bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo
Authors: Kumar Dileep , Rahman Hafeez , Tyagi Ethika , Liu Tong , Li Chelsea , Lu Ran , Lum David , Holmen Sheri L. , Maschek J. Alan , Cox James E. , VanBrocklin Matthew W. , Grossman Douglas
Published: July 2018

There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5′-adenosine monophosphate–activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo. This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629–42. ©2018 AACR.
Evidence of Tumour Microenvironment and Stromal Cellular Components in Retinoblastoma
Authors: Raguraman Rajeswari , Parameswaran Sowmya  , Kanwar Jagat Rakesh , Khetan Vikas , Rishi Pukhraj , Kanwar Rupinder Kaur , Krishnakumar Subramanian
Published: July 2018

Background: The tumour microenvironment (TME) consisting of tumour cells and multiple stromal cell types regulate tumour growth, invasion and metastasis. While the concept of TME and presence of stromal cellular components is widely established in cancers, its significance in the paediatric intraocular malignancy, retinoblastoma (RB), remains unknown. Methods: The study qualitatively identified the presence of multiple stromal cellular subtypes in RB TME by immunohistochemistry. Results: Results of the study identified the presence of stromal cell types such as endothelial cells, tumour-associated macrophages, fibroblasts, cancer-associated fibroblasts, retinal astrocytes and glia in RB TME. The extent of stromal marker positivity, however, did not correlate with histopathological features of RB. Conclusions: The findings of the study convincingly suggest the presence of a stromal component in RB tumours. The interactions between stromal cells and tumour cells might be of profound importance in RB progression.
The Aging Process Alters IL-1β and CD63 Levels Differently in Extracellular Vesicles Obtained from the Plasma and Cerebrospinal Fluid
Authors: Gomes de Andrade Gisele , Reck Cechinel Laura , Bertoldi Karine , Galvão Fernando , Valdeci Worm Paulo , Rodrigues Siqueira Ionara
Published: July 2018

Objective(s): The aim of this study was to investigate exosomal markers and inflammatory cargo of extracellular vesicles (EVs) obtained from cerebrospinal fluid (CSF) and plasma in the aging process. We also studied the inflammatory cargo by quantifying IL-1β levels. Methods: Male Wistar rats, aged 3 and 21 months, were used (n = 12 in each group). The CSF and plasma of animals were collected, and isolation of EVs was performed using a commercial kit. Total protein concentration, acetylcholinesterase (AChE) activity, and CD63 and IL-1β levels were evaluated. Results: AChE activity in EVs increased in both samples, specifically in the circulating EVs and those in the CSF of the older group. An age-related increase was observed in CD63 levels in EVs from the CSF but a decrease was observed in plasma EVs of the older group. Student’s t test showed that the young adult rats had significantly higher circulating IL-1β levels in the EVs compared to the aged ones, without any effect on central content. Conclusion: Our data suggest that the normal aging process causes different changes in the profiles of central and circulating EVs. Altered IL-1β levels in circulating EVs can be linked, at least partly, to age-related inflammatory conditions, and a disruption of the CFS exosomes in aged rats, evaluated by CD63 levels, can be related to susceptibility to neurodegenerative disorders.
NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C
Authors: D’Aliberti Deborah , Cacciola Irene , Musolino Cristina , Raffa Giuseppina , Filomia Roberto , Alibrandi Angela , Benfatto Salvatore , Beninati Concetta , Saitta Carlo , Giosa Domenico , Romeo Orazio , Raimondo Giovanni , Pollicino Teresa
Published: July 2018

Background: Hepatitis C virus (HCV) NS3 resistance-associated substitutions (RASs) reduce HCV susceptibility to protease inhibitors. Little is known about NS3 RASs in viral isolates from the liver of chronic hepatitis C (CHC) patients infected with HCV genotype-1a (G1a). Aim: The objective of this work was to study NS3 variability in isolates from the serum and liver of HCV-G1a-infected patients naïve to direct-acting antivirals (DAAs). Methods: NS3 variability of HCV-G1a isolates from the serum and liver of 11 naïve CHC patients, and from sera of an additional 20 naïve CHC patients, was investigated by next-generation sequencing. Results: At a cutoff of 1%, NS3 RASs were detected in all the samples examined. At a cutoff of 15%, they were found in 54.5% (6/11) and 27.3% (3/11) of the paired liver and serum samples, respectively, and in 22.5% (7/31) of the overall serum samples examined. Twenty-six out of thirty-one (84%) patients showed NS3 variants with multiple RASs. Phylogenetic analysis showed that NS3 sequences clustered within 2 clades, with 10/31 (32.2%) patients infected by clade I, 15/31 (48.8%) by clade II, and 6/31 (19.3%) by both clades. Conclusions: Though the number of patients examined was limited, NS3 variants with RASs appear to be major components of both intrahepatic and circulating viral quasispecies populations in DAA-naïve patients.
PLA1A Participates in the Antiviral Innate Immune Response by Facilitating the Recruitment of TANK-Binding Kinase 1 to Mitochondria
Authors: Gao Xiaoxiao , Chen Dan , Hu Xue , Zhou Yuan , Wang Yun , Wu Chunchen , Chen Jizheng , Wang Yanyi , Pei Rongjuan , Chen Xinwen
Published: July 2018

As a key molecule in the antiviral innate immune response, the activation of TANK-binding kinase 1 (TBK1) is under tight regulation. In this report, we identified phosphatidylserine-specific phospholipase PLA1A as a host factor that modulates the TBK1 activation. Knockdown of PLA1A expression suppressed the innate immune signaling induced by RNA viruses, while PLA1A overexpression enhanced the signaling. PLA1A functioned at the TBK1 level of the signaling pathway, as PLA1A silencing blocked TBK1, but not interferon regulatory factor 3 (IRF3) induced interferon-β (IFN-β) promoter activity. The phosphorylation and kinase activity of TBK1 was reduced in PLA1A knockdown cells. Mechanistically, PLA1A was required in TBK1-mitochondrial antiviral signaling protein (MAVS) interactions but not the interactions of TBK1 with other adaptor proteins. Furthermore, PLA1A knockdown reduced the recruitment of TBK1 and IRF3 to mitochondria, concomitant with altered mitochondria morphology.
A Feasibility Study Utilizing the Thulium and Holmium Laser in Patients for the Treatment of Recurrent Benign Prostatic Hyperplasia after Previous Prostatic Surgery
Authors: Becker Benedikt , Netsch Christopher , Glybochko Peter , Rapoport Leonid , Taratkin Mark , Enikeev Dmitry
Published: July 2018

Background: Transurethral resection of the prostate (TURP) is considered to be the standard treatment for patients with benign prostatic obstruction (BPO) ≤80 mL. However, up to 14.7% of the patients require secondary TURP due to recurrent BPO. The aim of our study was to describe specific features of holmium laser enucleation of the prostate (HoLEP) and thulium laser enucleation of the prostate (ThuLEP) in patients with recurrent BPO after previous prostate surgery. Materials and Methods: A total of 768 consecutive patients from our prospective collected database were retrospectively reviewed and divided into 4 groups: group A (489 patients) and group C (253 patients) underwent primary HoLEP and ThuLEP treatment, while group B (17 patients) and D (9 patients) included patients with recurrent BPO who were treated with HoLEP and ThuLEP, respectively. Results: There were no significant differences in preoperative parameters between the groups at primary (A and C) and secondary (B and D) treatment except their age. At 6-month follow-up, voiding parameters and symptom scores showed statistically significant improvements compared to baseline without differences between the groups. The mean operative time was comparable between the groups and did not differ significantly (p > 0.05). Conclusions: Laser enucleation for the treatment of recurrent BPO is feasible and seems to be a safe and effective procedure.
Reference Ranges and Determinants of Tricuspid Regurgitation Velocity in Healthy Adults Assessed by Two-Dimensional Doppler-Echocardiography
Authors: Marra Alberto M. , Naeije Robert , Ferrara Francesco , Vriz Olga , Stanziola Anna Agnese , D’Alto Michele , D’Andrea Antonello , Carannante Luca , Eichstaedt Christina Alessandra , Cittadini Antonio , Benjamin Nicola , Grünig Ekkehard , Bossone Eduardo
Published: July 2018

Background: Tricuspid regurgitation velocity (TRV) is the most widely used parameter by transthoracic echocardiography (TTE) in the evaluation of patients with suspected pulmonary hypertension (PH). Objectives: To explore the physiologic range of TRV in healthy adults and to investigate its clinical determinants. Methods: In the first part of the study, 614 healthy individuals (age 45.7± 14.7 years, 60.26% women) were prospectively assessed by TTE. In the second part, a pooled meta-analysis of 16 already published studies with TRV values in healthy subjects (n = 981) was performed. Statistical analysis included the calculation of 95% quantiles for defining reference ranges. Results: In the prospectively enrolled cohort, mean TRV was 2.01 ± 0.29 m/s (5–95% CI 1.987–2.033 m/s). It was significantly but weakly positively correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, left atrial volume and negative with mitral inflow E/A ratio. No significant differences were found between males and females. The prospectively enrolled data revealed similar values to the literature-based datasets resulting in a mean TRV of 1.96 m/s (95% CI 1.91–2.02 m/s) and a 95% quantile of 2.55 m/s. Conclusions: To the best of our knowledge, this is the largest dataset to describe reference ranges of TRV and their clinical determinants in healthy adults years. The determined cut-off value of 2.55 m/s of this study has to be confirmed in specific pathologies such as patients at risk of PH.
Chlorhexidine, a Matrix Metalloproteinase Inhibitor and the Development of Secondary Caries Wall Lesions in a Microcosm Biofilm Model
Authors: Maske Tamires T. , Kuper Nicolien K. , Cenci Maximiliano S. , Huysmans Marie-Charlotte D.N.J.M.
Published: July 2018

This study investigated the role of a matrix metalloproteinase (MMP) inhibitor (CHX 2%) in the development of secondary caries wall lesions in different interface conditions with small (run 1) and wider gaps (run 2). Dentin discs were restored and pretreated with or without CHX 2%. In run 1, interfaces were made with gaps of 30, 60, or 90 µm. Interfaces with composite placed directly onto the dentin were either bonded (Adper Single Bond 2) or not bonded. In run 2, interfaces were made with gaps of 100 µm, with or without adhesive on the composite side (CLEARFIL SE Bond). Interfaces were either bonded or not bonded, as in run 1. Microcosm biofilms were grown on dentin-composite samples for 14 days. Caries lesion outcomes were analyzed by transversal wavelength-independent microradiography at 3 locations: the outer surface, and the interface wall at a distance of 200 and 500 µm from the gap entrance. Linear regression analyses showed that pretreatment with MMP inhibitor did not influence progression of the wall lesion at any location (p ≥ 0.218). Interfaces with intentional gaps showed positive and significant effect on the wall lesion progression at 200 µm from the gap entrance (p ≤ 0.005). A small trend of increase in wall lesion development was observed at the 200-µm location when bonding was present on the composite side. In conclusion, the dentin pretreatment with CHX 2% was not able to slow down the development of secondary caries wall lesions in small and wide gaps in this biofilm model.
Ultrasonography and the American Thyroid Association Ultrasound-Based Risk Stratification Tool: Utility in Pediatric and Adolescent Thyroid Nodules
Authors: Creo Ana , Alahdab Fares , Al Nofal Alaa , Thomas Kristen , Kolbe Amy , Pittock Siobhan T.
Published: July 2018

Background: Pediatric thyroid nodules are more likely to be malignant compared to those in adults and may have different concerning ultrasound (US) features. Recent adult guidelines stratify malignancy risk by US features. Our aim is to (1) describe and confirm US features that predict pediatric malignancy, and (2) apply the Adult American Thyroid Association (ATA) Risk Stratification Guidelines to a large pediatric cohort. Methods: We identified 112 children with 145 thyroid nodules from 1996 to 2015. Two blinded pediatric radiologists independently read all US images, described multiple features, and reported their overall impression: benign, indeterminate, or malignant. Each nodule was assigned an ATA risk stratification category. Radiologists’ impressions and ATA risk stratification were compared to histology and cytology results. Results: Multiple US features including a solid composition, presence of microcalcifications, irregular margins, increased blood flow, and hypoechogenicity were associated with increased odds of malignancy. ATA risk stratification correlated with the radiologists’ overall impression (p < 0.001). The sensitivity for detecting malignancy was comparable between both ATA stratification (91%) and the radiologists’ overall impression (90%). The specificity of the radiologists’ malignant overall impression (80%) was better compared to the ATA high risk stratification (54%). Conclusions: At our institution, pediatric radiologists’ overall impressions had similar sensitivity but better specificity for detecting malignancy than the ATA risk stratification tool by our convention. However, neither US-based methods perfectly discriminated benign from malignant nodules, supporting the continued need for fine needle aspiration for suspicious nodules. Further work is needed to develop an US-based scoring system specific to pediatric patients.
Usefulness of Cone Beam Intra-Arterial CTA for Evaluation of Flow Diverters: A Practical Approach for Daily Use
Authors: Reyes Dennys , Becerra Victor , Alcala Indiana , Linfante Italo , Dabus Guilherme
Published: July 2018

Cone beam computed tomography (CBCT), initially used for evaluation of intraprocedural complications such as hemorrhage, has evolved to provide details of implanted devices such as flow diverters. The study aim is to present our experience in using CBCT with intra-arterial injection and provide a step-by-step approach for postprocessing in a practical protocol for daily use. IRB approval was obtained, and the neurointerventional database was retrospectively reviewed from July 2012 to June 2017. Patients who underwent cone beam intra-arterial CT angiography for evaluation of implanted flow diverter devices were reviewed. Patient demographics, aneurysm location (internal carotid artery [ICA]-cavernous, ICA-paraclinoid, and ICA-distal; middle cerebral artery [MCA], anterior cerebral artery [ACA]-acom, ACA-pericallosal, vertebral artery [VA]), type (saccular, dissecting fusiform, or blister) and size, device, injection technique (contrast dilution, rate, and volume), and reconstruction protocol were recorded. Acquired images were postprocessed using a Philips Xtravision workstation. Eighty patients (63 women and 17 men) met the inclusion criteria of our study. Age range was 25–80 years old. Treated aneurysms were located in the ICA-paraclinoid in 48 cases (60%), ICA-distal in 12 cases, ICA-cavernous in 8 cases, MCA in 4 cases, VA in 4 cases, ACA-acom in 2 cases, ACA-pericallosal in 2 cases; 69 were saccular, 8 fusiform, and 3 ruptured blister aneurysms. There were 52 small, 20 large, and 8 giant aneurysms. Pipeline (Medtronic, MN, USA) was the predominant device used in 77 procedures. Two injection techniques were used: 2.5 mL/s for a total volume of 55 mL with a 2-s imaging delay or 3 mL/s for a total volume of 70 mL with a 3-s imaging delay; contrast (Ioxilan 300 mgI/mL) dilution was 10–20% in all cases. The device’s landing zones, conformability, presence of deformities, and wall apposition were successfully visualized in all cases. Metal artifact reduction program was applied in 9 coiled aneurysms, and this was satisfactory as well.
Incidence of Aneurysmal Subarachnoid Hemorrhage with Procedures Requiring General Anesthesia in Patients with Unruptured Intracranial Aneurysms
Authors: Masoud Hesham , Nair Vijaylakshmi , Odulate-Williams Adekorewale  , Sharma Sameer , Gould Grahame , Thatcher Joshua , Nguyen Thanh N.
Published: July 2018

Background: The role of general anesthesia in precipitating aneurysm rupture is not clearly defined. In this study, we aimed to assess the natural history of unruptured aneurysms in patients undergoing non-aneurysm-related procedures requiring general anesthesia. Methods: Retrospective review of consecutive patients with untreated intracranial aneurysms that underwent unrelated surgery with operative note documentation of general anesthesia. Events of intraoperative and postoperative subarachnoid hemorrhage were recorded to determine the incidence of rupture. Results: A total of 110 patients harboring 134 unsecured aneurysms were studied. The mean age was 56.5 years (range, 17–92), and 68% were women (n = 75/110). Mean aneurysm size was 3.5 mm (range 1.5–17). A total of 208 procedures were performed under general anesthesia. There were no events of subarachnoid hemorrhage in 5.7 years of follow-up. Conclusion: In our study, general anesthesia did not precipitate aneurysm rupture, and there were no instances of subarachnoid hemorrhage during the follow-up period. Our results suggest a benign natural history for aneurysms undergoing unrelated general anesthesia. However, this should be interpreted with caution given limitations related to our small sample size and retrospective study design.
Recurrent Urinary Tract Infections in Women: What Is the Evidence for Investigating with Flexible Cystoscopy, Imaging and Urodynamics?
Authors: Santoni Nicola , Ng Angela , Skews Rachel , Aboumarzouk Omar M.
Published: July 2018

Background/Aims/Objectives: Women with recurrent urinary tract infections (UTIs) are commonly referred to urology outpatient clinics. However, there is no clear consensus in existing guidelines as to if, or how, these should be investigated. The primary outcome was to evaluate all available literature to determine the percentage of abnormal findings in non-pregnant women with recurrent simple UTIs. Secondary outcomes were to determine the percentage that were serious, consequential or incidental findings. Methods: A full literature search was performed of the following databases: MEDLINE; Pubmed; Cochrane Central Register of Controlled Trials-CENTRAL; and ClinicalTrials.gov. Two assessors reviewed the articles independently. Any discrepancy was discussed and an agreement reached. Results: The literature search yielded 662 titles; 652 were excluded on initial review. A further 13 studies were gathered from references of yielded papers. After full review, 12 were included for analysis. These showed that < 1.5% of women investigated for recurrent simple UTIs with imaging or flexible cystoscopy had life-threatening pathology, but up to 67% had abnormal urodynamics. Conclusions: Women presenting with simple recurrent UTIs should have a flow rate and post-void residual measured. Cystoscopy is not warranted and imaging is unlikely to be of value in the absence of symptoms of upper tract disease or gynaecological problems.
The Effects of Pitch, Gender, and Prosodic Context on the Identification of Creaky Voice
Authors: Davidson Lisa
Published: July 2018

Background/Aims: Creaky voice in American English plays both a prosodic role, as a phrase-final marker, and a sociolinguistic one, but it is unclear how accurately naïve listeners can identify creak, and what factors facilitate or hinder ist identification. Methods: In this study, American listeners are presented with 2 experiments containing stimuli from both high- and low-pitched male and female speakers. Other manipulations include whether the auditory stimulus is a full sentence or a sentence fragment, and whether it is completely modally voiced, completely creaky, or partially creaky (final 40-50% of the utterance). Results: Accuracy is lowest on partial creak, suggesting that creaky voice is least salient when it serves as an utterance-final marker. There are no strong gender effects aside from a weak tendency to identify creak more often in females than males in the whole creak condition in one experiment. In contrast, when no creak is present, listeners false alarm on the low-pitched males. Conclusion: Rates of identifying creak in male and female speakers are similar, suggesting that listeners have a comparable ability to hear creaky voice in all speakers.
F0Timing and Tone Contrasts in Luganda
Authors: Myers Scott , Namyalo Saudah , Kiriggwajjo Anatole
Published: July 2018

Scholars of Luganda (Bantu, Uganda) have described a contrast between falling and high tone, which is limited to syllables with a long vowel or a coda. The contrast has been represented with H on the first mora of a falling-tone syllable and on both moras in a high-tone syllable. This article explores this contrast through an instrumental study of the timing of f0 events in Luganda. It was found that the 2-tone classes differed in the timing of both the f0 rise and the subsequent f0 fall, supporting a reanalysis of the contrast as one between an early high tone and a late high tone. It was also found that for the speakers in this study, the contrast was limited to syllables with long vowels. The timing of f0 events was sensitive to the duration of segments in the CVC interval centered on the high-toned syllable, including non-moraic elements and consonants outside the syllable. The association of a tone to a syllable identifies the segments relevant for the timing of the f0 contour, but that timing is not directly sensitive to the interval of the syllable.
Preoperative Alfa-Fetoprotein and Fibrinogen Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation Regardless of the Milan Criteria: Model Development with External Validation
Authors: Jiang Nan , Zeng Kai-Ning , Dou Ke-Feng , Lv Yi , Zhou Jie , Li Hai-Bo , Tang Jian-Xin , Li Jin-Jun , Wang Guo-Ying , Yi Shu-Hong , Yi Hui-Min , Li Hua , Chen Gui-Hua , Yang Yang
Published: July 2018

Background/Aims: Patient selection is critically important in improving the outcomes of liver transplantation for hepatocellular carcinoma. The aim of the current study was to identify biochemical measures that could affect patient prognosis after liver transplantation. Methods: A total of 119 patients receiving liver transplantation for hepatocellular carcinoma were used to construct a model for predicting recurrence. The results were validated using an independent sample of 109 patients from independent hospitals. All subjects in both cohorts met the Hangzhou criteria. Results: Analysis of the discovery cohort revealed an association of recurrence with preoperative fibrinogen and AFP levels. A mathematical model was developed for predicting probability of recurrence within 5 years: Y = logit(P) = -4.595 + 0.824 ×fibrinogen concentration (g/L) + 0.641 × AFP score (1 for AFP<=20ng/ml, 2 for 20<AFP<=100ng/ml, 3 for 100<AFP<=200ng/ml, 4 for 200<AFP<=400ng/ml, 5 for AFP> 400ng/ml). At a cutoff score of -0.85, the area under the curve (AUC) was 0.819 in predicting recurrence (vs. 0.655 when using the Milan criteria). In the validation cohort, this model had reasonable performance in predicting 5-year overall survival (68.8% vs. 28.1% in using the -0.85 cutoff, p< 0.001) and disease-free survival (65.7% vs. 25.9%, p< 0.001). The sensitivity and specificity were 77.0% and 62.5%, respectively. The AUC of this newly developed model was similar to that with the Milan criteria (0.698 vs. 0.678). Surprisingly, the DFS in patients with score <= -0.85 under this model but not meeting the Milan criteria was similar to that in patients meeting the Milan criteria (53.8% vs. 60.0%, p=0.380). Conclusions: Preoperative AFP and fibrinogen are useful in predicting recurrence of hepatocellular carcinoma after liver transplantation.
IL-8 Enhances Therapeutic Effects of BMSCs on Bone Regeneration via CXCR2-Mediated PI3k/Akt Signaling Pathway
Authors: Yang Aijun , Lu Yanzhu , Xing Junchao , Li Zhilin , Yin Xiaolong , Dou Ce , Dong Shiwu , Luo Fei , Xie Zhao , Hou Tianyong , Xu Jianzhong
Published: July 2018

Background/Aims: Tissue engineering bone transplantation with bone marrow mesenchymal stem cells (BMSCs) is an effective technology to treat massive bone loss, while molecular regulation of the bone regeneration processes remains poorly understood. Here, we aimed to assess the role of interleukin-8 (IL-8) in the recruitment of host cells by seeded BMSCs and in the bone regeneration. Methods: A transwell assay was performed to examine the role of IL-8/CXCR1/CXCR2/PI3k/Akt on the migration potential of hBMSCs. The in vitro chondrogenic differentiation of hBMSCs was assessed by examination of 2 chondrogenic markers, Sox9 and type 2 collagen (COL2). mBMSCs were used in tissue engineered bone (TEB) with/without IL-8 implanted into bone defect area with CXCR2 or Akt inhibitors. Density and Masson staining of the regenerated bone were assessed. The chondrogenesis was assessed by expression levels of associated proteins, Sox9 and COL2, by RT-qPCR and by immunohistochemistry. Results: IL-8 may trigger in vitro migration of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway. IL-8 enhances osteogenesis in the TEB-implanted bone defect in mice. IL-8 induces chondrogenic differentiation of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway in vitro and in vivo. Conclusions: IL-8 enhances therapeutic effects of MSCs on bone regeneration via CXCR2-mediated PI3k/Akt signaling pathway.
LncRNA NEAT1 Promotes Deterioration of Hepatocellular Carcinoma Based on In Vitro Experiments, Data Mining, and RT-qPCR Analysis
Authors: Ling Zhi-an , Xiong Dan-dan , Meng Rong-mei , Cen Jie-Mei , Zhao Na , Chen Gang , Li Ruo-lin , Dang Yi-wu
Published: July 2018

Background/Aims: Accumulated evidence indicates that lncRNA NEAT1 has important roles in various malignant tumors. In this study, we conducted a comprehensive analysis to explore the exact role of NEAT1 in hepatocellular carcinoma (HCC). Methods: The effects of NEAT1 on cell proliferation, apoptosis, migration, and invasion were measured by in vitro experiments. The expression level and clinical value of NEAT1 in HCC was evaluated based on data from The Cancer Genome Atlas (TCGA), Oncomine, and in-house real-time quantitative (RT-qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses were conducted to investigate the potential molecular mechanisms of NEAT1. Results: NEAT1 siRNA not only inhibited proliferation, migration, and invasion of HCC cells but also induced HCC cell apoptosis. A total of four records from TCGA, Oncomine, and RT-qPCR analysis were combined to assess the expression level of NEAT1 in HCC. The pooled standard mean deviation (SMD) indicated that NEAT1 was up-regulated in HCC (SMD = 0.54; 95% CI, 0.36–0.73; P < 0.0001). The area under the curve value of the summary receiver operating characteristic curve was 0.71. NEAT1 expression was also related to race (P = 0.025) and distant metastasis (P = 0.002). Additionally, the results of GO, KEGG pathway, and PPI network analyses suggest that NEAT1 may promote the progression of HCC by interacting with several tumor-related genes (SP1, MDM4, CREBBP, TRAF5, CASP8, TRAF1, KAT2A, and HIST4H4). Conclusions: NEAT1 contributes to the deterioration of HCC and provides a potential biomarker for the diagnosis and therapy of HCC.
Transfusion Support of Minority Patients: Extended Antigen Donor Typing and Recruitment of Minority Blood Donors
Authors: Khan Jenna , Delaney Meghan
Published: July 2018

One of the most important and persistent complications of blood transfusion is red blood cell (RBC) alloimmunization. When a patient is exposed to RBC antigens that differ from their own they can form alloantibodies to these foreign antigens. Blood group antigens are highly conserved and follow ancestral patterns of inheritance that may demonstrate population restriction. Minority populations who require chronic transfusion are at particularly high risk of alloimmunization when the blood donor population does not share the same ancestral background, resulting in exposure to non-self RBC antigens. It is incumbent on blood collectors to support patients with risk factors for alloimmunization as well as patients who have already formed alloantibodies. Increasing utilization of RBC genotyping may represent an opportunity to improve access to RBC units from donors that match the extended RBC phenotype of all possible patients.
Ergosterol Attenuates LPS-Induced Myocardial Injury by Modulating Oxidative Stress and Apoptosis in Rats
Authors: Xu Jianjun , Lin Cai , Wang Tingting , Zhang Peng , Liu Zhengjun , Lu Caijiao
Published: July 2018

Background/Aims: Ergosterol (ER) is the primary sterol found in fungi and is named after the ergot fungus. A variety of pharmacological activities have been reported for ER, including antioxidative, anti-proliferative, and anti-inflammatory effects, although its role in sepsis remains unclear. Methods: The protective effect of ER on lipopolysaccharide (LPS)-induced sepsis myocardial injury was evaluated both in vivo and in vitro. Rats were pretreated with ER and then with LPS. Histopathology of heart tissues was first performed. Subsequently, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), creatine kinase MB fraction (CK-MB), and lactate dehydrogenase (LDH) in serum and heart tissues were assessed by enzyme-linked immunosorbent assay kits. Western blotting was further used to evaluate the expression of antioxidant proteins (HO-1 and cytochrome c) and apoptosis associated proteins (Bcl-2, Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP). In addition, the effects of ER on oxidative stress biomarkers and apoptosis proteins were also detected in LPS-treated H9C2 cells. Moreover, small interfering Nrf2 RNA was transfected to H9C2 cells to study the role of Nrf2 signaling in connection with the protective effects of ER. Results: Pretreatment with ER ameliorated the histopathological changes in heart tissue induced by LPS injection, increased SOD activity, and reduced MDA content, and CK-MB and LDH levels. Furthermore, ER restored the expression of Nrf-2 and HO-1 in rat hearts, attenuating apoptotic damage via up-regulation of Bcl-2 in combination with the inhibition of Bax, cytochrome c, cleaved-caspase-3 and 9, and PARP, as revealed by western blot. When Nrf2 was blocked by siRNA, the effects of ER on SOD and MDA activity, as well as the expression of the antioxidant proteins and apoptosis-associated proteins were abolished. Conclusions: We demonstrated that ER has a cardioprotective effect in LPS-induced sepsis model through modulation of the antioxidant activity and anti-apoptosis effects and this process might be regulated by Nrf2 signaling.
Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington’s Disease
Authors: Yusuf Issa Olakunle , Cheng Pei-Hsun , Chen Hsiu-Mei , Chang Yu-Fan , Chang Chih-Yi , Yang Han-In , Lin Chia-Wei , Tsai Shaw-Jenq , Chuang Jih-Ing , Wu Chia-Ching , Huang Bu-Miin , Sun H. Sunny , Yang Shang-Hsun
Published: July 2018

Background/Aims: Huntington’s disease (HD) is a heritable neurodegenerative disorder, and there is no cure for HD to date. A type of fibroblast growth factor (FGF), FGF9, has been reported to play prosurvival roles in other neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. However, the effects of FGF9 on HD is still unknown. With many similarities in the cellular and pathological mechanisms that eventually cause cell death in neurodegenerative diseases, we hypothesize that FGF9 might provide neuroprotective functions in HD. Methods: In this study, STHdhQ7/Q7 (WT) and STHdhQ111/Q111 (HD) striatal knock-in cell lines were used to evaluate the neuroprotective effects of FGF9. Cell proliferation, cell death and neuroprotective markers were determined via the MTT assay, propidium iodide staining and Western blotting, respectively. The signaling pathways regulated by FGF9 were demonstrated using Western blotting. Additionally, HD transgenic mouse models were used to further confirm the neuroprotective effects of FGF9 via ELISA, Western blotting and immunostaining. Results: Results show that FGF9 not only enhances cell proliferation, but also alleviates cell death as cells under starvation stress. In addition, FGF9 significantly upregulates glial cell line-derived neurotrophic factor (GDNF) and an anti-apoptotic marker, Bcl-xL, and decreases the expression level of an apoptotic marker, cleaved caspase 3. Furthermore, FGF9 functions through ERK, AKT and JNK pathways. Especially, ERK pathway plays a critical role to influence the effects of FGF9 toward cell survival and GDNF production. Conclusions: These results not only show the neuroprotective effects of FGF9, but also clarify the critical mechanisms in HD cells, further providing an insight for the therapeutic potential of FGF9 in HD.
Micropenis
Authors: Cezarino Bruno Nicolino , Lopes Roberto Iglesias , Machado Marcos Gianetti , Oliveira Lorena Macalo , Giron Amilcar Martins , Tavares Alessandro , Sircilli Maria Helena , Denes Francisco Tibor
Published: July 2018

Micropenis refers to a normally structured penis, which is abnormally small, with a stretched length of less than 2.5 standard deviations (SD) below the mean of age or stage of sexual development. Patients with true micropenis usually have a 46,XY karyotype, associated to normally located male gonads, without any sign of other penile malformations. Penile length is measured from the point where the penis meets the pubic bone to the distal tip of the glans on maximal stretch, compressing any fat over suprapubic area. Differential diagnosis include buried penis (inability to adequately expose the penis, due to a severe phymosis associated to a decreased length of penile skin, which retain the shaft inside the preputial cavity), and obesity with excess fat pad over supra pubic area. The causes of congenital or true micropenis can be divided into three major groups: hypogonadotropic hypogonadism (pituitary/hypothalamic failure), hypergonadotropic hypogonadism (primary testicular failure) and idiopathic (associated with a functional hypothalamus–pituitary–testicular axis). Clinical treatment is based on testosterone therapy. Surgical treatment options are used after failed penile enlargement with testosterone therapy and include penile elongation, suprapubic fat pad aspiration and eventually neophaloplasty.
The aging bladder
Authors: Bruschini Homero
Published: July 2018

The aging of the population is exposing patients and physicians to new challenging urological conditions. The prevalence of lower urinary tract symptoms (LUTS) increases significantly over the age of 65 in both sexes and severely impairs patients’ quality of life (QOL). A better understanding of the possible causes involved in this process will clarify some forms of treatment and stimulate new researches on this matter. The purpose of this review is to better describe the pathophysiological implications related to the aging bladder, allowing a more accurate management of this specific entity.
AVE isquêmico em paciente jovem sem fatores de risco: relato de caso
Authors: Lacerda Isadora Dias , Brito Josué Da Silva , Souza Daniel Lima , Costa Júnior Wesley Lobo , Faria Talitha Araújo
Published: July 2018

Acidente vascular encefálico (AVE) caracteriza-se por um complexo de sintomas decorrentes de alterações no suporte sanguíneo cerebral, que duram pelo menos 24 horas causam lesões cerebrais. Pode ser classificado em isquêmico (AVEi) e hemorrágico (AVEh), sendo que o mais comum deles é o AVEi, caracterizado por interrupção do fluxo sanguíneo em uma determinada área do encéfalo devido a obstrução arterial ou venosa. A falta de suprimento sanguíneo causa um infarto na área vascularizada pelo vaso obstruído, causando morte neuronal. Existem fatores de risco modificáveis e não modificáveis para o AVE, sendo alguns deles: hipertensão, diabetes, tabagismo, etilismo, sedentarismo, dislipidemias, idade superior aos 55 anos, raça negra, história familiar e AVE prévio. O diagnóstico segue protocolos de acordo com o tempo de início dos sintomas, e basicamente, avalia-se quadro clínico, TC de crânio sem contraste ou ressonância magnética de crânio e exames laboratoriais. O tratamento varia de acordo com sua classificação. No caso apresentado a paciente do sexo feminino, sem comorbidades prévias e fatores de risco, desenvolveu um AVEi mesencefálico com graves sequelas. Não foram investigados alterações em genes da coagulação que pudessem explicar a causa da patologia. O AVEi jovem consiste no acidente vascular encefálico presente em adultos com menos de 45 anos. A patologia necessita, além das investigações padrões, de uma averiguação quanto a etiologia genética. Várias patologias estão associadas ao quadro, como CADASIL, doença de Fraby, coagulopatias, anemia de células falciformes, síndrome de Sneddon, MELAS, síndrome de Ehlers-Danlos tipo IV, neurofibrimatose tipo 1 e doença de Moya-Moya. Diante disso evidencia-se a necessidade de se conhecer sobre novos estudos e atualizações que descrevam causas não tão conhecidas de AVE.
Cultura organizacional e desempenho nas empresas estrangeiras listadas na NYSE
Authors: Parente Paulo Henrique Nobre , De Luca Marcia Martins Mendes , Lima Gerlando Augusto Sampaio Franco de , Vasconcelos Alessandra Carvalho de
Published: July 2018

Fundamentado nos preceitos da teoria da visão baseada em recursos, o estudo investiga a cultura organizacional como recurso estratégico sustentável para o desempenho das empresas estrangeiras listadas na New York Stock Exchange. Analisou-se a cultura organizacional de 141 empresas pela análise textual dos relatórios 20-F apresentados por elas à US Securities and Exchange Commission, entre 2009 e 2014, classificando os radicais de palavras em quatro tipologias culturais. Os resultados mostram a predominância de uma cultura organizacional mais competitiva, enquanto a cultura organizacional criativa tem menor representatividade. Os resultados revelam ainda que a cultura colaborativa e de controle influem, respectivamente, de forma positiva e negativa no desempenho empresarial. Estes efeitos são distintos entre a origem das empresas e entre o tipo do sistema legal dos países de origem das empresas. Considerando que a cultura organizacional pode ser considerada um ativo estratégico capaz de afetar o desempenho da empresa, sugere-se que gestores, investidores e acadêmicos, fiquem atentos à cultura organizacional como um componente da estratégia dos negócios.
Cardiomyopathy and Preeclampsia
Authors: Gammill Hilary S. , Chettier Rakesh , Brewer Alina , Roberts James M. , Shree Raj , Tsigas Eleni , Ward Kenneth
Published: July 2018

Background:

Preeclampsia is associated with diastolic dysfunction, peripartum cardiomyopathy, and both pre-existing and subsequent maternal cardiovascular disease. Gene mutations causing idiopathic cardiomyopathy were recently implicated in peripartum cardiomyopathy. We sought to determine whether cardiomyopathy gene mutations are also a contributory factor in preeclampsia.

Methods:

Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of preeclampsia completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with cardiomyopathy. Missense variants were deemed damaging missense if so classified by any of 7 standard function prediction algorithms. Variants were defined as loss-of-function if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from 2 control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33 000 subjects in the Exome Aggregation Consortium. Preeclampsia was not excluded in control groups.

Results:

Of 181 subjects with confirmed preeclampsia, 96% were white. Seventy-two percent had ≥1 preterm preeclampsia delivery <37 weeks. Among preeclampsia subjects, whole exome sequencing demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 cardiomyopathy genes considered. The prevalence of these loss-of-function variants was significantly higher in preeclampsia subjects (5.5%) compared with the local control (2.5%) population (
P
=0.014). Sixty-eight percent of women with preeclampsia carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum cardiomyopathy, most mutations (55%) were found in the TTN gene. Seventy-three percent of preeclampsia subjects had TTN mutations in the preeclampsia cohort versus 48% in local controls (
P
=1.36E-11).

Discussion:

Women who develop preeclampsia are more likely to carry protein-altering mutations in genes associated with cardiomyopathy, particularly in TTN. Mutations promoting cardiomyopathy are prevalent in preeclampsia, idiopathic cardiomyopathy, and peripartum cardiomyopathy, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.
Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence
Authors: Aday Aaron W. , Lawler Patrick R. , Cook Nancy R. , Ridker Paul M , Mora Samia , Pradhan Aruna D.
Published: July 2018

Background:

Despite strong and consistent prospective associations of elevated low-density lipoprotein (LDL) cholesterol concentration with incident coronary and cerebrovascular disease, data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle (LDL-P) concentration, rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein (HDL) cholesterol (HDL-C), may be the primary lipid driver of PAD risk.

Methods:

The study population was a prospective cohort study of 27 888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations, as well as nuclear magnetic resonance spectroscopy–derived lipoprotein measures, were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization.

Results:

In age-adjusted analyses, while LDL cholesterol was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very LDL (VLDL) particle (VLDL-P) subclasses, increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle (HDL-P) concentration (all
P
for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (adjusted hazard ratio [HR
adj
] 2.03; 95% CI, 1.14–3.59), small LDL-P (HR
adj
2.17; 95% CI, 1.10–4.27), very large VLDL-P (HR
adj
1.68; 95% CI, 1.06–2.66), medium VLDL-P (HR
adj
1.98; 95% CI, 1.15–3.41), and TC:HDL-C (HR
adj
, 3.11; 95% CI, 1.67–5.81). HDL was inversely associated with risk; HR
adj
for extreme tertiles of HDL-C and HDL-P concentration were 0.30 (
P
trend < 0.0001) and 0.29 (
P
trend < 0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident coronary and cerebrovascular disease. Finally, the addition of LDL-P and HDL-P concentration to TC:HDL-C measures identified women at heightened PAD risk.

Conclusions:

In this prospective study, nuclear magnetic resonance–derived measures of LDL-P, but not LDL cholesterol, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and nuclear magnetic resonance–derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to coronary and cerebrovascular disease.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov/
. Unique Identifier: NCT00000479.