bluuebunny/crossref_metadata_2025 huggingface dataset:
Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment
Authors: Pilch Zofia , Tonecka Katarzyna , Braniewska Agata , Sas Zuzanna , Skorzynski Marcin , Boon Louis , Golab Jakub , Meyaard Linde , Rygiel Tomasz P.
Published: July 2018

Stimulation of Toll-like receptor 7 (TLR7) activates myeloid cells and boosts the immune response. Previously, we have shown that stimulation of the inhibitory CD200 receptor (CD200R) suppresses TLR7 signaling and that the absence of CD200R signaling leads to a decreased number of papillomas in mice. Here, we investigated the effects of agonistic anti-CD200R on the antitumor activity of a TLR7 agonist (R848) in a syngeneic mouse tumor model. Intratumoral administration of R848 inhibited the growth of the CT26 colon carcinoma and simultaneously decreased CD200R expression in tumor-infiltrating immune cells. The antitumor effects of R848 were potentiated by anti-CD200R. Successfully treated mice were resistant to rechallenge with the same tumor cells. However, the immediate antitumor effects were independent of lymphocytes, because treatment efficacy was similar in wild-type and Rag1tm1Mom mice. Administration of R848, particularly in combination with anti-CD200R, changed the phenotype of intratumoral myeloid cells. The infiltration with immature MHC-II+ macrophages decreased and in parallel monocytes and immature MHC-II− macrophages increased. Combined treatment decreased the expression of the macrophage markers F4/80, CD206, CD86, CD115, and the ability to produce IL1β, suggesting a shift in the composition of intratumor myeloid cells. Adoptively transferred CD11b+ myeloid cells, isolated from the tumors of mice treated with R848 and anti-CD200R, inhibited tumor outgrowth in recipient mice. We conclude that administration of agonistic anti-CD200R improves the antitumor effects of TLR7 signaling and changes the local tumor microenvironment, which becomes less supportive of tumor progression. Cancer Immunol Res; 6(8); 930–40. ©2018 AACR.
Large-Volume Infusions into the Brain: A Comparative Study of Catheter Designs
Authors: Brady Martin L. , Raghavan Raghu , Mata Jaime , Wilson Mike , Wilson Scott , Odland Rick M. , Broaddus William C.
Published: July 2018

Background/Aims: “Whole-brain” infusions have emerged as a potential need with the promise of disease-modifying therapies for neurodegenerative diseases. In addition, several current clinical trials in brain cancer utilize direct delivery of drugs that are required to fill large volumes. Such requirements may not be well served by conventional single port catheters with their “point source” of delivery. Our aim is to examine infusions into large volumes of heterogeneous tissue, aiming for uniformity of distribution. Methods: A porous catheter (porous brain infusion catheter, PBIC), designed by Twin Star TDS LLC, for brain infusions was developed for this study and compared with another convection-enhanced delivery catheter (SmartFlowTM NGS-NC-03 from MRI Interventions, a step end-port catheter, SEPC) in current use in clinical trials. The studies were in vivo in porcine brain. A total of 8 pigs were used: the size of the pig brain limited the porous length to 15 mm. The placements of the tips of the two catheters were chosen to be the same (at the respective brain hemispheres). Results: The PBIC and SEPC both performed comparably and well, with the PBIC having some advantage in effecting larger distributions: p ∼ 0.045, with 5 infusions from each. Conclusions: Given the performance of the PBIC, it would be highly appropriate to use the device for therapeutic infusions in human clinical trials to assess its capability for large-volume infusions.
Prevention of Infectious Diseases due to Immunosuppression and Vaccinations in Asian Patients with Inflammatory Bowel Disease
Authors: Sagami Shintaro , Kobayashi Taku , Hibi Toshifumi
Published: July 2018

Background: Inflammatory bowel disease (IBD) patients with immunocompromise have a high risk of developing complications related to viral infections. Western countries were the first to formulate vaccine guideline. Asian countries developed their national and international vaccine guidelines a little later in order to reduce the risk of mortality from viral infections. However, no studies to date have examined the differences in vaccinations that prevail among Asian countries. Summary: This review summarizes the vaccination status and schedules in various Asian countries for immunocompromised IBD patients. Vaccination rates, regardless of the specific vaccine, were high in Japan, South Korea, and China and low in India and the Philippines. Vaccine schedules differed by country, and outbreaks of measles and rubella were seen due to low vaccination rates in Southeast Asia and South Asia. Live vaccines cannot be administered during immunosuppressive treatment. Infection with measles, mumps, and varicella during immunosuppressive therapy carries a high risk of mortality, and thus confirmation of immunization status is recommended as soon as IBD is diagnosed and, when possible, live vaccines should be administered before the initiation of immunosuppressive treatment. In patients seronegative for hepatitis B, administration of the hepatitis B vaccine is also recommended. Key Messages: Physicians, while considering severity of outbreaks, should understand the differences in vaccination status that exist among the various Asian countries and regions.
Obstructive Sleep Apnea Is Closely Related to Cardiovascular Risk Factors, but Not to Clinical Recurrence of Atrial Fibrillation after Catheter Ablation: An Analysis of Atrial Fibrillation Patients
Authors: Lee Chan Joo , Kim Tae-Hoon , Park Sungha , Pak Hui-Nam 
Published: July 2018

Background: Obstructive sleep apnea (OSA) is a well-known predictor of atrial fibrillation (AF). However, OSA usually accompanies other risk factors of AF. We tried to investigate whether OSA is related to AF recurrence after catheter ablation. Methods: A total of 378 patients (mean age 59.9 ± 10.7 years, 72.5% male) who underwent catheter ablation of AF were enrolled and underwent overnight ambulatory polysomnography before the ablation procedure. These patients were examined once every 3 months at the outpatient clinic to determine AF recurrence. Results: Based on the apnea-hypopnea index (AHI), we divided the study subjects into 3 groups defined as mild (AHI < 10), moderate (10 <AHI < 30), or severe (AHI > 30) OSA. Patients with severe OSA had a higher prevalence of hypertension, diabetes mellitus, and coronary artery disease (CAD). However, AF recurrence was not different between the three groups. The Kaplan-Meier analysis also showed no significant difference in AF recurrence according to the degree of severity of OSA. Multivariate logistic regression analysis revealed that OSA might be a predictor of CAD; however, Cox regression analysis showed that only early recurrence is closely related to AF recurrence after catheter ablation, rather than the severity of OSA. Conclusion: This study shows that the severity of OSA is not associated with the recurrence of AF after catheter ablation in Korean patients. Treatment of OSA for the sole indication of lowering AF recurrence may need to be reconsidered.
Trough-Shaped Audiograms Are Common in Patients with Acoustic Neuroma and Sudden Sensorineural Hearing Loss
Authors: Hosokawa Kumiko , Hosokawa Seiji , Takebayashi Satoru , Mineta Hiroyuki
Published: July 2018

Acoustic neuroma sometimes presents with sudden-onset sensorineural hearing loss as a primary symptom. We investigated 848 untreated cases that included 20 cases with acoustic neuroma with sudden-onset sensorineural hearing loss and 828 cases without acoustic neuroma. Fourteen of the 20 acoustic neuroma and 90 of the 828 cases of sudden-onset sensorineural hearing loss showed a trough-shaped audiogram with the greatest amount of hearing loss in the mid-frequency range. The incidence of a trough-shaped audiogram was significantly higher in patients with acoustic neuroma than in those without (p < 0.01). This study suggests that a trough audiogram is a significant finding in patients with sudden-onset sensorineural hearing loss and indicates the presence of acoustic neuroma.
The Relationship of Pollen Dispersal with Allergy Symptoms and Immunotherapy: Allergen Immunotherapy Improves Symptoms in the Late Period of Japanese Cedar Pollen Dispersal
Authors: Sakurai Toshioki , Yonekura Syuji , Iinuma Tomohisa , Sakurai Daiju , Morimoto Yuki , Kaneko Shinya , Okamoto Yoshitaka
Published: July 2018

Background: The severity of symptoms of pollen-induced allergic rhinitis is affected by the amount of scattered pollen. However, the relationships between the pollen dispersal pattern, symptom severity, and treatment efficacy are not clear. Methods: Between 2007 and 2012, we performed 4 randomized, placebo-controlled studies of sublingual immunotherapy (SLIT) on patients with Japanese cedar-induced allergic rhinitis who lived in or around Chiba, Japan. The participants were asked to avoid using rescue medicines during the cedar pollen season as much as possible and to record their nasal symptoms in allergy diaries. The amount of pollen dispersed daily was quantified using the Durham method, and the season was divided into early and late periods based on the pollen count. Results: A total of 721 patients were enrolled in the 4 studies during the 6-year study period. In the placebo group (n = 349), a correlation was observed between the amount of pollen dispersed and the severity of symptoms in the early but not late period of pollen dispersal. Treatment with SLIT (n = 372) significantly improved symptom severity in the late but not early period. Conclusion: For patients with Japanese cedar pollen-induced allergic rhinitis, the fluctuation of daily pollen dispersal had a minimal effect on the severity of symptoms during the late period. SLIT was remarkably effective in alleviating symptoms during this period but not in the early period.
HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection
Authors: Owusu Sekyere Solomon , Schlevogt Bernhard , Mettke Friederike , Kabbani Mohammad , Deterding Katja , Wirth Thomas Christian , Vogel Arndt , Manns Michael Peter , Falk Christine Susanne , Cornberg Markus , Wedemeyer Heiner
Published: July 2018

Objective: HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis. Design: PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology. Results: Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epi­topes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs – with evidence of IL-12 being a major culprit. Conclusion: Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.
CXCL12 in Patients with Chronic Kidney Disease and Healthy Controls: Relationships to Ambulatory 24-Hour Blood Pressure and Echocardiographic Measures
Authors: Klimczak-Tomaniak Dominika , Pilecki Tomasz , Żochowska Dorota , Sieńko Damian , Janiszewski Maciej , Pączek Leszek , Kuch Marek
Published: July 2018

Background/Aims: Chronic kidney disease is a pro-inflammatory condition where the interplay between different regulatory pathways and immune cells mediates an unfavorable remodeling of the vascular wall and myocardial hypertrophy. These mechanisms include the action of CXCL12. The aim of this study is to evaluate the association between serum CXCL12 with left ventricular hypertrophy (LVH) and blood pressure control in chronic kidney disease (CKD) patients. Methods: This single-center observational study involved 90 stable CKD stage 1–5 patients (including 33 renal transplant recipients) and 25 healthy age- and sex-matched control subjects. CXCL12 was quantified by ELISA. 24-h ambulatory blood pressure monitoring was performed in 90 patients and 25 healthy controls. Left ventricular mass index (LVMI) was calculated based on the transthoracic echocardiography measurements in 27 patients out of the CKD population and in the whole control group. Results: CXCL12 correlated significantly with LVMI by multivariate regression analysis (coefficient B = 0.33, p = 0.02) together with age (B = 0.30, p = 0.03) and gender (B = 0.41, p = 0.003). A positive correlation was observed between CXCL12 and average 24-h systolic blood pressure (SBP) (rho = 0.35, p = 0.001), daytime SBP (rho = 0.35, p = 0.001), and nocturnal SBP (rho = 0.30, p = 0.002). Nocturnal hypertension was frequent (46% of CKD patients). Conclusions: The results of our study point towards a link between CXCL12 and LVH as well as blood pressure control among patients with CKD, supporting the thesis that CXCL12 may be regarded as a new potential uremic toxin.
Perinevoid Alopecia: A Case Report
Authors: Ruiz-Arriaga León Felipe , López-García Lirio , Vega-Memije María Elisa
Published: July 2018

Perinevoid alopecia has been described as an associated alopecia surrounding a pigmented nevus due to an inflammatory response against nevus structures. It is described as a part of other nevocentric phenomena in which a cellular inflammatory response against nevus antigens develops. A 35-year-old male presented with a unique area of non-scarring alopecia surrounding an asymptomatic, pigmented nevus with a 1-month evolution. Trichoscopic and histologic findings were compatible with alopecia areata (AA). One month after excision, hair regrowth was reported by the patient. We concluded that perinevoid alopecia is an extremely rare clinical presentation of AA associated with a central, pigmented nevus where a cellular inflammatory response is triggered against hair follicles, nevoid cells, and melanocytic structures.
Potential Role of Gr-1+ CD8+ T Lymphocytes as a Source of Interferon-γ and M1/M2 Polarization during the Acute Phase of Murine Legionella pneumophila Pneumonia
Authors: Kusaka Yu , Kajiwara Chiaki , Shimada Sho , Ishii Yoshikazu , Miyazaki Yasunari , Inase Naohiko , Standiford Theodore J. , Tateda Kazuhiro
Published: July 2018

In this study, we analyzed interferon (IFN)-γ-producing cells and M1/M2 macrophage polarization in Legionella pneumophila pneumonia following anti-Gr-1 antibody treatment. Anti-Gr-1 treatment induced an M1-to-M2 shift of macrophage subtypes in the lungs and weakly in the peripheral blood, which was associated with increased mortality in legionella-infected mice. CD8+ T lymphocytes and natural killer cells were the dominant sources of IFN-γ in the acute phase, and anti-Gr-1 treatment reduced the number of IFN-γ-producing CD8+ T lymphocytes. In the CD3-gated population, most Gr-1-positive cells were CD8+ T lymphocytes in the lungs and lymph nodes (LNs) of infected mice. Additionally, the number of IFN-γ-producing Gr-1+ CD8+ T lymphocytes in the lungs and LNs increased 2 and 4 days after L. pneumophila infection, with anti-Gr-1 treatment attenuating these populations. Antibody staining revealed that Gr-1+ CD8+ T lymphocytes were Ly6C-positive cells rather than Ly6G, a phenotype regarded as memory type cells. Furthermore, the adoptive transfer of Gr-1+ CD8+ T lymphocytes induced increases in IFN-γ, M1 shifting and reduced bacterial number in the Legionella pneumonia model. These data identified Ly6C+ CD8+ T lymphocytes as a source of IFN-γ in innate immunity and partially associated with reduced IFN-γ production, M2 polarization, and high mortality in anti-Gr-1 antibody-treated mice with L. pneumophila pneumonia.
G1359A Variant of the Cannabinoid Receptor Gene (rs1049353) and Obesity-Related Traits and Related Endophenotypes: A Meta-Analysis
Authors: Sadeghian Mehdi , Rahmani Sepideh , Mansoori Anahita
Published: July 2018

Background: This study aimed to investigate the comparison of G1359A variant of cannabinoid receptor gene (rs1049353) with obesity-related traits including body mass index (BMI), fat mass (FM), fat-free mass (FFM), food-related traits, and leptin among healthy and non-healthy adults. Methods: We searched PubMed, Cochrane, Scopus, Web of Science, and EMBASE until December 2016 for observational studies assessing each of the anthropometric measurements, food-related traits, and leptin of 1359 G/A polymorphism of CNR1 gene. A total of 22 studies were included in the meta-analysis comparing mean and SD differences of the anthropometric measurements, leptin, and dietary intake between GA/AA and GG genotypes. Results: The results showed that subjects with GA/AA genotype had significantly lower BMI (weighted mean difference = –0.59 kg/m2, p < 0.001) compared to those with the GG genotype. Dietary intake of fat, carbohydrate, and protein as well as serum levels of leptin was not significantly different between GA/AA and GG genotypes. Conclusion: It was revealed that subjects with mutant polymorphism (GA/AA) of CNR1, compared to the wild-type group (GG), had lower BMI (although there was unexplained heterogeneity).
Meningitis due to a Combination of Streptococcus mitis and Neisseria subflava: A Case Report
Authors: Fukumoto Kana , Manabe Yasuhiro , Fujiwara Shunya , Omote Yoshio , Narai Hisashi , Yamada Haruto , Saito Takashi , Abe Koji
Published: July 2018

We report a rare case of meningitis due to a combination of Streptococcus mitis and Neisseria subflava. An 80-year-old female had a 4-year history of type II diabetes mellitus (DM) and an 11-year history of rheumatoid arthritis, which was treated with prednisolone, tacrolimus, and methotrexate. One month after the removal of a dental implant, she complained of a disturbance of consciousness and suffered a convulsion. A cerebrospinal fluid culture was found to be positive for both S. mitis and N. subflava. After 14 days of antibiotic treatment with 4 g/day ceftriaxone, her stiff neck, somnolence, and laboratory data greatly improved, and she was successfully discharged at 27 days after admission. Although both S. mitis and N. subflava are generally considered to be benign bacteria, they can cause meningitis in patients with the following risk factors: older age, on immunosuppressive treatment, DM, or dental treatment.
Neoadjuvant Trabectedin plus Radiotherapy in High-Grade Sarcoma of the Leg: A Case Report
Authors: Loureiro da Silva António José , Carvalho Carolina , Jacobetty Miguel , Freitas João , Fonseca Ruben , Tavares Paulo F. , Garcia Helena , Borrego Margarida , Casanova José M.
Published: July 2018

Here, we present the case of a 78-year-old male patient with undifferentiated spindle cell sarcoma on the posteromedial surface of the right leg who experienced a long-lasting progression-free survival. Due to an underlying cardiac disease, the patient was not suitable for anthracyclines. In September 2015, he received first-line chemotherapy with trabectedin (Yondelis®) at the approved dosage and regimen – concomitant with external radiotherapy (RT). After the first 9 cycles of trabectedin plus RT given in the neoadjuvant setting, the patient underwent surgical resection. At that stage, we observed a very good pathological response with 80% of necrotic area. The patient resumed the therapy with trabectedin; however, approximately 5 months later, we observed a new nodular heterogeneous lesion with ill-defined margins in the right leg and suggestive of tumor relapse. Subsequently an above-the-knee amputation was performed, and the patient resumed his trabectedin therapy with the same dosage and regimen. In January 2018, almost 2 1/2 years after the start of trabectedin treatment and 30+ cycles of trabectedin, the patient is locoregionally and distant metastatically disease-free. Currently, the treatment with trabectedin is maintained without any significant serious toxicity. Future clinical trials are needed to gain additional insights into the role of trabectedin maintenance therapy until disease progression in the neoadjuvant setting and to identify predictive and prognostic criteria for response to trabectedin in patients with advanced sarcoma.
Interferon Regulatory Factor 1 Activates Autophagy to Aggravate Hepatic Ischemia-Reperfusion Injury by Increasing High Mobility Group Box 1 Release
Authors: Cui Zilin , Li Shipeng , Liu Zirong , Zhang Yamin , Zhang Haiming
Published: July 2018

Background/Aims: Interferon regulatory factor 1(IRF-1) and high mobility group box 1(HMGB1) have been independently identified as being key players in hepatic ischemia-reperfusion injury (IRI). We attempted to determine whether IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release. Methods: The hepatic IRI model was generated in C57BL/6 mice, euthanized at 2, 6, 12 or 24 h after reperfusion. To examine the effects of HMGB1 release inhibition, Glycyrrhiza acid (GA) was administered to the mice and at six hours after injectiont. AML12 cells were immersed in mineral oil for 90 min and then cultured in complete Dulbecco’s Modified Eagle’s Medium (DMEM)/F12 to simulate IRI. AML12 cells were treated with IRF-1 siRNA, Ad-IRF-1 or GA. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Next, autophagic vacuoles were detected by transmission electron microscopy (TEM) or LC3 dots. The expression of IRF-1 and HMGB1 mRNA were measured by real-time polymerase chain reaction. The expression of IRF-1, microtubule-associated protein 1 light chain 3 (LC3), Bcl-2, Beclin 1, HMGB1 were detected by western blotting or immunohistochemistry. Results: The levels of hepatic IRF-1, mRNA and protein were significantly increased in livers after exposure to IRI, together with, IRI-induced increase of HMGB1 mRNA and release of HMGB1 in liver tissue. Knockout of IRF-1 decreased expression and release of HMGB1 in liver, and inhibiting the release of HMGB1 could alleviate hepatic IRI. In addition, knockout of IRF-1 downregulated LC3II and Beclin1, while number of autophagosomes or LC3 dots were increased. Up-regulating IRF-1 expression could increase the levels of LC3Ⅱ expression in AML12 cells after exposure to IRI. The levels of HMGB1 in Ad-IRF-1 transfected AML12 cell supernatants increased, together with number of LC3 dots increasing. However, GA could inhibit both Ad-IRF-1 induced HMGB1 release and the increase in the number of LC3 dots. Conclusions: IRF-1 activates autophagy to aggravate hepatic IRI by increasing HMGB1 release.
LncRNA TP73-AS1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Clear Cell Renal Cell Carcinoma Through Repressing KISS1 Expression and Inactivation of PI3K/Akt/mTOR Signaling Pathway
Authors: Liu Guanghua , Zhao Xin , Zhou Jingmin , Cheng Xiangming , Ye Zixing , Ji Zhigang
Published: July 2018

Background/Aims: Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a vital regulatory role in the pathogenesis and progression of renal cell carcinoma (RCC). We aim to determine lncRNA profiles in clear cell RCC (ccRCC) and investigate key lncRNAs involved in ccRCC tumorigenesis and progression. Methods: RNA sequencing technique and qPCR were used to determine the candidate lncRNAs in ccRCC tissues. The correlations between lncRNA P73 antisense RNA 1T (TP73-AS1) levels and survival outcomes were analyzed to elucidate its clinical significance. The underlying mechanisms of TP73-AS1 in ccRCC were analyzed through in vitro functional assays. Results: We found TP73-AS1 was upregulated in 40 ccRCC tissues compared with adjacent normal renal tissues and increased TP73-AS1 was correlated to aggressive clinicopathologic features and unfavorable prognosis. Knockdown of TP73-AS1 suppressed cell proliferation, invasion and induced cell apoptosis. We also identified KISS-1 metastasis-suppressor (KISS1) was significantly upregulated in TP73-AS1 knockdown cells. Further, we revealed that TP73-AS1 suppressed KISS1 expression through the interaction with Enhancer of zeste homolog 2 (EZH2) and the specific binding to KISS1 gene promoter region. Knockdown of KISS1 partly reversed TP73-AS1 knockdown-induced inhibition of cell proliferation and promotion of apoptosis. We further determined that TP73-AS1 knockdown activated PI3K/Akt/mTOR signaling pathway, while overexpression of TP73-AS1 induced inhibition of PI3K/Akt/mTOR pathway and these effects could be partly abolished by overexpression of KISS1. Conclusion: In conclusion, we identified that TP73-AS1 as an oncogenic lncRNA in the development of ccRCC and a potential target for human renal carcinoma treatment.
VEGF-A and VEGF-B Coordinate the Arteriogenesis to Repair the Infarcted Heart with Vagus Nerve Stimulation
Authors: Lv Yan-xia , Zhong Sen , Tang Hexin , Luo Bin , Chen Shao-Juan , Chen Long , Zheng Fei , Zhang Lei , Wang Lu , Li Xing-yuan , Yan Yu-wen , Pan Ya-mu , Jiang Miao , Zhang You-en , Wang Lei , Yang Jian-ye , Guo Ling-yun , Chen Shi-you , Wang Jia-ning , Tang Jun-ming
Published: July 2018

Background/Aims: Vagus nerve stimulation (VNS) suppresses arrhythmic activity and minimizes cardiomyocyte injury. However, how VNS affects angiogenesis/arteriogenesis in infarcted hearts, is poorly understood. Methods: Myocardial infarction (MI) was achieved by ligation of the left anterior descending coronary artery (LAD) in rats. 7 days after LAD, stainless-steel wires were looped around the left and right vagal nerve in the neck for vagus nerve stimulation (VNS). The vagal nerve was stimulated with regular pulses of 0.2ms duration at 20 Hz for 10 seconds every minute for 4 hours, and then ACh levels by ELISA in cardiac tissue and serum were evaluated for its release after VNS. Three and 14 days after VNS, Real-time PCR, immunostaining and western blot were respectively used to determine VEGF-A/B expressions and α-SMA- and CD31-postive vessels in VNS-hearts with pretreatment of α7-nAChR blocker mecamylamine (10 mg/kg, ip) or mACh-R blocker atropine (10 mg/kg, ip) for 1 hour. The coronary function and left ventricular performance were analyzed by Langendorff system and hemodynamic parameters in VNS-hearts with pretreatment of VEGF-A/B-knockdown or VEGFR blocker AMG706. Coronary arterial endothelial cells proliferation, migration and tube formation were evaluated for angiogenesis following the stimulation of VNS in coronary arterial smooth muscle cells (VSMCs). Results: VNS has been shown to stimulate VEGF-A and VEGF-B expressions in coronary arterial smooth muscle cells (VSMCs) and endothelial cells (ECs) with an increase of α-SMA- and CD31-postive vessel number in infarcted hearts. The VNS-induced VEGF-A/B expressions and angiogenesis were abolished by m-AChR inhibitor atropine and α7-nAChR blocker mecamylamine in vivo. Interestingly, knockdown of VEGF-A by shRNA mainly reduced VNS-mediated formation of CD31+ microvessels. In contrast, knockdown of VEGF-B powerfully abrogated VNS-induced formation of α-SMA+ vessels. Consistently, VNS-induced VEGF-A showed a greater effect on EC tube formation as compared to VNS-induced VEGF-B. Moreover, VEGF-A promoted EC proliferation and VSMC migration while VEGF-B induced VSMC proliferation and EC migration in vitro. Mechanistically, vagal neurotransmitter acetylcholine stimulated VEGF-A/B expressions through m/nACh-R/PI3K/Akt/Sp1 pathway in EC. Functionally, VNS improved the coronary function and left ventricular performance. However, blockade of VEGF receptor by antagonist AMG706 or knockdown of VEGF-A or VEGF-B by shRNA significantly diminished the beneficial effects of VNS on ventricular performance. Conclusion: VNS promoted angiogenesis/arteriogenesis to repair the infracted heart through the synergistic effects of VEGF-A and VEGF-B.
The Unexpected Effects of L-Carnitine Supplementation on Lipid Metabolism in Hemodialysis Patients
Authors: Katalinic Lea , Krtalic Branimir , Jelakovic Bojan , Basic-Jukic Nikolina
Published: July 2018

Background/Aims: There is a growing body of evidence that the long-term hemodialysis (HD) treatment leads to disturbances of carnitine homeostasis but the results of L-carnitine supplementation in HD patients have been conflicting. In the present prospective study, we investigated the effectiveness of intravenous L-carnitine in mitigating dialysis-related protein-energy wasting (PEW) based on pre-treatment albumin levels. Methods: Fifty patients (46% male, mean age 63±18.28 years, HD vintage 37.5 (7-288) months) received 1 g L-carnitine intravenously at the end of every HD session for 12 months. Clinical data were obtained from the medical records and charts. Intradialytic hypotension periods (defined as a decrease of systolic blood pressure by ≥ 20 mmHg) were recorded. Dietary habits were evaluated using a self-administered questionnaire prior to L-carnitine supplementation. Laboratory parameters were measured prior to the supplementation and controlled in 6-months intervals. Anthropometric measurements were performed prior to HD session, including „dry“ body weight and height, body mass index (BMI), and body composition analysis using bioimpedance spectroscopy. Malnutrition-inflammation score (MIS) was used as a scoring system representing the severity of PEW and an indicator of general functional capacity. Results: A significant increase in total cholesterol, predominantly on the account of LDL was found (p=0.005). Simultaneously, HDL decreased (p=0.001) while triglyceride levels remained unchanged. Although the rise in serum prealbumin could be observed, lean tissue index (LTI) decreased and fat tissue index (FTI) increased which resulted in reduction of the LTI/FTI ratio (p=0.002). When divided into two groups according to the pre-treatment albumin values (< 35 g/L or ≥35 g/L), patients from the higher albumin group showed significant increase in prealbumin (p=0.005), and improved MIS (p=0.03). Multivariate regression analysis showed that higher FTI after introduction of L-carnitine led to greater hemodynamic stability (OR 1.709, 95% CI 1.006-2.905, p=0.048). As there was no differences in HD treatment characteristics, primery kidney disease or residual diuresis we could conclude that positive energy balance (with an increase in prealbumin and FTI) eventually led to better hemodynamic stability. Conclusion: Our results show significant effects of L-carnitine supplementation on lipid metabolism. Further clinical trials, as well as experimental research are needed to define the role of lipid metabolism in CKD population. Significant benefits of L-carnitine supplementation in patients with better initial serum albumin levels suggest that this therapy should not be restricted to patients with the worst nutritional and overall status.
Clinicopathological Characteristics, Role of Immunosuppressive Therapy and Progression in IgA Nephropathy with Hyperuricemia
Authors: Ruan Yiping , Hong Fuyuan , Wu Jiabin , Lin Miao , Wang Chen , Lian Fayang , Cao Fang , Yang Guokai , Gao Meizhu
Published: July 2018

Background/Aims: The aim of the study was to investigate clinicopathological characteristics, the role of immunosuppressive therapy and renal outcome in IgA nephropathy (IgAN) patients with hyperuricemia. Methods: 206 biopsy-proven primary IgAN patients were included between January 2010 and December 2015, and divided into two groups: patients without hyperuricemia (n=122), and patients with hyperuricemia (n=84). The clinicopathological features, response, renal outcome and safety were recorded. In univariate and multivariate models, hyperuricemia-associated pathological factors were analyzed. Results: The patients with hyperuricemia presented higher systolic blood pressure, worse kidney function and more severe time-averaged proteinuria. Proportions of glomerulosclerosis, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, lymphocytes and monocytes infiltration were higher, while the proportion of segmental adhesion was lower in patients with hyperuricemia. By multivariate logistic regression analysis, only tubular atrophy/interstitial fibrosis (T1∼2) (HR=3.969, 95% CI=1.439−10.945, P=0.008) was significantly associated with hyperuricemia. For hyperuricemic patients, the response rate to therapy and renal survival rate were significantly higher in patients that received RAS blockade in combination with immunosuppressive therapy. After RAS blockade treatment, renal survival in the patients with hyperuricemia was worse compared with the patients without hyperuricemia. Conclusion: Hyperuricemic IgAN patients presented more severe clinical features. Tubulointerstitial injury could be a pathological feature closely related to hyperuricemia in IgAN. Immunosuppressive therapy and RAS blockade could reduce proteinuria and improve renal outcome in IgAN patients with hyperuricemia.
MiR-298 Exacerbates Ischemia/Reperfusion Injury Following Ischemic Stroke by Targeting Act1
Authors: Sun Hongxue , Zhong Di , Wang Cheng , Sun Yilei , Zhao Jiaying , Li Guozhong
Published: July 2018

Background/Aims: This study investigated the role of the microRNA miR-298 and its target Act1 in ischemic stroke. Methods: Cell viability was assessed with the 3-(4,5-dimethythiazol-2- yl)-2,5-diphenyl tetrazolium bromide assay. Apoptotic cells were detected by flow cytometry, and mRNA and protein expression were assessed by quantitative real-time PCR and western blotting, respectively. The regulatory relationship between miR-298 and Act1 was evaluated with the luciferase assay. To clarify the role of Act1 following ischemic stroke, the transcript was knocked down by short interfering RNA. The in vitro findings were validated in a mouse model of middle cerebral artery occlusion by administration of miR-298 mimic. Results: Act1 was upregulated whereas miR-298 was downregulated in ischemic stroke. miR-298 overexpression by transfection of a mimic suppressed Act1 protein levels in vitro and in vivo, and the luciferase assay showed that miR-298 directly binds to the 3’ untranslated region of the Act1 transcript. miR-298 overexpression enhanced cell apoptosis and autophagy and exacerbated ischemic infarction and neurological deficits, effects that were exerted via negative regulation of Act1/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB signaling and downstream autophagy pathways. Conclusions: Upregulation of miR-298 following ischemic stroke promotes brain injury in vitro and vivo by inhibiting the Act1/JNK/NF-κB signaling cascade and the downstream autophagy pathway. Therapeutic strategies that target miR-298 could be beneficial for the treatment of ischemic stroke.
Browning of Pig White Preadipocytes by Co-Overexpressing Pig PGC-1α and Mice UCP1
Authors: Hou Lianjie , Xie Meiying , Cao Lingbo , Shi Jia , Xu Guli , Hu Chingyuan , Wang Chong
Published: July 2018

Background/Aims: Brown adipose tissue (BAT) is critical for mammals’ survival in the cold environment. BAT-dependent non-shivering thermogenesis is attributed to uncoupling protein 1 (UCP1)’s disengagement of oxidative phosphorylation from ATP synthesis and dissipates energy as heat. Thus individuals with a substantial amount of BAT are better equipped during cold stress and less likely to become obese. Recently, our laboratory has shown pig adipocytes have no UCP1 protein. The inability of newborn piglets to generate heat contributed to its high death rate. Repairing the genetic defect of UCP1 in pig adipocytes has implications in defending against cold for piglets and developing an alternative treatment for human obesity. Methods: Q-PCR, western blotting (WB) and oxygen consumption measurement were used to enable functional UCP1 protein in preadipocytes. Immunoprecipitation (IP), chromatin immunoprecipitation (CHIP), and dual-luciferase reporter assay system were used to clarify the thermogenesis mechanism of functional UCP1. Results: Only co-overexpressing mice UCP1 and pig PGC-1α increased not only the mitochondrial number but also the uncoupled respiration rate in the transfected pig adipocytes. The functional mice UCP1 increased the pig PGC-1α activity through the AMPK-SIRT1 pathway. The active form PGC-1α interacted with transcription factors Lhx8, Zic1, ERRα, and PPARα to regulate the expression of mitochondrial energy metabolism and adipocytes browning-related genes. Conclusion: Our data suggest a model in which pig PGC-1α and mice UCP1 work collaboratively to restore uncoupling respiration in pig preadipocytes. These results have great implications for piglet survival and developing an alternative treatment for human obesity in the future.
Liposomal Curcumin Targeting Endometrial Cancer Through the NF-κB Pathway
Authors: Xu Hanzi , Gong Zhen , Zhou Siying , Yang Sujin , Wang Dandan , Chen Xiu , Wu Jiaqi , Liu Liucheng , Zhong Shanliang , Zhao Jianhua , Tang Jinhai
Published: July 2018

Background/Aims: Emerging evidence suggests that curcumin possesses chemopreventive properties against various cancers. However, its poor bioavailability limits its clinical application. In this study, we aimed to utilize encapsulation in liposomes (Lipo) as a strategy for the clinical administration of curcumin for endometrial carcinoma (EC). Methods: Curcumin was encapsulated in a liposomal delivery system to prepare a formulation of liposomal curcumin (LC). EC cell lines Ishikawa and HEC-1 were treated with the compound and cell proliferation was measured using MTT assay. Hoechst 33258 staining assay and flow cytometry were used to detect apoptosis of the cells. Wound healing and cell invasion assays were employed to monitor cell motility. Underlying target signaling, such as NF-κB, caspases, and MMPs, were further studied via qRT-PCR and western blot. Thereafter, a zebrafish model was used to assess the toxicity of LC. Finally, a zebrafish transplantation tumor model of EC was grown and treated with LC. Tumors were monitored and harvested to study the expression of NF-κB. Results: The formation of LC was successfully developed with excellent purity and physical properties. In vitro, LC resulted in dose-dependent inhibition of proliferation, induction of apoptosis, and suppression of Ishikawa and HEC-1 cell motility. LC treatment also suppressed the activation and/or expression of NF-κB, caspase-3, and MMP-9. No demonstrable toxicity was found in the zebrafish model and tumors were suppressed after treatment with LC. PCR analysis also showed down-regulated expression of NF-κB. Conclusions: LC was successfully prepared and played biological roles against EC probably through negative regulation of the NF-κB pathway in vitro and in vivo, which demonstrates its potential therapeutic effects in EC.
Antenal hydronephrosis
Authors: Giron Amilcar Martins
Published: July 2018

Genitourinary anomalies can be detected in the antenatal period with incidence of 0.5 a 1% in gestational population; 20 a 30% of these anomalies involve the urinary tract. Hydronephrosis is the most frequent urinary tract anomaly followed by cystic anomalies. Currently, technical advances of high-resolution ultrasound identify, in a non-invasive way, the gestational anatomy. The evaluation of the urinary tract, by means of complementary examinations: precocious abdominal and pelvic ultrasound (US), laboratory analysis, functional evaluation (DTPA99 -glomerular function; DMSA99 -tubular function and MAG99 -MAG-3), voiding cystourethrography and others if necessary. Conclusion - Every pregnant woman should undergo at least one morphological ultrasound examination carried out in satisfactory conditions and by qualified professional during the prenatal follow-up to identify possible malformations of the fetus. Following a pre-established roadmap of complementary examinations, it is possible to treat the pathology safely, allowing the newborn to receive hospital discharge in good condition, with a mandatory multidisciplinary outpatient follow-up with pediatric, nephrologist and pediatric urologist’s consultations.
Androgen replacement therapy in men: current evidence and controversy
Authors: Barbosa João Arthur Brunhara Alves , Cury José
Published: July 2018

The decline in Testosterone (T) levels in the ageing male - known as andropause or late-onset hypogonadism - may be responsible for several aspects of quality of life decline in older men: erectile dysfunction, impaired libido, decreased strength and energy, sarcopenia, osteopenia, fatigue and even depression in some cases. Many of these signs and symptoms represent the same alterations that are usually attributed to the process of ageing. When some individual presents with such symptoms, hypogonadism should be suspected, and serum T level should be evaluated. Men who are symptomatic and present low levels of serum Testosterone (generally below 300 ng/ml) are candidates for T replacement therapy. Current evidence shows that, when correctly selected, patients receiving T replacement may benefit from improvement in libido, erectile function, overall and sexual related quality of life, bone density and muscle mass. Conversely, patients with physiological circulating levels of T who receive hormone, aiming at supraphysiologic levels, may face severe side effects, including testicular atrophy and behavioral changes. Of note, T replacement, regardless of age and pre-therapy levels, leads to fertility impairment which can be transient or persistent. Direct testosterone replacement should not be indicated in men who wish to conceive children, although other options are available. The effect of Testosterone replacement on prostate cancer and on cardiovascular risk is still controversial; hypogonadal men known to have prostate cancer or high cardiovascular risk should be examined individually to have their risks stratified and mitigated.
Minimally invasive techniques for the treatment of benign prostatic hyperplasia
Authors: Barbosa João Arthur Brunhara Alves , Antunes Alberto Azoubel
Published: July 2018

Benign Prostatic Hyperplasia (BPH) occurs in up to 80% of men older than 70 years. The prevalence of BPH increases with age, from approximately 25% of men at 50 years of age to 50 to 90% of individuals in their 8th decade of life. Treatment options for lower urinary tract symptoms (LUTS) secondary to BPH have been long restricted to drug therapy and, after failure of the former, surgical treatment. However, prostate surgery is associated with risks such as bleeding, necessity of transfusion and ejaculatory dysfunction. Several novel and minimally invasive methods for treatment of BPH have arisen in the past years. Common to all of these techniques are a more favorable safety profile and varying rates of success and clinical improvement, however frequently inferior to standard surgical techniques. Patients who will benefit the most from these procedures are those who would not wish to undergo surgery, those at prohibitively high risk for surgery, and those wishing to avoid ejaculatory dysfunction secondary to trans-urethral resection of the prostate (TURP) or open resection. Mechanical devices such as Temporary implantable nitinol device and Urolift appear to provide satisfying results with a favorable safety profile. Persistence of improvement is still questionable since follow-up longer than 5 years is not available for these methods. Of note, these methods may be of limited performance for larger prostates, in special, Urolift for those with a large median lobe or a prostate larger than 100 grams. Similarly, novel techniques for tissue ablation, including convective water vapor energy, appear to offer promising and safe results, yet with limited follow-up. Prostate artery embolization (PAE) is another safe procedure and an option for patients who are not suited for surgery, with satisfying short and medium-term follow-up but unknown results at long-term.
Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice
Authors: Qasim Hanan , Karim Zubair A. , Silva‐Espinoza Juan C. , Khasawneh Fadi T. , Rivera José O. , Ellis Cameron C. , Bauer Stephanie L. , Almeida Igor C. , Alshbool Fatima Z.
Published: July 2018

Background

Cardiovascular disease is the main cause of death in the United States, with smoking being the primary preventable cause of premature death, and thrombosis being the main mechanism of cardiovascular mortality in smokers. Due to the perception that electronic/e‐cigarettes are “safer/less harmful” than conventional cigarettes, their usage—among a variety of ages—has increased tremendously during the past decade. Notably, there are limited studies regarding the negative effects of e‐cigarettes on the cardiovascular system, which is also the subject of significant debate.

Methods and Results

We employed a passive e‐Vape

TM

vapor inhalation system and developed an in vivo whole‐body e‐cigarette mouse exposure protocol that mimics real‐life human exposure scenarios/conditions and investigated the effects of e‐cigarettes and clean air on platelet function and thrombogenesis. Our results show that platelets from e‐cigarette–exposed mice are hyperactive, with enhanced aggregation, dense and α granule secretion, activation of the α
II
bβ3 integrin, phosphatidylserine expression, and Akt and
ERK
activation, when compared with clean air–exposed platelets. E‐cigarette–exposed platelets were also found to be resistant to inhibition by prostacyclin, relative to clean air. Furthermore, the e‐cigarette–exposed mice exhibited a shortened thrombosis occlusion and bleeding times.

Conclusions

Taken together, our data demonstrate for the first time that e‐cigarettes alter physiological hemostasis and increase the risk of thrombogenic events. This is attributable, at least in part, to the hyperactive state of platelets. Thus, the negative health consequences of e‐cigarette exposure should not be underestimated and warrant further investigation.
Computing with Spikes: The Advantage of Fine-Grained Timing
Authors: Verzi Stephen J. , Rothganger Fredrick , Parekh Ojas D. , Quach Tu-Thach , Miner Nadine E. , Vineyard Craig M. , James Conrad D. , Aimone James B.
Published: July 2018

Neural-inspired spike-based computing machines often claim to achieve considerable advantages in terms of energy and time efficiency by using spikes for computation and communication. However, fundamental questions about spike-based computation remain unanswered. For instance, how much advantage do spike-based approaches have over conventional methods, and under what circumstances does spike-based computing provide a comparative advantage? Simply implementing existing algorithms using spikes as the medium of computation and communication is not guaranteed to yield an advantage. Here, we demonstrate that spike-based communication and computation within algorithms can increase throughput, and they can decrease energy cost in some cases. We present several spiking algorithms, including sorting a set of numbers in ascending/descending order, as well as finding the maximum or minimum or median of a set of numbers. We also provide an example application: a spiking median-filtering approach for image processing providing a low-energy, parallel implementation. The algorithms and analyses presented here demonstrate that spiking algorithms can provide performance advantages and offer efficient computation of fundamental operations useful in more complex algorithms.