bluuebunny/crossref_metadata_2025 huggingface dataset:
R213G polymorphism in SOD3 protects against bleomycin-induced inflammation and attenuates induction of proinflammatory pathways
Authors: Garcia Anastacia M. , Allawzi Ayed , Tatman Philip , Hernandez-Lagunas Laura , Swain Kalin , Mouradian Gary , Bowler Russell , Karimpour-Fard Anis , Sucharov Carmen C. , Nozik-Grayck Eva
Published: July 2018

Extracellular superoxide dismutase (EC-SOD), one of three mammalian SOD isoforms, is the sole extracellular enzymatic defense against superoxide. A known human single nucleotide polymorphism (SNP) in the matrix-binding domain of EC-SOD characterized by an arginine-to-glycine substitution at position 213 (R213G) redistributes EC-SOD from the matrix into extracellular fluids. We previously reported that knock-in mice harboring the human R213G SNP (R213G mice) exhibited enhanced resolution of inflammation with subsequent protection against fibrosis following bleomycin treatment compared with wild-type (WT) littermates. Herein we set out to determine the underlying pathways with RNA-Seq analysis of WT and R213G lungs 7 days post-PBS and bleomycin. RNA-Seq analysis uncovered significant differential gene expression changes induced in WT and R213G strains in response to bleomycin. Ingenuity Pathways Analysis was used to predict differentially regulated up- and downstream processes based on transcriptional changes. Most prominent was the induction of inflammatory and immune responses in WT mice, which were suppressed in the R213G mice. Specifically, PKC signaling in T lymphocytes, IL-6, and NFΚB signaling were opposed in WT mice when compared with R213G. Several upstream regulators such as IFNγ, IRF3, and IKBKG were implicated in the divergent responses between WT and R213G mice. Our data suggest that the redistributed EC-SOD due to the R213G SNP attenuates the dysregulated inflammatory responses observed in WT mice. We speculate that redistributed EC-SOD protects against dysregulated alveolar inflammation via reprogramming of recruited immune cells toward a proresolving state.
Involvement of the IL23/Th17 Pathway in the Pathogenesis of Tunisian Pemphigus Foliaceus
Authors: Ben Jmaa M. , Abida O. , Fakhfakh R. , Bahloul E. , Sellami Kh. , Gaddour L. , Elloumi N. , Ben Ayed M. , Masmoudi A. , Dhouib M. , Abdelmoula M. , Mahfoudh N. , Makni H. , Turki H. , Masmoudi H.
Published: July 2018

Pemphigus foliaceus (PF) is a rare autoimmune skin disease caused by anti-Dsg1 pathogenic autoantibodies. It is considered as a Th2-mediated disease. Likewise, Th17 cells were recently described in the pathogenesis of the disease but their role is still unclear. We aimed to unravel the eventual implication of the IL23/Th17 pathway in the development of PF. A case-control study was conducted on 115 PF patients and 201 healthy controls using PCR-RFLP and AS-PCR methods. SNPs inIL23R,RORγt,IL17A,IL17F,IL17AR,TNFa, andSTAT3genes were genotyped. mRNA expression ofIL23RandRORγtwas evaluated using Q-PCR. The frequency of circulating Th17 cells was analyzed by flow cytometry. Genetic associations betweenIL23R>rs11209026,IL17A>rs3748067,IL17F>rs763780, andTNFa>rs1800629 and the susceptibility to PF were reported. Moreover, we revealed a significant increased frequency of circulating CD4+IL17+cells as well as higher mRNA levels of RORγt and IL23R in PBMCs of patients. However, no significant increase of RORγt and IL23R mRNA expression was observed in lesional skin biopsies. In spite of the little size of specimens, our results provide converging arguments for the contribution of the IL23/Th17 pathway in the pathogenesis of PF.
Energy Efficiency Maximization of Dynamic CoMP‐JT Algorithm in Dense Small Cell Networks
Authors: Peng Xuefei , Li Jiandong , Xu Yifei
Published: July 2018

We firstly formulate the energy efficiency (EE) maximization problem of joint user association and power allocation considering minimum data rate requirement of small cell users (SUEs) and maximum transmit power constraint of small cell base stations (SBSs), which is NP‐hard. Then, we propose a dynamic coordinated multipoint joint transmission (CoMP‐JT) algorithm to improve EE. In the first phase, SUEs are associated with the SBSs close to them to reduce the loss of power by the proposed user association algorithm, where the associated SBSs of each small cell user (SUE) form a dynamic CoMP‐JT set. In the second phase, through the methods of fractional programming and successive convex approximation, we transform the EE maximization subproblem of power allocation for SBSs into a convex problem that can be solved by proposed power allocation optimization algorithm. Moreover, we show that the proposed solution has a much lower computational complexity than that of the optimal solution obtained by exhaustive search. Simulation results demonstrate that the proposed solution has a better performance.
Text Case-Based Reasoning Framework for Fault Diagnosis and Predication by Cloud Computing
Authors: Zhong Zhiwang , Xu Tianhua , Wang Feng , Tang Tao
Published: July 2018

In Discrete Event System, such as railway onboard system, overwhelming volume of textual data is recorded in the form of repair verbatim collected during the fault diagnosis process. Efficient text mining of such maintenance data plays an important role in discovering the best-practice repair knowledge from millions of repair verbatims, which help to conduct accurate fault diagnosis and predication. This paper presents a text case-based reasoning framework by cloud computing, which uses the diagnosis ontology for annotating fault features recorded in the repair verbatim. The extracted fault features are further reduced by rough set theory. Finally, the case retrieval is employed to search the best-practice repair actions for fixing faulty parts. By cloud computing, rough set-based attribute reduction and case retrieval are able to scale up the Big Data records and improve the efficiency of fault diagnosis and predication. The effectiveness of the proposed method is validated through a fault diagnosis of train onboard equipment.
Predictive Factors for Non-Sentinel Lymph Node Metastasis in Patients with ACOSOG Z0011 Criteria
Authors: Loza Carlos Martin , Mandó Pablo , Ponce Carolina , Coló Federico , Fabiano Veronica , Loza Jose , Costanzo Maria Victoria , Nervo Adrian , Nadal Jorge , Nuñez de Pierro Anibal , Chacon Reinaldo ,   RCM Database Contributors
Published: July 2018

Background: Nodal staging constitutes an element of great importance in the treatment planning for early breast cancer. The ACOSOG Z0011 trial demonstrated that sentinel lymph node (SLN) biopsy alone results in rates of local control, disease-free survival, and overall survival equivalent to those seen after axillary lymph node dissection. The purpose of this study was to determine the rate of patients that fulfill the ACOSOG Z0011 inclusion criteria and to define predictive factors for non-SLN positivity. Methods: A retrospective analysis of the breast surgery database of the Argentinian Society of Mastology was carried out. Patients were selected if they fulfilled the ACOSOG Z0011 inclusion criteria. The association of clinical and pathological factors with non-SLN positivity was evaluated in univariate and multivariate analysis. Results: Among 8,262 patients, 973 had positive SLN, and 348 satisfied the inclusion criteria. Histological grade (G3 vs. G1-2, odds ratio (OR) 1.81; p = 0.024), tumor size (T2 vs. T1, OR 2.39; p = 0.001), and age (>50 vs. <50 years, OR 1.95; p = 0.007) were associated with non-SLN positivity in multivariate analysis. Conclusion: Although the clinical relevance of our data is not established, older women with tumors bigger than 2 cm and/or high histological grade are at greater risk of having metastatic disease in the lymph nodes if axillary lymph node dissection is avoided. This subgroup of patients represents only 30% of the trial population.
Spectrum of Clinical, Neuroimaging, and Cerebrospinal Fluid Features of Adult Neurocutaneous Melanocytosis
Authors: Qian Min , Ren Haitao , Qu Tao , Lu Zhaohui , Zou Yueli , He Junying , Zhao Yanhuan , Chen Lin , Guan Hongzhi
Published: July 2018

Background: Neurocutaneous melanocytosis (NCM) is a poorly understood disease due to its rarity. This study aimed to summarize the characteristics of adult NCM and improve the awareness of this disease. Methods: The clinical data of 13 adult patients with NCM were retrospectively reviewed, including neuroimages, cerebrospinal fluid (CSF), and histological features. Results: There were 9 males and 4 females. The mean age at symptom onset was 36.5 years. The initial symptoms included intracranial hypertension in 8 patients and seizure in 4 patients. Ten patients had large and/or multiple congenital melanocytic nevi. MRI revealed hydrocephalus and diffuse thickening of the leptomeninges with T1 shortening in all patients. Post-contrast T1-weighted images showed diffuse linear enhancement of the leptomeninges. Lumbar punctures showed increased open pressure, and elevated protein levels and decreased glucose concentrations in CSF. Cells with intracytoplasmic coarse black granules were found in the CSF and were positive for S100, HMB45, and vimentin. Histopathology of the cutaneous lesions and meninges showed melanocytes but no evidence of malignant melanoma. Conclusion: Adult NCM patients present a diversity of clinical manifestations. Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing NCM. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases.
A Comprehensive Diagnostic Algorithm for Direct Antiglobulin Test-Negative Autoimmune Hemolytic Anemia Reveals the Relative Ratio of Three Mechanisms in a Single Laboratory
Authors: Kamesaki Toyomi , Kajii Eiji
Published: July 2018

Background: Direct antiglobulin test (DAT)-negative warm autoimmune hemolytic anemia (AIHA) is mainly caused by three mechanisms: red blood cell (RBC)-bound immunoglobulin (Ig)G below the detection limit of routine DAT; RBC-bound IgA or IgM; or low-affinity autoantibodies. Although most cases of DAT-negative AIHA are thought to be caused by RBC-bound IgG, and combinatory serological analyses are recommended, the relative ratios of each mechanism have not been clarified. Methods: Two groups of patients with undiagnosed hemolytic anemia and negative conventional tube method-DAT (TM-DAT) were investigated using anti-IgA and anti-IgM sera, or column agglutination method-DAT (CM-DAT), respectively, in addition to radioimmunological quantitation of RBC-bound IgG. Results: Three of 73 patients with DAT-negative AIHA showed positive RBC-bound IgA and normal amounts of RBC-bound IgG. Another group of 3 patients were RBC-bound IgM-positive, but only one of these showed normal amounts of RBC-bound IgG. In another group of patients with DAT-negative AIHA, 4 of the 20 showed positive CM-DAT and negative CM-DAT after washing RBCs. Three of these patients had normal amounts of RBC-bound IgG. Five patients with positive CM-DAT both before and after washing RBCs had high amounts of RBC-bound IgG. Conclusion: Relative ratios of patients with DAT-negative AIHA resulting from RBC-bound IgG, RBC-bound IgA, RBC-bound IgM, and low-affinity IgG were estimated as 80, 4, 1 and 15%, respectively. A new classification and diagnostic algorithm for DAT-negative AIHA were proposed.
Stärken der Graft-versus-Leukämie-Effekte durch richtig terminierte Photochemotherapie
Authors: Lehmann Percy
Published: July 2018

Background: Cure of acute leukemia after transplantation is mediated by the grafted cells. We investigated the graft-versus-leukemia effect (GVL) in patients with cutaneous acute graft-versus-host disease (GVHD) treated with photochemotherapy (psoralen and ultraviolet light type A). Method: Forty-seven patients with acute leukemia were followed 5,000 days after transplantation to assess survival and GVL by multivariate analysis. The primary predictor was time to treatment of cutaneous acute GVHD by photochemotherapy separated into treatment start during the first week of acute GVHD versus after the first week of acute GVHD. Results: Photochemotherapy started after the first week of acute GVHD predicted GVL with a hazard ratio (HR) of 3.94 (95% confidence interval, CI, 1.67-9.33, p = 0.0018) and survival with preserved GVL with an HR of 2.63 (95% CI 1.30-5.32, p = 0.007). The effects on GVL and survival with preserved GVL were present regardless of whether the patients were transplanted in remission or relapse (p < 0.05). Chronic GVHD came earlier in the group that started photochemotherapy after 1 week of acute GHVD, but chronic GVHD did not increase the GVL. Conclusion: The timing of photochemotherapy after cutaneous acute GVHD may direct the GVL and predict long-term leukemia-free survival.
Correlation between Anatomical Segments of the Pudendal Nerve and Clinical Findings of the Patient with Pudendal Neuralgia
Authors: Pereira Augusto , Pérez-Medina Tirso , Rodríguez-Tapia Ana , Chiverto Yoana , Lizarraga Santiago
Published: July 2018

Background: The objective was to describe clinical findings and outcomes of patients with pudendal neuralgia in relation with the anatomical segment affected. Methods: Fifty-one consecutive patients with chronic perineal pain (CPP) located in the areas supplied by the pudendal nerve (PN), from January 2011 to June 2012, were analyzed. Results: The distribution of pain at perineal, dorsal clitoris and inferior anal nerves was 92.2, 31.4 and 25.5% respectively. The duration of pain was longer when the dorsal clitoris nerve (DCN) was affected (p < 0,003). The pain in the pudendal canal was frequently associated with the radiation of pain to the inferior members (p < 0.043). Conclusion: CPP and radiation of pain to lower limbs suggest a disorder at the second segment of PN. A positive Tinel sign in the third segment indicates a nerve entrapment. In terminal branches, pain was more frequent at the perineal nerve and more persistent at the DCN.
Synergic Effects of CD40 and CD86 Silencing in Dendritic Cells on the Control of Allergic Diseases
Authors: Suzuki Motohiko , Yokota Makoto , Matsumoto Tamami , Ozaki Shinya
Published: July 2018

Background: We previously reported that siRNA-induced CD40-silenced dendritic cells (DCs) inhibit allergic responses and symptoms. However, more potent therapies are needed. To our knowledge, synergic effects of gene silencing in DCs by ≥2 siRNAs have not been reported to control allergic diseases. Therefore, we investigated the synergistic effects of the silencing of CD40 and CD86 in DCs on allergic responses. Methods: Mice were treated with CD40/CD86-silenced DCs, which were transfected with CD40/CD86 siRNAs and pulsed with ovalbumin (OVA) antigen. The effects of these DCs on allergic symptoms and allergic responses were estimated. Results: The administration of CD40/CD86-silenced OVA-pulsed DCs significantly inhibited the number of sneezes and nasal rubbing movements, the number of eosinophils in the nasal mucosa, and the level of OVA-specific IgE when compared with those for CD40- or CD86-silenced OVA-pulsed DCs alone (p < 0.01). These inhibitory effects were detected before sensitization as well as after the establishment of allergic rhinitis. CD40/CD86-silenced OVA-pulsed DCs did not inhibit KLH-induced allergies. Foxp3 gene expression was significantly upregulated in CD40-silenced DCs compared to in CD86-silenced DCs (p < 0.01). IL-4 production by T cells was suppressed more substantially when using CD86-silenced DCs than with CD40-silenced DCs (p < 0.01). Conclusions: These results indicate, for the first time, that siRNA-induced CD40/CD86-silenced antigen-specific DCs have greater inhibitory effects against allergic responses than those of CD40- or CD86-silenced antigen-specific DCs alone. This study also suggests that the synergic effects of gene silencing in DCs by ≥2 siRNAs are useful for the control of allergic diseases. Thus, owing to the synergistic effects, CD40 and CD86 silencing has the potential to substantially improve the treatment of allergic diseases.
Behandlung der multiplen aktinischen Keratose und Feldkanzerisierung mit topischem Piroxicam 0,8% und Sonnenschutz (LSF 50+) bei Organtransplantat-Empfängern: Eine Serie von 10 Fällen
Authors: Garofalo Virginia , Ventura Alessandra , Mazzilli Sara , Diluvio Laura , Bianchi Luca , Toti Luca , Tisone Giuseppe , Milani Massimo , Campione Elena
Published: July 2018

Empfänger von Organtransplantaten (organ transplant recipients, OTR) haben ein hohes Risiko, Hautkrebs wie z.B. ein Plattenepithelkarzinom und ein Basalzellkarzinom zu entwickeln. Die aktinische Keratose (AK) wird als Vorstufe dieser nicht-melanozytären Hautkrebsarten angesehen. Sonnenschutz ist für Patienten mit AK unerlässlich und eine wichtige vorbeugende Maßnahme bei Organtransplantat-Empfängern. Die Behandlung der Feldkanzerisierung ist außerdem entscheidend, um das Risiko für ein Rezidiv der Hautläsionen bei AK und bei Patienten mit nicht-melanozytärem Hautkrebs zu reduzieren. Bei der Pathogenese von Hautkrebserkrankungen spielt die Aktivierung von Cyclooxygenase-1- und -2-Enzymen eine wichtige Rolle. Die topische Anwendung von Cyclooxygenase-Inhibitoren wie Diclofenac und, seit Kurzem, Piroxicam hat sich bei der Verringerung der AK-Läsionen bei immunkompetenten Patienten als wirksam erwiesen. Es wurde gezeigt, dass ein Medizinprodukt, das Piroxicam und Sonnenschutz (LSF 50+) (P+SS) enthält, die AK-Läsionen reduziert und die Feldkanzerisierung verbessert. Wir berichten über den Effekt der Anwendung von P+SS über 16 Wochen in einer Fallserie mit 10 Patienten mit multiplen AK-Läsionen. Die Behandlung mit P+SS führte bei 7 Patienten zu einem klinisch relevanten Rückgang der AK-Läsionen (>75%) (mit vollständiger Abheilung bei 3 Patienten) und zu einer Besserung der Feldkanzerisierung: Dieses Medizinprodukt kann als Erfolg versprechende kurative und präventive Langzeittherapie bei OTR-Patienten mit hohem Risiko für nicht-melanozytären Hautkrebs angesehen werden. Übersetzung aus Case Rep Dermatol 2017;9:211-216 (DOI: 10.1159/000481770)
Antenatal Care of Preeclampsia: From the Inverted Pyramid to the Arrow Model?
Authors: Ghi Tullio , Dall’Asta Andrea , Valensise Herbert
Published: July 2018

The recent demonstration of the effectiveness of low-dose aspirin administered from the first trimester in the prevention of preeclampsia will probably lead to establishing and radicating the “inverted pyramid” screening model for preeclampsia. Such a multiparametric approach for the screening of preeclampsia in the first trimester, albeit highly sensitive in identifying early-onset disease, is poor at screening the forms of preeclampsia occurring close to term. Late-onset preeclampsia is 3 to 6 times more common than early-onset preeclampsia and currently represents the major determinant of maternal morbidity related to hypertensive disorders of the pregnancy. On this ground, we discuss our idea to construct a second “screening checkpoint” in the third trimester with the aim of reassessing the risk of preeclampsia of those women who screened negative in the first trimester. If implemented, the sequential screening model we propose would convert the “inverted pyramid model” into an “arrow model” for the antenatal care of preeclampsia.
Total Dorsal Pancreatectomy, an Alternative to Total Pancreatectomy: Report of a New Case and Literature Review
Authors: Conci Simone , Ruzzenente Andrea , Bertuzzo Francesca , Campagnaro Tommaso , Guglielmi Alfredo , Iacono Calogero
Published: July 2018

Background: Total dorsal pancreatectomy (TDP) is a conservative pancreatic resection that should be considered in cases of benign or low malignant tumors confined to the dorsal pancreas to preserve the viability of both digestive and biliary tracts, and to avoid the endocrine and metabolic consequences of total pancreatectomy. We report a new case of TDP and provide a literature review of this procedure. Methods: The case reported was a 35-year-old female patient with a solid pseudopapillary tumor. We resected the dorsal segment of the pancreas while preserving the common bile duct, gastroduodenal artery, and pancreaticoduodenal arcades, and the spleen and splenic vessels. The MEDLINE® and Embase® databases were searched for English language studies, case series, or case reports published through August 31, 2017. Results: The postoperative course was uneventful and patient was discharged on postoperative day 11. The patient was alive and in good condition at the 10-year follow-up. To date in English literature, there are only 3 reported cases of TDP, and all cases were patients with intraductal papillary mucinous neoplasia and pancreas divisum. There was no postoperative mortality, and 2 grade B pancreatic fistulas healed 1 month postoperatively. Conclusions: TDP is a feasible and safe operation for benign or low grade malignant pancreatic tumors involving the dorsal pancreas, as an alternative to total pancreatectomy.
Gut-Liver Axis Links Portal Hypertension to Acute-on-Chronic Liver Failure
Authors: Trebicka Jonel , Reiberger Thomas , Laleman Wim
Published: July 2018

Acute-on-chronic liver failure (ACLF) is considered a distinct syndrome in patients with liver disease, with systemic inflammation playing a central role. Portal hypertension (PHT) is also aggravated by inflammation and may subsequently impact the course of ACLF. PHT is more than just an increase in portal pressure in the portal venous system; it aggravates the course of liver disease and, thus, also facilitates the development of acute decompensation and ACLF. A critical mechanistic link between PHT and ACLF might be the gut-liver axis, which is discussed in this review.
Different Developmental Pattern of Brain Activities in ADHD: A Study of Resting-State fMRI
Authors: Tang Chao , Wei Yuqing , Zhao Jiajia , Nie Jingxin
Published: July 2018

There are distinct symptoms for attention deficit hyperactivity disorder (ADHD) at different ages. To explore the developmental mechanism of ADHD from childhood to adolescence, patients from different age groups with ADHD drawn from a large dataset should be investigated. In this study, we hypothesized that there are significant differences in the developmental patterns of local and global brain activities between ADHD and typically developing (TD) individuals. Three voxel-based measurements and the functional connectivity (FC) of the brain networks were extracted from resting-state functional magnetic resonance imaging (fMRI) of both ADHD and TD participants 7–16 years of age. The topological properties of brain networks in both groups were also analyzed, including hubs, hemispheric symmetry, together with local and global efficiency. The results showed, from the local perspective, that the ADHD group had abnormal amplitude of low-frequency fluctuation, fractional amplitude of low-frequency fluctuation, and regional homogeneity in the medial orbital frontal cortex, anterior cingulate cortex, postcentral gyrus, thalamus, precuneus, and cerebellum compared with the TD group. From the global perspective, the aberrant FC between multiple networks, such as the default mode network (DMN), the attention network, and the executive control network, might directly contribute to symptom differences in childhood and adolescence in ADHD patients. Finally, from the developmental perspective, there was delayed maturation of brain networks in the ADHD group, especially in the DMN. Overall, we presented the differences in brain networks between the ADHD and TD group from multiple perspectives and demonstrated the developmental abnormality of brain networks in ADHD patients, contributing to the study of the etiology of ADHD.
Management of Diverticular Hemorrhage: Catching That Culprit Diverticulum Red-Handed!
Authors: Mizuki Akira , Tatemichi Masayuki , Nagata Hiroshi
Published: July 2018

Background/Summary: Acute colonic diverticular hemorrhage (CDH) represents a significant challenge for gastroenterologists. There are some clinical problems in the diagnosis, treatment, and prevention of CDH. CDH is the most common cause of overt lower gastrointestinal bleeding in adults in Eastern and Western countries. Moreover, CDH imposes significant economic and clinical burdens on the health care system. Colonoscopy is recommended as a useful diagnostic tool for CDH after bowel preparation. Colonoscopy can be used to identify the culprit diverticulum and to provide endoscopic therapy. In most cases, however, the bleeding stops spontaneously. For this reason, it is still controversial whether urgent colonoscopy or elective colonoscopy is “preferable.” Key Messages: This review aims to highlight the various clinical problems (purge, timing of colonoscopy, CT angiography, and endoscopy) encountered in the attempt to identify and treat the culprit diverticulum red-handed.
Anterior Segment Optical Coherence Tomography of Ocular Cystinosis Confirmed by Electron Microscopy
Authors: Golla Abhinav , Weikert Mitchell P. , Chevez-Barrios Patricia , Al-Mohtaseb Zaina
Published: July 2018

Purpose: To report a case of ocular cystinosis diagnosed by anterior segment optical coherence tomography (AS-OCT) and histopathology. Methods: A 67-year-old man who presented with eye pain was found to have unilateral corneal crystal deposition. Ocular cystinosis was diagnosed by histopathology, AS-OCT, and lack of renal involvement of the disease. Results: AS-OCT showed hyperreflective densities in the corneal epithelium. The patient underwent superficial keratectomy given irregular astigmatism prior to cataract surgery. Electron microscopy of the corneal scrapings revealed epithelial cells with intracystoplasmic membrane-bound crystals confirming the diagnosis of cystinosis. Conclusion: To our knowledge, this is the first reported case of ocular cystinosis involving strictly the epithelial layer of the cornea that has been imaged by AS-OCT.
Ranibizumab and Bevacizumab but Not Aflibercept Inhibit Proliferation of Primary Human Retinal Pigment Epithelium in vitro
Authors: Parisi Lorenzo , Fuhrer Reto , Zinkernagel Martin , Enzmann Volker
Published: July 2018

Aim: Treatment of exudative age-related macular degeneration by using vascular endothelial growth factor (VEGF) antagonists is the gold standard today. So far, several bioactive molecules have been approved for therapeutic use. In this study, we investigate the effects of ranibizumab (Lucentis®), bevacizumab (Avastin®), and aflibercept (Eylea®) on primary human retinal pigment epithelial (hRPE) cells in vitro. Methods: hRPE cells were prepared from donor eyes and cultured under standard culture conditions. Scleral fibroblasts also prepared from donor tissue served as physiological controls. The impact of the anti-VEGF molecules on cell viability was investigated with the trypan blue exclusion assay, whereas proliferation was measured using the MTT assay. Biological activity of the molecules was quantified in a VEGF-enzyme-linked immunosorbent assay (ELISA). Results: All tested substances were biologically active in vitro. They displayed no cytotoxicity on RPE cells or scleral fibroblasts. However, proliferation of RPE cells was significantly decreased after treatment with ranibizumab or bevacizumab but not with aflibercept. Conclusions: The humanized antibodies (fragments) interfered specifically with the RPE cells. The thereby measured inhibition of cell proliferation may indicate possible side effects on the physiology of RPE cells.
Methodological Recommendations for Trials of Psychological Interventions
Authors: Guidi Jenny , Brakemeier Eva-Lotta , Bockting Claudi L.H. , Cosci Fiammetta , Cuijpers Pim , Jarrett Robin B. , Linden Michael , Marks Isaac , Peretti Charles S. , Rafanelli Chiara , Rief Winfried , Schneider Silvia , Schnyder Ulrich , Sensky Tom , Tomba Elena , Vazquez Carmelo , Vieta Eduard , Zipfel Stephan , Wright Jesse H. , Fava Giovanni A.
Published: July 2018

Recent years have seen major developments in psychotherapy research that suggest the need to address critical methodological issues. These recommendations, developed by an international group of researchers, do not replace those for randomized controlled trials, but rather supplement strategies that need to be taken into account when considering psychological treatments. The limitations of traditional taxonomy and assessment methods are outlined, with suggestions for consideration of staging methods. Active psychotherapy control groups are recommended, and adaptive and dismantling study designs offer important opportunities. The treatments that are used, and particularly their specific ingredients, need to be described in detail for both the experimental and the control groups. Assessment should be performed blind before and after treatment and at long-term follow-up. A combination of observer- and self-rated measures is recommended. Side effects of psychotherapy should be evaluated using appropriate methods. Finally, the number of participants who deteriorate after treatment should be noted according to the methods that were used to define response or remission.
Favorable Response to Treatment with Avelumab in an HIV-Positive Patient with Advanced Merkel Cell Carcinoma Previously Refractory to Chemotherapy
Authors: Al Homsi Mohammed U. , Mostafa Mai , Fahim Khaled
Published: July 2018

Avelumab is indicated for the management of Merkel cell carcinoma, a rare and aggressive neuroendocrine skin cancer. Its regulatory approval followed the positive outcome of a Phase 2 trial on 88 patients with stage IV disease, which excluded patients with immunodeficiency due to HIV, a risk factor for this cancer type. We report a positive and sustained response to avelumab in an HIV-positive patient with stage IV Merkel cell carcinoma refractory to previous chemotherapy (cisplatin/etoposide) and radiotherapy. Five cycles of avelumab 10 mg/m2 resulted in the resolution of tumor activity visualized using PET-CT scanning in all affected lymph nodes. The only major side effect associated with avelumab was thyroiditis and mild hypothyroidism, a known adverse effect of this treatment, which was well controlled by L-thyroxine treatment. Treatment is ongoing and the positive response has been sustained during 5 further cycles of treatment up to date. This apparently durable response is consistent with the earlier clinical trial experience with avelumab, but seen here in a patient with HIV-associated immunodeficiency as a predisposing factor (an exclusion criterion from the previous trial). Further clinical trials with avelumab in a broader patient population with Merkel cell carcinoma are warranted.
Proline-Rich Protein 11 Regulates Self-Renewal and Tumorigenicity of Gastric Cancer Stem Cells
Authors: Hu Hongtao , Song Zongchang , Yao Quanjun , Geng Xiang , Jiang Li , Guo Chenyang , Li Hailiang
Published: July 2018

Background/Aims: Gastric cancer is a highly aggressive tumor containing cancer stem cells (CSCs), which participate in tumor initiation, therapeutic resistance, and tumor relapse. Proline-rich protein 11 (PRR11) has been shown to be up-regulated in human cancers; however, its role in gastric CSCs is unknown. We hypothesize that PRR11 may affect tumorigenicity of gastric CSCs. In this study, we explored the biological function and regulation of PRR11 in gastric CSCs. Methods: Expression of PRR11 was evaluated in gastric CSC cell line by real-time quantitative PCR and western blot. The effect of PRR11 on tumorigenicity was examined by interference with gene expression using lentiviral vector-loaded shRNA. A xenograft tumor model using NOD/SCID mice was established to examine the role of PRR11 in tumor development. Results: Data showed that PRR11 was highly expressed in gastric CSCs. PRR11 was responsible for the maintenance of self-renewal and tumorigenicity of gastric CSCs, and overexpression of exogenous PRR11 could restore the self-renewal of gastric non-CSCs. Furthermore, interference with PRR11 altered the expression of stemness transcription factors. Interestingly, MAPK signaling controlled PRR11 expression by increasing PRR11 protein stability, and maintained gastric CSCs self-renewal in a PRR11 dependent manner. Conclusions: PRR11 regulated self-renewal and tumorigenicity of gastric CSCs through MAPK signaling, and could be used as a therapeutic target for gastric cancer.
A Rationale for Timing of Luteal Support Post Gonadotropin-Releasing Hormone Agonist Trigger
Authors: Kol Shahar
Published: July 2018

Gonadotropin-releasing hormone (GnRH) antagonist-based ovarian stimulation protocol is gaining popularity. This protocol allows for the use of GnRH agonist as a trigger of final oocyte maturation, instead of the “gold standard” human chorionic gonadotropin (hCG) trigger. GnRH agonist trigger causes quick luteolysis, hence its widespread use in the context of ovarian hyperstimulation syndrome (OHSS) prevention. To secure pregnancy post GnRH agonist trigger, the luteal phase must be supplemented to counteract the luteolysis. Several luteal phase protocols post GnRH agonist trigger have been suggested, most notably based on increasing luteal luteinizing hormone (LH) activity (by adding LH or hCG). The current review aims at delineating a rationale for timing luteal support with a single hCG bolus post GnRH agonist trigger. The review also suggests a set of simple rules that must be followed when designing luteal phase support post GnRH agonist trigger.
Delayed Graft Function: The AKI of Kidney Transplantation
Authors: Mannon Roslyn B.
Published: July 2018

With the growing wait list of individuals waiting for kidney transplantation, there has been renewed interest in the quality and function of donor organs. In particular, concern about the development of delayed allograft function (DGF) after transplantation continues to lead to the avoidance of donor organs offered to a transplant center. DGF is associated with worse short-and long-term outcomes and associated with higher rejection rates. There are no FDA-approved therapies to mitigate the ischemic injury that occurs. Risk factors include both donor and recipient characteristics, although their prediction is not precise. With new understanding about mechanisms of injury and new focus on the function of the deceased donor, there is opportunity to identify not only novel therapies to improve allograft function but to identify potential biomarkers of DGF. DGF remains a significant factor in impacting kidney transplant outcome, and finding biomarkers will assist in the development and approval of novel agents to ameliorate early and later injury. This mini-review highlights our presentation at the 23rd International Conference on Advances in Critical Care Nephrology and UAB/UCSD O’Brien Center Acute Kidney Injury (AKI) Pre-Meeting.
Apocynin Attenuates Cobalt Chloride-Induced Pheochromocytoma Cell Apoptosis by Inhibiting P38-MAPK/Caspase-3 Pathway
Authors: Liu Jie  , Zhu Yuzhang , Chen Shipiao , Shen Bin , Yu Fang , Zhang Yi , Shen Ruilin
Published: July 2018

Background/Aims: Apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been identified as a potential neuroprotectant. In this study, we aimed to investigate the protective effect of apocynin against cobalt chloride (CoCl2)-induced pheochromocytoma (PC12) cell apoptosis. Methods: The PC12 cell culture was pretreated with apocynin and/or SB203580 (p38 mitogen-activated protein kinase [p38-MAPK] inhibitor) at different time points prior to CoCl2 incubation. The cell viability, apoptosis rate, DAN damage, and antioxidant activity were detected using cell counting kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA), and comet assay respectively. The protein and mRNA expressions of p38-MAPK and caspase-3 in the cells were measured by qRT-PCR and Western blotting. Results: Apocynin inhibited CoCl2-mediated apoptosis, reduced oxidative stress, and down-regulated the expression of p38-MAPK and caspase-3. Conclusions: Our findings show that apocynin attenuated CoCl2-induced apoptosis by potently restraining p38-MAPK-caspase-3 signaling pathway in PC12 cells, suggesting that apocynin may be a potent prophylactic reagent against CoCl2-mediated PC12 cell apoptosis.
Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells
Authors: Gu Qingguo , Tian Haijun , Zhang Kai , Chen Deyu , Chen Dechun , Wang Xinwei , Zhao Jie
Published: July 2018

Background/Aims: Mechanical stimulation and WNT signalling have essential roles in regulating the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone formation. However, little is known regarding the regulation of WNT signalling molecule expression and therefore the osteogenic differentiation of BMSCs during osteogenesis. Methods: Microarrays of BMSCs from elderly individuals or patients with osteoporosis (GSE35959) from the GEO database were analysed using GeneSight-Lite 4.1.6 (BioDiscovery) and C2 curated gene sets downloaded from Molecular Signatures Database (MSigDB). Realtime PCR and western blotting were used to measure the expression of the indicated genes. ALP and Alizarin red staining were used to evaluate the osteogenesis of BMSCs. Results: In this study, we investigated whether mechanical loading directly regulates the expression of WNT signalling molecules and examined the role of WNT signalling in mechanical loading-triggered osteogenic differentiation and bone formation. We first studied the microarrays of samples from patients with osteoporosis and found downregulation of the GPCR ligand binding gene set in the BMSCs of patients with osteoporosis. Then, we demonstrated that mechanical stimuli can regulate osteogenesis and bone formation both in vivo and in vitro. FZD4 was upregulated during cyclic mechanical stretch (CMS)-induced osteogenic differentiation, and the JNK signalling pathway was activated. FZD4 knockdown inhibited the mechanical stimuli-induced osteogenesis and JNK activity. More importantly, we found an activating effect of WNT5A and FZD4 that regulated bone formation in response to hindlimb unloading in mice, and pretreatment with WNT5A or activation of the expression of FZD4 partly rescued the osteoporosis caused by mechanical unloading. Conclusions: Our results demonstrate, for the first time, that mechanical stimulation alters the expression of genes involved in the osteogenic differentiation of BMSCs via the direct regulation of FZD4 and that therapeutic WNT5A and FZD saRNA may be an efficient strategy for enhancing bone formation under mechanical stimulation.
Heat-Induced Epithelial Barrier Dysfunction Occurs via C-Src Kinase and P120ctn Expression Regulation in the Lungs
Authors: Li Jie , Ren Xiaohu , Wang Lingwei , Yu Xiu , Khan Khalid , Feng Mengjie , He Qi , Luo Huanmin , Qiu Chen
Published: July 2018

Background/Aims: Thermal injury causes pulmonary edema and can lead to death. Intercellular junctions are composed of adhesive (p120ctn, E-cadherin, α-catenin and β-catenin) and compact (occludin and ZO-1) junctions. Heat deteriorates intercellular junctions and increases cell gaps to ultimately induce pulmonary edema, but the underlying mechanism remains elusive. Methods: Mouse lung epithelial (MLE-12) cells pre-treated with the c-Src inhibitor PP2, p120ctn catenin (p120ctn) small interfering RNA and p120ctn catenin (p120ctn) complementary DNA were subjected to heat treatment. Western blotting and real-time polymerase chain reaction assays were used to evaluate junction protein expression changes after heat treatment, and co-immunoprecipitation was used to test the binding state of junction proteins. In addition, hematoxylin and eosin staining and immunohistochemistry were used to evaluate changes in junction protein expression and lung injury in a Wistar rat model of thermal inhalation injury. Results: Heat increased cell permeability; induced ZO-1, occludin, α-catenin and β-catenin degradation; and decreased E-cadherin distribution in cell membranes. Heat also activated c-Src and decreased both p120ctn expression levels and occludin and ZO-1 association. c-Src inhibitor (PP2) treatment and p120ctn overexpression reversed these effects and attenuated lung injury in vivo. Conclusion: Heat induces junction protein degradation and dissociation to increase membrane permeability and cause lung edema via c-Src kinase activation and p120ctn expression downregulation.
Imatinib Ameliorated Retinal Neovascularization by Suppressing PDGFR-α and PDGFR-β
Authors: Zhou Lingli , Sun Xiaowei , Huang Zijing , Zhou Tian , Zhu Xiaowei , Liu Yan , Wang Jing , Cheng Bing , Li Mei , He Chang , Liu Xialin
Published: July 2018

Background/Aims: Platelet-derived growth factors (PDGFs) have emerged as pivotal in pathological angiogenesis, which is a hallmark of various tumors and retinal diseases. Here we evaluated the anti-angiogenic effect of imatinib, an inhibitor of PDGF receptors α and β (PDGFR-α and -β), in retinal neovascularization using an oxygen-induced retinopathy (OIR) model. Methods: The OIR model was established and given imatinib or vehicle treatments daily from P12 to P16. At the peak of angiogenesis at P17, the neovascularization area was quantified on retinal whole-mounts with isolectin B4 staining. Immunofluorescence staining and western blots were used to determine the effect of imatinib on different vascular cells and the pathway molecules involved. Results: Imatinib effectively suppressed pathological angiogenesis in OIR mice and reduced the number of all three types of vascular cells, including endothelial cells, pericytes, and smooth muscle cells. Moreover, the expression and activation of PDGFR-α and -β were inhibited by imatinib. The imatinib-treated OIR mice presented with reduced expression of other potent pro-angiogenic factors such as VEGF and FGF2. No obvious retinal or systemic side effects were observed in the imatinib treatment group. Conclusions: Imatinib appears to be safe and effective in suppressing retinal neovascularization. Targeting PDGFs/PDGFRs may also be important for anti-angiogenic treatment and offer a viable alternative treatment for retinal angiogenic diseases.
ZFX Promotes Proliferation and Metastasis of Pancreatic Cancer Cells via the MAPK Pathway
Authors: Song Xiaoling , Zhu Minghui , Zhang Fahong , Zhang Fei , Zhang Yijian , Hu Yunping , Jiang Lin , Hao Yajuan , Chen Shili , Zhu Qin , Huang Wen , Lu Jianhua , Gu Jun , Gong Wei , Li Maolan , Liu Yingbin
Published: July 2018

Background/Aims: The role of ZFX in tumourigenesis is unclear. We aimed to study ZFX expression, regulation, and function and the clinical implications of this protein in human pancreatic cancer (PCa). Methods: One hundred and twenty patients with histologically confirmed PCa who underwent surgery were recruited for this study. Tumour samples and PCa cell lines were used to examine ZFX. Various cell functions related to tumourigenesis were assessed. In vivo mouse tumour xenografts were used to confirm the in vitro results. Results: Patients with ZFX-positive tumours had worse overall survival than patients with ZFX-negative tumours. The depletion of ZFX using lentiviral shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in G0/G1 phase and resulted in increased cell apoptosis and invasive repression. In vivo studies confirmed that ZFX promoted tumour growth. Mechanistically, MAPK pathway activation was involved in the oncogenic functions of ZFX. Conclusions: ZFX acts as a putative oncogene in PCa and could be a novel therapeutic target for this disease.
Vaccinations in Adult Patients with Inflammatory Bowel Diseases in the West
Authors: Kochar Bharati , Herfarth Hans H.
Published: July 2018

Background: Patients with moderate-severe inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis are commonly treated with long-term immunosuppressive therapies involving immunomodulators such as thiopurines, biologics (anti-TNF and anti-adhesion molecules), or novel small molecules such as Janus kinase inhibitors. Summary: Some infections seen with immunosuppressive therapy in IBD are preventable with vaccines. IBD-specific immunosuppressive therapy is generally initiated by gastroenterologists. Therefore, gastroenterologists should comprehend the appropriate application of vaccines such as hepatitis B, pneumonia, and herpes zoster vaccinations. This review summarizes the current guidance for vaccinations of IBD patients in the United States. Key Message: Gastroenterologists treating IBD patients must be aware of necessary vaccination schedules in the setting of immunosuppressive therapies.
Semiótica psicanalítica para crianças de 0-99 anos-luz
Authors: Cesarotto Oscar
Published: July 2018

Entrevista com Oscar Cesarotto
Emojis na publicidade e seus significados para marcas e consumidores: tipologias e questionamentos
Authors: Pompeu Bruno , Sato Silvio Koiti
Published: July 2018

Este artigo reflete sobre o uso dos emojis, destacando a apropriação desses códigos na comunicação das marcas. Identificamos que os emojis são utilizados na publicidade de diferentes maneiras, com significados negociados de forma multidirecional, e com a crescente participação e colaboração do público. Assim, propomos uma tipologia para o entendimento do fenômeno, com uma classificação de usos de emojis na publicidade que tem como base a semiótica peirceana e que distingue as estratégias possíveis identificadas.
O tempo e o espaço na vida cotidiana: reflexões a partir do filme O terminal
Authors: Gomes Luciana Buksztejn , Cidade Daniela Firmino
Published: July 2018

Neste artigo, nos propomos a realizar uma releitura do filme O terminal (The terminal, Steven Spielberg, 2004), destacando pontos que o aproximam às discussões acerca do tempo, espaço, lugar e não-lugar, por meio das lentes de alguns autores. Vemos o filme a partir da concepção de forasteiro, isto é, daquele que é estrangeiro em um determinado tempo e espaço. Com isso, buscamos trazer à tona aspectos que nos proporcionem pensar o cotidiano a partir dessas dimensões.
Benefit of Prolonged Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stent for Coronary Bifurcation Lesions
Authors: Jang Woo Jin , Ahn Sung Gyun , Song Young Bin , Choi Seung-Hyuk , Chun Woo Jung , Oh Ju Hyeon , Cho Sung Woo , Kim Bum Sung , Yoon Jung Han , Koo Bon-Kwon , Yu Cheol Woong , Jang Yang Soo , Tahk Seung-Jea , Kim Hyo-Soo , Gwon Hyeon-Cheol , Lee Sung Yun , Hahn Joo-Yong
Published: July 2018

Background:

Whether prolonged dual antiplatelet therapy (DAPT) improves clinical outcomes after percutaneous coronary intervention for coronary bifurcation lesion is uncertain.

Methods and Results:

We evaluated 2082 patients who were treated with drug-eluting stent for bifurcation lesions and were event free (no death, myocardial infarction [MI], cerebrovascular accident, stent thrombosis, or any revascularization) at 12 months after the index procedure. Patients were divided into 2 groups: DAPT ≥12-month group (n=1776) and DAPT <12-month group (n=306). Primary outcome was all-cause death or MI. At 4 years after the index procedure, death or MI occurred less frequently in the DAPT ≥12-month group than the DAPT <12-month group (2.8% versus 12.3%; adjusted hazard ratio, 0.21; 95% confidence interval, 0.13–0.35;
P
<0.001). After propensity score matching, incidence of death or MI was still lower in the DAPT ≥12-month group than the DAPT <12-month group (2.6% versus 12.3%; adjusted hazard ratio, 0.22; 95% confidence interval, 0.12–0.38;
P
<0.001). In subgroup analysis, the treatment effect of prolonged DAPT was consistent across subgroups regardless of lesion location, stenting technique, or type of used drug-eluting stent.

Conclusions:

The risk of all-cause death or MI was significantly lower in the ≥12-month DAPT group than the <12-month DAPT group after percutaneous coronary intervention for bifurcation lesion using drug-eluting stent. Our results suggest that prolonged DAPT may improve long-term clinical outcomes after percutaneous coronary intervention for bifurcation lesions.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01642992