were within the normal range. Jaundice outcomes remained similar to those of infants who underwent ECC. Although a larger sample size is required to assess the effects of cord clamping on neonatal jaundice, DCC may prevent anemia in newborn infants.Trial registration: UMIN-CTR; UMIN000022573, 06/01/2016 - retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000023056
An HPLC and UHPLC-HRMS Approach to Study PSMA-11 Instability in Aqueous Solution
Authors: IUDICELLO ANTONELLA , Genovese Filippo , Iorio Valentina Di , Cicoria Gianfranco , Boschi Stefano
Published: October 2020

Background. Stability of precursors and reagents are of utmost importance for developing a suitable, fast and routinely reproducible analytical method for the quality control of radiopharmaceuticals, for the validation of the analytical method itself, as well as for radiolabeling procedure. During the validation of the analytical method used for the determination of chemical and radiochemical purity of an injectable solution of 68Ga-PSMA-11, a trend to instability of the PSMA-11 standard, the same used as a precursor in the radiosynthesis of 68Ga-PSMA11, has been found. This instability led to the formation of a secondary compound in a time-dependent manner. The formation of this compound made difficult the validation of the analytical method and influenced the radiolabeling yield, by increasing free 68Ga which, obviously, decreased the final yield.Results. The nature of this compound was investigated by adding chelators, such as EDTA, to PSMA-11 solutions and by using the combination of UHPLC-HRMS. The results led to the definition of the secondary compound structure, as natFe-PSMA-11, from the combination of the high affinity chelator HBED-CC, present in the molecule of PSMA-11, and environmental Fe(III).Conclusions. Strategies to reduce the risk of low radiolabeling yields and to increase the stability of the standards were also discussed.
Usefulness of Speckle Tracking Echocardiography and Biomarkers for Detecting Acute Cellular Rejection After Heart Transplantation
Authors: Cruz Cecília Beatriz Bittencourt Viana , Hajjar Ludhmila A. , Bacal Fernando , Lofrano-Alves Marco S. , Lima Márcio S.M. , Abduch Maria C. , Viera Marcelo L.C. , Chiang Hsu P. , Salviano Juliana B. C. , costa isabela bispo , Fukushima Julia Tizue , Sbano Joao C.N. , Mathias Wilson , Tsutsui Jeane M.
Published: October 2020

Background: Acute cellular rejection (ACR) is a major complication after heart transplantation. Endomyocardial biopsy (EMB) remains the gold standard for its diagnosis, but it has concerning complications. We evaluated the usefulness of speckle tracking echocardiography (STE) and biomarkers for detecting ACR after heart transplantation.Methods: We prospectively studied 60 transplant patients with normal left and right ventricular systolic function who underwent EMB for surveillance six months after transplantation. Sixty age- and sex-matched healthy individuals constituted the control group. Conventional echocardiographic parameters, left ventricular global longitudinal, radial and circumferential strain (LV-GLS, LV-GRS and LV-GCS, respectively), left ventricular systolic twist (LV-twist) and right ventricular free wall longitudinal strain (RV-FWLS) were analyzed just before the procedure. We also measured biomarkers at the same moment. Results: Among the included 60 patients, 17 (28%) had severe ACR (grade ≥ 2R), and 43 (72%) had no significant ACR (grade 0 – 1R). The absolute values of LV-GLS, LV-twist and RV-FWLS were lower in transplant patients with ACR degree ≥ 2 R than in those without ACR (12.5% ± 2.9% vs 14.8% ± 2.3%, p=0.002; 13.9° ± 4.8° vs 17.1° ± 3.2°, p=0.048; 21.4%± 3.2% vs 16.6% ± 2.9%, p<0.001; respectively), while no differences were observed between the LV-GRS or LV-GCS. All of these parameters were lower in the transplant group without ACR than in the nontransplant control group, except for the LV-twist. Cardiac troponin I levels were significantly higher in patients with significant ACR than in patients without significant ACR [0.19 ng/mL (0.09–1.31) vs. 0.05 ng/mL (0.01–0.18), p=0.007]. The combination of troponin with LV-GLS, RV FWLS and LV-Twist had an AUC (area under curve) for the detection of ACR of 0.80 (0.68 – 0.92), 0.89 (0.81 – 0.93) and 0.79 (0.66 – 0.92), respectively. Conclusion: Heart transplant patients have altered left ventricular dynamics compared with control individuals. The combination of troponin with strain parameters had higher accuracy for the detection of ACR than the isolated variables and this association might select patients with a higher risk for ACR who will benefit from an EMB procedure in the first year after heart transplantation.
WITHDRAWN: The Clinical and Prognosis Value of the Number of Metastatic Lymph Nodes in Papillary Thyroid Carcinoma Patients
Authors: Zhan Ling , Feng Hong-fang , Yu Xi-zi , Li Ling-rui , Song Jun-long , Tu Yi , Yuan Jing-ping , Chen Chuang , SUN SHENG RONG
Published: October 2020

Objective: It has been reported that papillary thyroid carcinoma (PTC) patients with lymph node metastasis (LNM) are more associated with adverse outcomes. This study aimed to assess the correlation between the lymph node (LN) status and clinical prognosis in PTC patients. Methods: We retrospectively reviewed the medical records of PTC patients who underwent initial thyroid cancer surgery in Renmin Hospital of Wuhan University between 2017 and 2019. 1021 PTC patients with total checked number of lymph nodes ≥5 were involved in this study. The clinicopathological characteristics of patients were compared according to the LN status and the number of metastatic lymph nodes (NMLNs). Results: The LNM and NMLNs>5 were seen in 694 (68.0%) and 222 (21.7%) cases, respectively. Young patients, patients with larger tumor diameter, bilaterality, multifocality and gross extrathyroidal extension (ETE) were more inclined to LNM and NMLNs >5 (P<0.001). The patients with LNM (pN1) were mainly among males and were exhibited multifocality and advanced tumor stage (P<0.001), while pN1 patients with NMLNs >5 were negatively associated with advanced tumour stage (P<0.05). Recurrence-free survival among pN1 patients was significantly different between 2 groups (NMLNs ≤5: 0/472, 100.0%; NMLNs >5: 5/222, 97.7%; P=0.002). In multivariate logistic regression analysis, the male (OR=2.580, P<0.001), 10-mm tumor size (OR=1.770, P<0.001), tumor gross ETE (OR=2.004, P<0.001) were independent predictors for the high prevalence of LNM. Similarly, 10-mm tumor size (OR=1.399, P<0.05), bilaterality (OR=2.350, P<0.001) and tumor gross ETE (OR=2.660, P<0.05) were also independent predictors for the high prevalence of NMLNs >5; 10-year age was an independent predictor for the low prevalence of the LNM (OR=0.658, P<0.001) and NMLNs >5 (OR=0.678, P<0.001). Conclusions: The status of the cervical LNs and the NMLNs should be correctly evaluated to guide reasonable treatment and careful follow-up.
High TRAF3IP3 Level Predicts Poor Prognosis of Patients with Gliomas
Authors: Yang Guorong , Tang Shu , Zhang Jie , Qin Ling
Published: October 2020

Purpose: TRAF3IP3 is involved in the maturation of immune cells, the development of immune tissues and the immune response of the body. TRAF3IP3 is shown to expressed in a variety of malignant tumor cell lines. Down-regulated expression of TRAF3IP3 in malignant melanoma can inhibit tumor growth. However, the role of TRAF3IP3 in glioma is still unknown. In this study, we aimed to study the relationship between TRAF3IP3 and glioma based on TCGA data.Method: We used the Wilcoxon rank sum test to compare the expression of TRAF3IP3 in glioma and normal tissues. Subsequently, Kruskal-Wallis test, Wilcoxon rank sum test, and logistics regression were used to evaluate the relationship between TRAF3IP3 and clinicopathological parameters of glioma patients. GSEA was used to verify the key signal pathways involved in TRAF3IP3. We used the ssGSEA method to analyze the relationship between the expression level of TRAF3IP3 and the immune infiltration in the glioma tumor microenvironment. Finally, we used Kaplan-Meier and COX regression to evaluate the prognostic value of TRAF3IP3.Results: TRAF3IP3 transcription level was highly expressed in gliomas(P<0.001). And the high expression of TRAF3IP3 and WHO grade(OR=3.57(2.42-5.34), P<0.001), IDH status (OR=4.79(3.40-6.83), P<0.001), 1P /19q codeletion (OR=0.07(0.04-0.11), P<0.001), EGFR status (OR=2.77(1.65-4.81), P<0.001), histological type (OR=3.64(2.48-5.43), P<0.001), age (OR=1.64(1.13-2.41), P=0.01), and primary therapy outcome (OR=2.29(1.47-3.61), P<0.001) were significantly correlated. GSEA showed that six signaling pathways were significantly enriched in the TRAF3IP3 high expression phenotype group, including JAK STAT signaling pathway, interferon-γ signaling pathway, apoptosis, P53 signaling pathway, PD-1 signaling pathway, and CTLA4 signaling pathway. ssGSEA showed that the expression of TRAF3IP3 was significantly positively correlated with the infiltration of Macrophages, Th17 cells, etc. Multivariate COX regression showed that TRAF3IP3 was an independent prognostic factor for glioma OS (HR=2.169(1.301-3.615), P=0.003). Kaplan-Meier analysis showed that high expression of TRAF3IP3 was associated with worse PFS(HR=2.39(1.39-3.01), P<0.001), DFS(HR=3.02(2.27-4.01), P<0.001) and OS(HR=2.87(2.20-3.75), P<0.001).Conclusion: TRAF3IP3 may play an important role in the occurrence and development of glioma, and may be a potential biomarker for the diagnosis and prognosis of glioma.
WITHDRAWN: Development and Validation of Nomograms for Predicting Survival of Elderly Patients With Stage I Small-cell Lung Cancer
Authors: Yang Yaji , Sun Shusen , Xiong Feng , Xiao Yin , Huang Jing
Published: October 2020

Background Predictive models to determine the prognosis of elderly patients with Stage I small-cell lung cancer (SCLC) are lacking. This study aimed to establish a useful nomogram for predicting the cancer-specific survival (CSS) of elderly patients with Stage I SCLC.MethodsUsing the Surveillance, Epidemiology, and End Results registry database, we identified patients aged ≥ 65 years with pathological AJCC (American Joint Committee on Cancer) Stage I SCLC from 2004 to 2014. The CSS was evaluated by the Kaplan-Meier method. Patients were divided into training and validation cohorts. In the training cohort, univariate analysis and multivariate analysis by the Cox proportional hazards regression identified risk factors that predicted CSS and the results were used to formulate a nomogram for the 1-, 3-, and 5-year CSS rates of elderly patients with Stage I SCLC. The performance of the nomograms was internally and externally validated by the bootstrap resampling.Results: In total, we extracted 1,623 elderly patients with Stage I SCLC. The median CSS was 34 months, and the 5-year CSS was 41 months. Multivariate analysis revealed that age, histologic type, tumor size, and AJCC Stage were significant predictors of CSS. A nomogram was formulated based on the results of multivariate analysis. The C-indices of the nomogram for training and validation cohorts were 0.68 and 0.62, indicating that the nomogram exhibited a sufficient level of discrimination. The calibration curves demonstrated good agreement between the nomogram prediction and actual observation.Conclusion:A practical nomogram to predict the CSS of elderly patients with Stage I SCLC is constructed. The predictive tool is helpful for patient counseling and treatment decision making.
Stakeholder Engagement in Developing A Father-Inclusive Early Life Obesity Prevention Intervention: First Heroes
Authors: Silver Santana R. , Whooten Rachel , Kwete Gracia M. , Farrar-Muir Haley , Cournoyer Rachel N. , Barth Elizabeth A. , Kotelchuck Milton , Taveras Elsie M.
Published: October 2020

Background: Although paternal involvement in the perinatal period is associated with benefits for maternal-child health and reduced obesity risk, fathers are seldom included in perinatal or obesity prevention efforts. Engaging community leaders and fathers as stakeholders in intervention development is a critical step in designing a father-inclusive intervention that is efficacious and responsive to their needs.Methods: We conducted a structured engagement study, including community stakeholder engagement and qualitative interviews with new fathers, to inform the development of a prospective randomized controlled trial that includes mothers and fathers as equal partners in infant obesity prevention. We interpreted stakeholder feedback through the Consolidated Framework for Implementation Research (CFIR) framework.Results: Between September 2019 and April 2020, we held a Community Engagement meeting, formed a Community Advisory Board, and conducted 16 qualitative interviews with new fathers. Stakeholder engagement revealed insights across CFIR domains including intervention characteristics (relative advantage, complexity, design quality & packaging), outer setting factors (cosmopolitanism and culture), individual characteristics (including self-efficacy, state of change, identification with the organization) and process (engagement and adaptation). Stakeholders discussed the diverse challenges and rewards of fatherhood, as well as the intrinsic paternal motivation to be a loving, supportive father and partner. Both community leaders and fathers emphasized the importance of tailoring program delivery and content to meet specific parental needs, including a focus on the social-emotional needs of new parents.Conclusions: A structured process of multidimensional stakeholder engagement was successful in improving the design of a father-inclusive perinatal obesity prevention interventions. Father engagement was instrumental in both reinforcing community ties and increasing our understanding of fathers’ needs, resulting in improvements to program values, delivery strategies, personnel, and content. This study provides a practical approach for investigators looking to involve key stakeholders in the pre-implementation phase of intervention development.Trial registration: ClinicalTrials.gov, NCT04477577. Registered 20 July 2020, https://clinicaltrials.gov/ct2/show/NCT04477577
A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience
Authors: Özdoğan Mustafa , PAPADOPOULOU EIRINI , Tsoulos Nikolaos , Tsantikidi Aikaterini , Metaxa-Mariatou Vasiliki , Tsaousis George , Kapeni Evgenia , Bourkoula Evgenia , Fotiou Dimitrios , Kapetsis Georgios , Boukovinas Ioannis , Touroutoglou Nikolaos , Fassas Athanasios , Adamidis Achilleas , Kosmidis Paraskevas , Trafalis Dimitrios , Galani Eleni , Lypas George , Orhan Bülent , Sualp Tansan , Özatlı Tahsin , Kırca Onder , Çakır Okan , Nasioulas George
Published: October 2020

Background: Tumor molecular profile is of great importance for the detection of biomarkers of response to targeted treatment due to the increased availability, with concomitant reduction of cost, of Next Generation Sequencing technology (NGS). In parallel to targeted therapies’, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite Instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly.Methods: In the present study, a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection, was used for tumor molecular profile analysis. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied.Results: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. At least one actionable alteration was detected in 77.70% of the patients. 54.59% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers’ analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.40%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. Conclusions: Tumor molecular profile analysis by NGS is a first-tier methodology for a variety of tumor types, which provides critical information for treatment decision making in cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to a better tumor characterization and provide actionable information in the majority of patients. Moreover, our results indicate that one in two patients is eligible for ICI treatment based on the biomarkers’ analysis. However, when these analyses are performed, the challenge is their implementation in clinical practice. Multidisciplinary patient management is critical to the refinement of the strategy incorporating such information.
Cranial Manipulation Affects Cholinergic Pathway Gene Expression in an Animal Model of Age-related Cognitive Decline
Authors: Anandakrishnan Ramu , Tobey Hope , Nguyen Steven , Sandoval Osscar Gonzalez , Klein Bradley G. , Costa Blaise M.
Published: October 2020

Age dependent dementia is a devastating disorder afflicting the growing older population around the world. Although pharmacological agents improve symptoms of dementia, age related co-morbidities combined with adverse effects often outweigh their clinical benefits. Therefore, non-pharmacological therapies are being investigated as an alternative. Randomized controlled trials and observational studies have shown promising results for cranial manipulation as a treatment for dementia and other nervous system disorders. In this study we examine the effect of osteopathic cranial manipulative medicine (OCMM) on gene expression, in an animal model for age-related cognitive decline (aged rats). We found that OCMM significantly affected the expression of 36 genes in the neuronal pathway (False Discovery Rate (FDR) < 0.004). The top five neuronal genes with the largest fold-change (Slc5a7, Chat, Slc18a3, Adcy5 and Cacna2d2, >2-fold change, FDR<0.004) are part of the cholinergic neurotransmission mechanism, which is known to affect cognitive function. Slc5a7, the highest overexpressed neuronal gene (3-fold change) encodes a sodium and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. This is the pathway enhanced by the clinically used Alzheimer’s disease drug Donepezil, which selectively inhibits acetylcholinesterase, an enzyme that catalyzes endogenous acetylcholine degradation. In addition, 40% of significant differentially expressed (SDE) genes (FDR<0.004), have been previously implicated in neurological disorders. Overall, SDE genes and their role in central nervous system signaling pathways suggest a connection to previously reported OCMM induced behavioral and biochemical changes in rat models of age-dependent dementia. Further investigation in this direction will provide a better understanding of the molecular mechanisms of OCMM and its potential in clinical applications. With clinical validation, OCMM could represent a much needed low-risk adjunct treatment for age-related dementia including Alzheimer’s disease.
Changes in Liver-related Mortality by Etiology and Sequelae: Underlying Versus Multiple Causes of Death
Authors: Sheu Ming-Jen , Liang Fu-Wen , Lin Ching-Yih , Lu Tsung-Hsueh
Published: October 2020

Background: The expanded definition of liver-related deaths includes a wide range of etiologies and sequelae. We compared the changes in liver-related mortality by etiology and sequelae for different age groups between 2008 and 2018 in the United States using both underlying and multiple cause of death (UCOD and MCOD) data. Methods: We extracted mortality data from the CDC WONDER. Both the absolute (rate difference) and relative (rate ratio and 95% confidence intervals) changes were calculated to quantify the magnitude of change using the expanded definition of liver-related mortality. Result: Using the expanded definition including secondary liver cancer and according to UCOD data, we identified 68,037 liver-related deaths among people aged 20 years and above in 2008 (29 per 100,000) and this increased to 90,635 in 2018 (33 per 100,000), a 13% increase from 2008 to 2018. However, according to MCOD data, the number of deaths was 113,219 (48 per 100,000) in 2008 and increased to 161,312 (58 per 100,000) in 2018, indicating a 20% increase. The increase according to MCOD was mainly due to increase in alcoholic liver disease and secondary liver cancer (liver metastasis) for each age group and hepatitis C virus (HCV) and primary liver cancer among decedents aged 65–74 years. Conclusion: The direction of mortality change (increasing or decreasing) was similar in UCOD and MCOD data in most etiologies and sequelae, except secondary liver cancer. However, the extent of change differed between UCOD and MCOD data.
Framework for Assessing the Performance of the Ghanaian Health System: Study Protocol
Authors: Kumah Emmanuel , Ankomah Samuel E. , Fusheini Adam , Baffour Peter Agyei , Ayanore Martin A. , Asravor Richard K. , Kesse Felix O. , Mwini Emmanuel , Otchere Godfrd
Published: October 2020

Background: Assessing the performance of health systems through quantitative and qualitative methods is recognized as an effective approach to strengthening national health systems. However, while many high-income countries have institutionalized health system performance assessment (HSPA) as an integral component of their respective health systems, few studies on HSPA have been documented in low and middle-income countries, including Ghana. This study aims at providing a comprehensive framework for periodic assessment of the performance of the entire health system in Ghana.Methods: The study will have four work packages. First, a structured review will be conducted to identify both international and national HSPA frameworks that could be applied to the Ghanaian context. Second, based on the structured review, an assessment framework tailored to the Ghanaian health system context will be developed. Third, the draft framework will be presented and discussed with experts and stakeholders for its appropriateness, feasibility and acceptability. Finally, the framework will be piloted to assess its effectiveness and suitability for full-scale implementation.Discussion: Currently, Ghana does not have a full-fledged HSPA tool that provides a holistic health sector-wide approach to assessing health system performance. Thus, developing this HSPA framework for the country will provide a tool for periodic and comprehensive assessment of the performance of the health system, which can be compared with that of other countries. Such a comparison will offer the opportunity for mutual learning and for exploring new options for formulating more effective national health policies. As this is expected to be the first attempt to develop a comprehensive HSPA framework in Ghana, this study will provide a basis for future discussions on how to further develop and implement HSPA programs in the country.
PGC-1α Regulates Airway Epithelial Barrier Dysfunction Induced by House Dust Mite.
Authors: Saito Tsutomu , Ichikawa Tomohiro , Numakura Tadahisa , Yamada Mitsuhiro , Koarai Akira , Fujino Naoya , Murakami Koji , Yamanaka Shun , Sasaki Yusaku , Kyogoku Yorihiko , Itakura Koji , Sano Hirohito , Takita Katsuya , Tanaka Rie , Tamada Tsutomu , Ichinose Masakazu , Sugiura Hisatoshi
Published: October 2020

Background: The airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens. Methods: BEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated. Results: The amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin. Conclusions: The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.