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  • Elsevier  (1,429,648)
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  • 1
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/3
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 605 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 2
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/1
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 585 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 3
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/2
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 577 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 4
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Biochimica et Biophysica Acta (BBA) - General Subjects Author(s): Paolo Ruzza, Rosa Maria Vitale, Rohanah Hussain, Alessia Montini, Claudia Honisch, Alice Pozzebon, Charlotte S. Hughes, Barbara Biondi, Pietro Amodeo, GianPietro Sechi, Giuliano Siligardi Background Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a β-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein and α-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. Methods Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. Results We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. Conclusions Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance These results, in addition to our previous studies on α-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis. Graphical abstract
    Print ISSN: 0304-4165
    Electronic ISSN: 1872-8006
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 5
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part B Author(s): Claudio Pinto, Debora Maria Giordano, Luca Maroni, Marco Marzioni Cholangiocytes, the epithelial cells lining the bile ducts, are an important subset of liver cells. They are involved in the modification of bile volume and composition, and respond to endogenous and exogenous stimuli. Along the biliary tree, two different kinds of cholangiocytes exist: small and large cholangiocytes. Each type has different features and biological role in physiologic and pathologic conditions, and their immunobiology is important for understanding biliary diseases. Cholangiocytes provide the first line of defence against luminal microbes in the hepatobiliary system. Indeed, they express a variety of pattern recognition receptors and may start an antimicrobial defence activating a set of intracellular signalling cascades. In response to injury, cholangiocytes that are normally quiescent become reactive and acquire a neuroendocrine-like phenotype with the release of proinflammatory mediators and antimicrobial peptides, which support biliary epithelial integrity. These molecules act in an autocrine/paracrine manner to modulate cholangiocyte biology and determine the evolution of biliary damage. Failure or dysregulation of such mechanisms may influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. In this review, we focus on the response of cholangiocytes in inflammatory conditions, with a particular focus on the mechanism driving cholangiocytes adaptation to damage. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 6
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part B Author(s): Nikolaj Ørntoft, Kim Frisch, Peter Ott, Susanne Keiding, Michael Sørensen Positron emission tomography (PET) with 11 C-cholylsarcosine ( 11 C-CSar), a radiolabelled synthetic N -methylglycine (sarcosine) conjugate of cholic acid, is a novel molecular imaging technique that enables quantitative assessment of the individual transport steps involved in hepatic secretion of conjugated bile acids. Here, we present the method and discuss its potential clinical and scientific applications based on findings in the first human study of healthy subjects and patients with cholestasis. We also present a clinical example of a patient studied during and six months after an episode of drug-induced cholestatic liver injury.
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 7
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 4, Part B Author(s): Jose J.G. Marin, Elisa Lozano, Elisa Herraez, Maitane Asensio, Silvia Di Giacomo, Marta R. Romero, Oscar Briz, Maria A. Serrano, Thomas Efferth, Rocio I.R. Macias One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 8
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: European Journal of Cancer, Volume 93 Author(s): Antonin Levy, Corinne Faivre-Finn, Baktiar Hasan, Eleonora De Maio, Anna S. Berghoff, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, Mary O'Brien, Martin Reck, Anne-Marie C. Dingemans, Silvia Novello, Thierry Berghmans, Benjamin Besse, Lizza Hendriks Background Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials. Methods An EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field. Results A total of 462 European physician responses (394 institutions) were analysed (radiation oncologist: 53% [n = 247], pulmonologist: 26% [n = 119], medical oncologist: 18% [n = 84]; 84% with >5 years' experience in NSCLC). Italy (18%, n = 85), Netherlands (15%, n = 68), UK (14%, n = 66), and France (12%, n = 55) contributed most. 393 physicians (85%) screened neurologically asymptomatic patients for BM at diagnosis (52% using magnetic resonance imaging). Most often screened patients were those with a driver mutation (MUT+; 51%, n = 234), stage III (63%, n = 289), and IV (43%, n = 199). 158 physicians (34%) used a prognostic classification to guide initial treatment decisions, and in 50%, lowest prognostic-score threshold to receive treatment differed between MUT+ and non-driver mutation (MUT−) patients. MUT+ patients with >4 BM were more likely to receive stereotactic radiosurgery (SRS) compared with MUT− (27% versus. 21%; p 〈 0.01). Most physicians (90%) had access to SRS. After single BM surgery, 50% systematically prescribed SRS or WBRT, and 45% only in case of incomplete resection. The preferred treatment in neurologically asymptomatic treatment-naive patients diagnosed with >5 BM was systemic treatment (79%). Of all, 45%/49% physicians stated that all tyrosine kinase inhibitors and immune checkpoint blockers were discontinued (timing varied) during SRS/WBRT, respectively. Drugs most often continued during SRS/WBRT were erlotinib (44%/40%), gefitinib (39%/34%), afatinib (29%/25%), crizotinib (33%/26%) and anti-PD-(L)-1 (28%/22%). Conclusion BM management is highly variable in Europe: screening is not uniform, prognostic classifications are not often used and MUT+ NSCLC patients generally receive more intensive local treatment. Prospective assessment of BM management in MUT+ NSCLC patients is required.
    Print ISSN: 0959-8049
    Electronic ISSN: 1879-0852
    Topics: Medicine
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  • 9
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: European Journal of Cancer, Volume 93 Author(s): Tarec Christoffer El-Galaly, Chan Yoon Cheah, Mette Dahl Bendtsen, Grzegorz S. Nowakowski, Roopesh Kansara, Kerry J. Savage, Joseph M. Connors, Laurie H. Sehn, Neta Goldschmidt, Adir Shaulov, Umar Farooq, Brian K. Link, Andrés J.M. Ferreri, Teresa Calimeri, Caterina Cecchetti, Eldad J. Dann, Carrie A. Thompson, Tsofia Inbar, Matthew J. Maurer, Inger Lise Gade, Maja Bech Juul, Jakob W. Hansen, Staffan Holmberg, Thomas S. Larsen, Sabrina Cordua, N. George Mikhaeel, Martin Hutchings, John F. Seymour, Michael Roost Clausen, Daniel Smith, Stephen Opat, Michael Gilbertson, Gita Thanarajasingam, Diego Villa Purpose Secondary CNS involvement (SCNS) is a profoundly adverse complication of diffuse large B-cell lymphoma. Evidence from older series indicated a median overall survival (OS) 〈 6 months; however, data from the immunochemotherapy era are limited. Methods Patients diagnosed with SCNS during or after first-line immunochemotherapy were identified from databases and/or regional/national registries from three continents. Clinical information was retrospectively collected from medical records. Results In total, 291 patients with SCNS were included. SCNS occurred as part of first relapse in 254 (87%) patients and 113 (39%) had concurrent systemic relapse. With a median post-SCNS follow-up of 48 months, the median post-SCNS OS was 3.9 months and 2-year OS rate was 20% (95% CI: 15–25). In multivariable analysis of 173 patients treated with curative/intensive therapy (such as high-dose methotrexate [HDMTX] or platinum-containing regimens), age ≤60 years, performance status 0–1, absence of combined leptomeningeal and parenchymal involvement, and SCNS occurring after completion of first-line therapy were associated with superior outcomes. Patients ≤60 years with performance status 0–1 and treated with HDMTX-based regimens for isolated parenchymal SCNS had a 2-year OS of 62% (95% CI: 36–80). In patients with isolated SCNS, the addition of rituximab to HDMTX-based regimens was associated with improved OS. Amongst patients with isolated SCNS in CR following intensive treatment, high-dose chemotherapy and autologous stem cell transplantation did not improve OS (P = 0.9). Conclusions In this large international cohort of patients treated with first-line immunochemotherapy, outcomes following SCNS remain poor. However, a moderate proportion of patients with isolated SCNS who received intensive therapies achieved durable remissions.
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    Electronic ISSN: 1879-0852
    Topics: Medicine
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  • 10
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: European Journal of Cancer, Volume 92 Author(s): Phoebe Star, Annabel Goodwin, Rony Kapoor, R. Max Conway, Georgina V. Long, Richard A. Scolyer, Pascale Guitera The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.
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    Electronic ISSN: 1879-0852
    Topics: Medicine
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  • 11
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: European Journal of Cancer, Volume 92 Author(s): Takayuki Yoshino, Yanzhi Hsu, Federico Nasroulah
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    Electronic ISSN: 1879-0852
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  • 12
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: European Journal of Cancer, Volume 91 Author(s): Jacques Raphael, Danielle Desautels, Kathleen I. Pritchard, Ekaterina Petkova, Prakeshkumar S. Shah Phosphoinositide 3-kinase (PI3K) inhibitors may overcome drug resistance and improve advanced breast cancer (ABC) outcomes. We conducted a systematic review and meta-analysis to assess the efficacy and safety of adding a PI3K inhibitor to the standard of care (SOC) treatment in ABC. The electronic databases Ovid, PubMed, Cochrane Central Register of Controlled Trials and Embase, were searched for relevant randomised trials. Pooled hazard ratios (HRs) for progression-free survival (PFS) and pooled risk ratios (RRs) for objective response rates (ORRs), disease control rates (DCRs) and toxicity were meta-analysed using the Mantel–Haenszel method and generic inverse variance. Five studies were included. In unselected patients, the addition of a PI3K inhibitor decreased the risk of progression by 21% (2329 participants, HR = 0.79; 95% confidence interval [CI], 0.71–0.88). A marginal improvement in ORR (2329 participants, RR = 1.26; 95% CI, 1.01–1.57) and no improvement in DCR (2146 participants, RR = 1.05; 95% CI, 0.94–1.18) were achieved with a significant increase in toxicity of any grade (2386 participants, RR = 1.05; 95% CI, 1.03–1.06) and of grade III and higher (2386 participants, RR = 1.91; 95% CI, 1.76–2.08). A PFS benefit was seen in patients with and without PI3K pathway activation assessed on tumour and only in patients with an activated PI3K pathway when it was assessed from the plasma using circulating tumour DNA (ct-DNA) analysis. The addition of a PI3K inhibitor decreases the risk of progression in unselected ABC patients and particularly in patients with an activated PI3K pathway detected on ct-DNA analysis. However, their significant dose-limiting toxicity is a limiting factor. Selective PI3K inhibitors are being tested to assess whether these better-tolerated agents have a role in ABC treatment.
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    Electronic ISSN: 1879-0852
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  • 13
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: European Journal of Cancer, Volume 91 Author(s): Sandy Figiel, Michelle Pinault, Isabelle Domingo, Cyrille Guimaraes, Roseline Guibon, Pierre Besson, Elsa Tavernier, Pascal Blanchet, Luc Multigner, Franck Bruyère, Olivier Haillot, Romain Mathieu, Sebastien Vincendeau, Nathalie Rioux-Leclercq, Souhil Lebdai, Abdel-Rahmene Azzouzi, Marie-Aimee Perrouin-Verbe, Georges Fournier, Laurent Doucet, Jerome Rigaud, Karine Renaudin, Karine Mahéo, Gaëlle Fromont Background Genetic and nutritional factors have been linked to the risk of aggressive prostate cancer (PCa). The fatty acid (FA) composition of peri-prostatic adipose tissue (PPAT), which reflects the past FA intake, is potentially involved in PCa progression. We analysed the FA composition of PPAT, in correlation with the ethno-geographical origin of the patients and markers of tumour aggressiveness. Methods From a cohort of 1000 men treated for PCa by radical prostatectomy, FA composition of PPAT was analysed in 156 patients (106 Caucasians and 50 African–Caribbeans), 78 with an indolent tumour (ISUP group 1 + pT2 + PSA 〈10 ng/mL) and 78 with an aggressive tumour (ISUP group 4–5 + pT3). The effect of FA extracted from PPAT on in-vitro migration of PCa cells DU145 was studied in 72 patients, 36 Caucasians, and 36 African–Caribbeans. Results FA composition differed according to the ethno-geographical origin. Linoleic acid, an essential n-6 FA, was 2-fold higher in African–Caribbeans compared with Caucasian patients, regardless of disease aggressiveness. In African–Caribbeans, the FA profile associated with PCa aggressiveness was characterised by low level of linoleic acid along with high levels of saturates. In Caucasians, a weak and negative association was observed between eicosapentaenoic acid level (an n-3 FA) and disease aggressiveness. In-vitro migration of PCa cells using PPAT from African–Caribbean patients was associated with lower content of linoleic acid. Conclusion These results highlight an important ethno-geographical variation of PPAT, in both their FA content and association with tumour aggressiveness.
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  • 14
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: European Journal of Cancer, Volume 91 Author(s): Melanie White-Koning, Caroline Osborne, Angelo Paci, Alan V. Boddy, Etienne Chatelut, Gareth J. Veal Background To make systemic anti-cancer therapy (SACT) preparation more practicable, dose-banding approaches are currently being introduced in many clinical centres. The present study aimed to determine the potential impact of using recently developed National Health Service in England (NHSE) dose-banding tables in a paediatric setting. Methods Using pharmacokinetic parameters obtained from 385 drug administrations in 352 children aged from 1 month to 18 years, treated with five drugs (dactinomycin, busulfan, carboplatin, cyclophosphamide and etoposide), individual exposures (area under the plasma drug concentration versus time curve; AUC) obtained using doses rounded according to the published NHSE tables were calculated and compared with those obtained by standard dose calculation methods. Results For all five drugs, the relative variation between the NHSE dose and the recommended dose (RecDose) (standard individually calculated dose) was between −6% and +5% as expected. In terms of AUC, there was no statistically significant difference in precision between exposures obtained by the RecDose and those obtained with dose banding (absolute value of relative difference 15–34%). Conclusion Based on pharmacokinetic data for these five drugs, the results generated support the implementation of NHSE dose-banding tables. Indeed, inter-patient variability in drug clearance and exposure far outweighs the impact of relatively small drug dose changes associated with dose banding.
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  • 15
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Free Radical Biology and Medicine Author(s): M. Fructuoso, L. Rachdi, E. Philippe, R.G. Denis, C. Magnan, H. Le Stunff, N. Janel, M. Dierssen
    Print ISSN: 0891-5849
    Electronic ISSN: 1873-4596
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 16
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Free Radical Biology and Medicine Author(s): Hao Zhuang, Qiang Li, Xinran Zhang, Xuda Ma, Zun Wang, Yun Liu, Xianfu Yi, Ruibing Chen, Feng Han, Ning Zhang, Yongmei Li Metabolic reprogramming is a hallmark of cancer. Glycine decarboxylase (GLDC), an oxidoreductase, plays an important role in amino acid metabolism. While GLDC promotes tumor initiation and proliferation in non-small cell lung cancer and glioma and it was reported as a putative tumor suppressor gene in gastric cancer, the role of GLDC in hepatocellular carcinoma (HCC) is unknown. In the current study, microarray-based analysis suggested that GLDC expression was low in highly malignant HCC cell lines, and clinicopathological analysis revealed a decrease in GLDC in HCC tumor samples. While the knockdown of GLDC enhanced cancer cell migration and invasion, GLDC overexpression inhibited them. Mechanistic studies revealed that GLDC knockdown increased the levels of reactive oxygen species (ROS) and decreased the ratio of glutathione/oxidized glutathione (GSH/GSSG), which in turn dampened the ubiquitination of cofilin, a key regulator of actin polymerization. Consequently, the protein level of cofilin was elevated, which accounted for the increase in cell migration. The overexpression of GLDC reversed the phenotype. Treatment with N-acetyl-L-cysteine decreased the protein level of cofilin while treatment with H 2 O 2 increased it, further confirming the role of ROS in regulating cofilin degradation. In a tumor xenographic transplant nude mouse model, the knockdown of GLDC promoted intrahepatic metastasis of HCC while GLDC overexpression inhibited it. Our data indicate that GLDC downregulation decreases ROS-mediated ubiquitination of cofilin to enhance HCC progression and intrahepatic metastasis. Graphical abstract
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    Electronic ISSN: 1873-4596
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 17
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Yuval A. Patel, Arun J. Sanyal, Veronica Miller
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
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  • 18
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Maurizio Bifulco, Patrizia Gazzerro
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
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  • 19
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Gin-Ho Lo
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    Electronic ISSN: 1528-0012
    Topics: Medicine
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  • 20
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Heidi M. Staudacher, Kevin Whelan
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
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  • 21
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Gastroenterology
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    Electronic ISSN: 1528-0012
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  • 22
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Neil Rustgi, Stuti G. Shroff, Bryson W. Katona
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
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  • 23
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Rhonda F. Souza, Joel Rubenstein, John Kao, Ikuo Hirano
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
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  • 24
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gastroenterology Author(s): Eithan Gallan, Hilla Giladi, Chofit Chai
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
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  • 25
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Gastroenterology
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
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  • 26
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: Gastroenterology, Volume 154, Issue 4
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
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  • 27
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Gynecologic Oncology Author(s): Xiaogang Mao, Xiaomin Qin, Lin Li, Jinting Zhou, Min Zhou, Xianxian Li, Ying Xu, Liyun Yuan, Qiong-Na Liu, Hui Xing Long non-coding RNAs (lncRNAs), which have little or no protein-coding capacity, caught a particular interest since their potential roles in the cancer paradigm. As the most common cancer in women, cervical squamous cell carcinoma remains one of the leading causes of deaths from cancer. However, limited evidence is available to determine the role of lncRNAs in the prognosis of cervical squamous cell carcinoma. In this study, we collected lncRNA expression profiling to identify prognosis related lncRNAs for cervical squamous cell carcinoma from TCGA database. In addition, we developed a 15-lncRNA signature based risk score to comprehensively assess the prognostic function of lncRNA. Furthermore, we performed a ROC analysis to identify the optimal cut-off point for classification risk level of the patients. Univariate Cox regression models were used to assess the association between lncRNAs and prognosis of patients with cervical squamous cell carcinoma. A 15-lncRNA based risk score was developed based on the Cox co-efficient of the individual lncRNAs. The prognostic value of this risk score was validated in the complete set and internal testing set. In summary, a 15-lncRNA expression signature (BAIAP2-AS1, RP11-203J24.8, LINC01133, RP1-7G5.6, RP11-147L13.15, SERHL, CTC-537E7.3, RP11-440L14.1, RP11-131N11.4, ILF3-AS1, RP11-80H18.4, RP11-1096G20.5, CTD-2192J16.26, RP11-621L6.3, and RP11-571M6.18) were identified and validated which can predict cervical cancer patient survival. The potential functions of this 15-lncRNA expression signature and individual lncRNAs as prognostic targets of cervical cancer were revealed by this study. Furthermore, these findings may have important implications in the understanding of the potential therapeutic method for the cervical squamous cell carcinoma patients.
    Print ISSN: 0090-8258
    Electronic ISSN: 1095-6859
    Topics: Medicine
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  • 28
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: Heliyon, Volume 4, Issue 3 Author(s): Priya Kapoor, Philip Murphy Objectives To evaluate the effect of antibiotic combination therapy versus single therapy against cystic fibrosis strains of Pseudomonas aeruginosa identified as common and rare among patient groups in different Irish hospitals. Methods This study compares the susceptibility profiles of P. aeruginosa isolates from different cystic fibrosis (CF) clinics in Ireland, collected from 2004–2005. Strains were recovered in small numbers and typed by pulsed-field gel electrophoresis. Five common clonal variants were identified in five different hospitals, described as ‘common strains’. A number of ‘rare strains’ associated with any single patient were also included in the study. Certain virulence factors were determined and in vitro assays such as minimum inhibitory concentrations (MIC) and biofilm inhibitory concentrations (BIC) were employed to assess potential synergistic effects of antipseudomonal antibiotic combination therapy. Results There was no distinct virulence factors associated with clinical strains that were common in comparison to those that were rare. Antibiotic combination testing revealed the majority of combinations were similar to the activity of either antibiotic used as single agents. Tobramycin-ceftazidime was the most effective combination exhibiting synergistic interactions (FIC ≤ 0.5) against certain clinical isolates of P. aeruginosa . Conclusion The efficacy of single antibiotics and synergistic interactions of antibiotic combinations were strain specific, irrespective of virulence characteristics of P. aeruginosa . Common clonal P. aeruginosa strains do not have distinct characteristics that possibly influence persistence in the chronic CF lung. Tobramycin-ceftazidime may be successful for controlling specific P. aeruginosa strains. Further studies on representative isolates are needed to support these results.
    Electronic ISSN: 2405-8440
    Topics: Natural Sciences in General
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  • 29
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Human Immunology Author(s): Redondo-Pachón Dolores, Pérez-Sáez María José, Mir Marisa, Gimeno Javier, Llinás Laura, García Carmen, Hernández Juan José, Yélamos Jose, Pascual Julio, Crespo Marta Preformed HLA donor-specific antibodies (DSA) only detected with Luminex have been associated with increased risk of antibody-mediated rejection (ABMR) and graft failure after kidney transplantation (KT). Their evolution after KT may modify this risk. We analyzed postransplant evolution of preformed DSA identified retrospectively and their impact on outcomes of 370 KT performed 2006-2014. Antibodies were monitored prospectively at 1-3-5 years after KT and if any dysfunction. Early acute ABMR was more frequent among patients with preformed DSA class-I or I+II than isolated class-II (29.4% vs 4.5%,p=0.02). One year post-KT, 20 of 34 patients with functioning KT had persistent DSA. Preformed DSA class-II persisted more frequently than class-I/I+II (66.7% vs. 33.3%; p=0.031). The only risk factor independently associated with persistence was pretransplant MFI. Patients with de novo DSA had the highest risk of ABMR (HR 22.2 [CI 6.1-81.2]). Although recipients with persisting preformed DSA had significantly increased ABMR risk (HR 14.7 [CI 6.5-33.0], those with cleared preformed DSA also had a higher risk than those without DSA (HR 7.01 [CI 2.2-21.8]). Preformed DSA are a very important risk factor for ABMR and graft loss. Patients who clear preformed DSA still show an increased risk of ABMR and graft loss after KT.
    Print ISSN: 0198-8859
    Electronic ISSN: 1879-1166
    Topics: Medicine
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  • 30
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: The Lancet Oncology Author(s): Priya Venkatesan
    Print ISSN: 1470-2045
    Electronic ISSN: 1474-5488
    Topics: Medicine
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  • 31
    Publication Date: 2018-03-09
    Description: Publication date: Available online 6 March 2018 Source: Methods Author(s): Carlo Annunziatella, Andrea M. Chiariello, Andrea Esposito, Simona Bianco, Luca Fiorillo, Mario Nicodemi In recent years interest has grown on the applications of polymer physics to model chromatin folding in order to try to make sense of the complexity of experimental data emerging from new technologies such as Hi-C or GAM, in a principled way. Here we review the methods employed to efficiently implement Molecular Dynamics computer simulations of polymer models, focusing in particular on the String&Binders Switch (SBS) model. The constant improvement of such methods and computer power is returning increasingly more accurate insights on the structure and molecular mechanisms underlying the spatial organization of chromosomes in the cell nucleus. We aim to provide an account of the state of the art of computational techniques employed in this type of investigations and to review recent applications of such methods to the description of real genomic loci, such as the Sox9 locus in mESC.
    Print ISSN: 1046-2023
    Topics: Biology , Medicine
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  • 32
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Molecular Cell Author(s): Philipp G. Maass, A. Rasim Barutcu, Catherine L. Weiner, John L. Rinn Imaging (fluorescence in situ hybridization [FISH]) and genome-wide chromosome conformation capture (Hi-C) are two major approaches to the study of higher-order genome organization in the nucleus. Intra-chromosomal and inter-chromosomal interactions (referred to as non-homologous chromosomal contacts [NHCCs]) have been observed by several FISH-based studies, but locus-specific NHCCs have not been detected by Hi-C. Due to crosslinking, neither of these approaches assesses spatiotemporal properties. Toward resolving the discrepancies between imaging and Hi-C, we sought to understand the spatiotemporal properties of NHCCs in living cells by CRISPR/Cas9 live-cell imaging (CLING). In mammalian cells, we find that NHCCs are stable and occur as frequently as intra-chromosomal interactions, but NHCCs occur at farther spatial distance that could explain their lack of detection in Hi-C. By revealing the spatiotemporal properties in living cells, our study provides fundamental insights into the biology of NHCCs. Graphical abstract Teaser Comparing time-lapse live-cell imaging, Maass et al. characterize the spatiotemporal properties of genomic contacts between non-homologous chromosomes. They determined that these contacts occur frequently in mammalian cells, remain stably associated over time, and occur at spatial distances that are not readily captured in genome-wide chromosome conformation capture (Hi-C).
    Print ISSN: 1097-2765
    Electronic ISSN: 1097-4164
    Topics: Biology , Medicine
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  • 33
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: Molecular Immunology, Volume 96 Author(s): Juehong Li, Yamin Li, Xiaochun Peng, Bin Li, Xiangwei Yuan, Yunsu chen Aseptic loosening due to wear particles is a serious challenge for orthopedic surgeons, sabotaging the long-term success of total joint arthroplasty. The existing treatments for aseptic loosening are still far from satisfactory, necessitating more aggressive drug exploration. Here, we examined the effect of emodin on titanium particle-induced osteolysis and further investigated its underlying mechanism in vivo and in vitro. Thirty-two C57BL/6 mice were randomly assigned into four groups: the Sham group (sham operation with vehicle injection), Vehicle group (titanium particle treatment with vehicle injections), Low group (titanium particle treatment with injections of 10 mg/kg/day emodin) and High group (titanium particle treatment with injections of 50 mg/kg/day emodin). Micro-CT scanning and histological analysis revealed that after emodin injections, the inflammatory response and bone destruction were markedly ameliorated. TRAP staining showed that osteoclast numbers were also dramatically reduced. Throughout the in vitro culture period, emodin significantly decreased the bone resorption area, number of osteoclasts and formation of F-actin rings. Mechanistic studies suggested that reduced NF-κB signaling might be mediating the inhibitory effects of emodin. Collectively, our findings suggest that emodin, a natural product extracted from Rheum palmatum , may be developed as a promising candidate for the treatment of wear particle-induced osteolysis and subsequent aseptic loosening.
    Print ISSN: 0161-5890
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  • 34
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: Molecular Immunology, Volume 96 Author(s): Wenshuai Liu, Haipeng Song, Quan Chen, Jianli Yu, Mo Xian, Rui Nian, Dongxiao Feng Nanobodies represent the next-generation antibody-derived biologics with significant advances over conventional antibodies. Several rapid and robust techniques for isolating highly specific nanobodies have been developed. Antigen specific nanobodies are selected from constructed nanobody libraries, which can be classified into 3 main types: immune library, naïve library, and semisynthetic/synthetic library. The immune library is the most widely used strategy for nanobody screening. Target specific nanobodies are highly enriched in immune libraries than in non-immune libraries; however, it is largely limited by the natural antigenicity of antigens. The naïve library is thus developed. Despite the lack of somatic maturation, protein engineering can be employed to significantly increase the affinities of selected binders. However, a substantial amount of blood samples collected from a large number of individual animals is a prerequisite to ensure the diversity of the naïve library. With this issue considered, the semisynthetic/synthetic library may be a promising path toward obtaining a limitless source of nanobodies against a variety of antigens without the need of animals. In this review, we summarize the state-of-the-art screening technologies with different libraries. The approaches presented here can further boost the diverse applications of nanobodies in biomedicine and biotechnology.
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  • 35
    Publication Date: 2018-03-09
    Description: Publication date: April 2018 Source: Molecular Immunology, Volume 96 Author(s): Linnea Thörnqvist, Mats Ohlin Inference of antibody gene repertoires using transcriptome data has emerged as an alternative approach to the complex process of sequencing of adaptive immune receptor germline gene loci. The diversity introduced during rearrangement of immunoglobulin heavy chain variable (IGHV), diversity, and joining genes has however been identified as potentially affecting inference specificity. In this study, we have addressed this issue by analysing the nucleotide composition of unmutated human immunoglobulin heavy chains-encoding transcripts, focusing on the 3ö most bases of 47 IGHV germline genes. Although transcripts derived from some of the germline genes predominately incorporated the germline encoded base even at position 320, the last base of most IGHV genes, transcripts originating in other genes presented other nucleotides to the same extent at this position. In transcripts derived from two of the germline genes , IGHV3-13*01 and IGHV4-30-2*01 , the predominating nucleotide ( G ) was in fact not that of the gene ( A ). Hence, we suggest that inference of IGHV genes should be limited to bases preceding nucleotide 320, as inference beyond this would jeopardize the specificity of the inference process. The different degree of incorporation of the final base of the IGHV gene directly influences the distribution of amino acids of the ascending strand of the third complementarity determining region of the heavy chain. Thereby it influences the nature of this specificity-determining part of the antibody population. In addition, we also present data that indicate the existence of a common so far un-recognized allelic variant of IGHV3-7 that carries an A318G difference in relation to IGHV3-7*02 . Graphical abstract
    Print ISSN: 0161-5890
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  • 36
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Molecular Immunology Author(s): Kelly R. Rhodes, Jordan J. Green Exciting developments in cancer nanomedicine include the engineering of nanocarriers to deliver drugs locally to tumors, increasing efficacy and reducing off-target toxicity associated with chemotherapies. Despite nanocarrier advances, metastatic cancer remains challenging to treat due to barriers that prevent nanoparticles from gaining access to remote, dispersed, and poorly vascularized metastatic tumors. Instead of relying on nanoparticles to directly destroy every tumor cell, immunotherapeutic approaches target immune cells to train them to recognize and destroy tumor cells, which, due to the amplification and specificity of an adaptive immune response, may be a more effective approach to treating metastatic cancer. One novel technology for cancer immunotherapy is the artificial antigen presenting cell (aAPC), a micro- or nanoparticle-based system that mimics an antigen presenting cell by presenting important signal proteins to T cells to activate them against cancer. Signal 1 molecules target the T cell receptor and facilitate antigen recognition by T cells, signal 2 molecules provide costimulation essential for T cell activation, and signal 3 consists of secreted cues that further stimulate T cells. Classic microscale aAPCs present signal 1 and 2 molecules on their surface, and biodegradable polymeric aAPCs offer the additional capability of releasing signal 3 cytokines and costimulatory molecules that modulate the T cell response. Although particles of approximately 5–10 μm in diameter may be considered the optimal size of an aAPC for ex vivo cellular expansion, nanoscale aAPCs have demonstrated superior in vivo pharmacokinetic properties and are more suitable for systemic injection. As sufficient surface contact between T cells and aAPCs is essential for activation, nano-aAPCs with microscale contact surface areas have been created through engineering approaches such as shape manipulation and nanoparticle clustering. These design strategies have demonstrated greatly enhanced efficacy of nano-aAPCs, endowing nano-aAPCs with the potential to be among the next generation of cancer nanomedicines. Graphical abstract
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  • 37
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: Molecular Immunology, Volume 95 Author(s): Xuelian Zhang, Chong Cao, Zhehui Qu, Wenjing Zhang, Yue Liu, Haihui Qi, Chunxue Hao, Wenlong Zhang, Mingchun Gao, Junwei Wang, Bo Ma Duck virus hepatitis caused by duck hepatitis A virus (DHAV) is an acute and contagious disease. To better understand the pathogenic mechanism of DHAV-3 in ducklings, an infection experiment was performed. Our results showed that typical symptoms were observed in the infected ducklings. DHAV-3 could infect many tissues, leading to pathological lesions, especially on the livers and spleen, and the host immune responses are activated in infection. Real-time quantitative PCR demonstrated that expression of many innate immune-related genes was mostly up-regulated in the livers and spleen, and antiviral innate immune response was established, but not sufficient to restrict the virus replication of lethal dose. Many major pattern recognition receptors (PRRs) (RIG-1, MDA5, and TLR7) are involved in the host immune response to DHAV-3, and the expression of interferon (IFNα, IFNβ and IFNγ) and antiviral proteins (MX, OAS and PKR) are also up-regulated in the liver and spleen. The expression of most cytokines (IL-1β, IL-2 and IL-6) was also up-regulated to different degrees and was various; the expression of IL-2 increased most significantly in liver. Our data provide a foundation for further study of the pathogenicity of duck virus hepatitis and extend our understanding of the immune responses of ducklings to DHAV-3 infection.
    Print ISSN: 0161-5890
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  • 38
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: Molecular Immunology, Volume 95 Author(s): Rita A. Costa, Deborah M. Power Skin wound healing has been widely studied in mammalian models but the information on teleost cutaneous healing is sparse and frequently considered in the context of viral or bacterial infections or parasitic infestations in aquaculture. In the present study a detailed time course (0 h, 6 h, 1, 2, 3 and 4 days) coupled to morphology and gene expression analysis revealed rapid regeneration of skin without scarring in a marine teleost after a superficial wound caused by the loss of a large area of scales. The integrity of the integument, as assessed by quantification of extracellular matrix (ECM) gene transcripts ( fn1a , colIα1 , colVα2 , colXα1 , ogn1 , ogn2 , crtac1a , cyr61 , pcna , krt2 and mmp9 ) was restored within 2 days. Epithelial-mesenchyme interactions assessed by expression of edar and shh were associated with epidermal closure, the re-establishment of the basement membrane and also scale eruption. Histological observations suggested tissue re-epithelialization was independent of inflammation and that transcripts representing the humoral and cellular elements of the immune response ( mpo , cyba and csf1r , cd48 and cd200 ) were modulated in the early stages of sea bream ( Sparus aurata ) skin repair after injury. Overall, the results indicate that after superficial skin damage tissue reconstitution started immediately with re-epithelialization, followed by ECM deposition and finally tissue maturation, indicating that in the skin regenerative process, reconstitution of the physical barrier was the priority over other integument functions, including immune surveillance.
    Print ISSN: 0161-5890
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  • 39
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: Molecular Immunology, Volume 95 Author(s): Jiling Sun, Qiujing Huang, Shufa Li, Fanqing Meng, Xunhua Li, Xiaoyun Gong Obesity is associated with a state of low-grade inflammatory response in adipose tissue, and contributes to the development of type 2 diabetes. Immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Therefore, adipose tissue promotes macrophage infiltration, resulting in local inflammation and insulin resistance. Tim-3 negatively regulates IFN-γ secretion and influences the ability to induce T cell tolerance in diabetes. MicroRNA contributes to the development of immunological tolerance and involves in macrophage polarization. However, the potential of Tim-3 to regulate macrophage polarization and the related microRNA has not been reported. In this experiment, 8-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks. The adipose tissue macrophages were isolated, miR-330-5p and Tim-3 levels, and M1/M2 polarization were analyzed. In addition, insulin tolerance tests was detected. The results demonstrated that miR-330-5p levels increased but Tim-3 levels decreased, leading to M1 polarization and insulin tolerance in diabetes mice. In addition, inhibition of miR-330-5p enhanced Tim-3 levels, leading to M2 polarization and insulin tolerance attenuation in diabetes mice. Furthermore, we detected the inverse relationship between miR-330-5p and Tim-3. We found that Tim-3 mRNA contained conserved miR-330-5p binding sites in its 3′UTR, and miR-330-5p could directly regulate Tim-3 expression through these 3′UTR sites. Our study demonstrated that miR-330-5p served as a regulator of the M2 polarization and miR-330-5p/Tim-3 axis potentially down-regulated insulin resistance in diabetes, probably through enhancing the M2 polarization of macrophage.
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  • 40
    Publication Date: 2018-03-09
    Description: Publication date: March 2018 Source: Molecular Immunology, Volume 95 Author(s): Jonathan Lalsiamthara, John Hwa Lee The enzyme 4-hydroxyproline 2-epimerase (PrpA) involves in modulation of host immunity and is also reported as a potent B-cell mitogen. Live attenuated Salmonella Typhimurium (ST) vector constitutively expressing heterologous Brucella abortus PrpA protein (ST-PrpA) was inoculated in BALB/c mice in order to investigate the influence of the enzyme, on safety aspects, humoral and cellular immunity as well as protective efficacies against wild type challenges. No aggravation of morbidity was observed upon mice inoculation of ST-PrpA. Immunized mice showed significantly quicker anti- Salmonella IgG responses as compared to ST only immunization. This finding is in congruency with the increase IL-4 production evident in in vitro pulsed mice splenocytes. Increase protection against Salmonella challenge was also observed. These findings suggest that PrpA can be used as a protein adjuvant in a live Salmonella delivery system, in order to increase humoral responses effectively without major interference on the cell mediated immunity.
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  • 41
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 17 January 2018 Source: Molecular Immunology Author(s): Jiajie Wei, Jonathan W. Yewdell The MHC class I antigen presentation pathway enables T cell immunosurveillance of cancer cells, viruses and other intracellular pathogens. Rapidly degraded newly synthesized proteins (DRiPs) are a major source of self-, and particularly, viral antigenic peptides. A number of findings support the idea that a substantial fraction of antigenic peptides are synthesized by “immunoribosomes”, a subset of translating ribosomes that generate class I peptides with enhanced efficiency. Here, we review the evidence for the immunoribosome hypothesis.
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  • 42
    Publication Date: 2018-03-09
    Description: Publication date: 7 March 2018 Source: Neuron, Volume 97, Issue 5 Author(s): Feng-Ju Weng, Rodrigo I. Garcia, Stefano Lutzu, Karina Alviña, Yuxiang Zhang, Margaret Dushko, Taeyun Ku, Khaled Zemoura, David Rich, Dario Garcia-Dominguez, Matthew Hung, Tushar D. Yelhekar, Andreas Toft Sørensen, Weifeng Xu, Kwanghun Chung, Pablo E. Castillo, Yingxi Lin Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation. Teaser Weng et al. report that the transcription factor Npas4 selectively regulates the number of functional synaptic contacts between CA3 pyramidal neurons and mossy fibers, allowing for learning-induced modification of MF-CA3 synapses during contextual memory formation.
    Print ISSN: 0896-6273
    Electronic ISSN: 1097-4199
    Topics: Biology , Medicine
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  • 43
    Publication Date: 2018-03-09
    Description: Publication date: 7 March 2018 Source: Neuron, Volume 97, Issue 5 Author(s): Zachariah M. Reagh, Jessica A. Noche, Nicholas J. Tustison, Derek Delisle, Elizabeth A. Murray, Michael A. Yassa The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer’s disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans. Teaser Reagh et al. identify a novel mechanistic pathway for the decline in pattern separation of object stimuli observed with aging—a network dysregulation characterized by hypoactivity in the anterolateral entorhinal cortex and hyperactivity in the dentate and CA3 subregions of the hippocampus. This novel biomarker yields a potential tool for assessing the neural basis of age-related memory decline.
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  • 44
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    In: Neuron
    Publication Date: 2018-03-09
    Description: Publication date: 7 March 2018 Source: Neuron, Volume 97, Issue 5 Author(s): Nikhilesh Natraj, Karunesh Ganguly Previous research has shown that mental rehearsal can improve performance. A new study by Vyas et al. (2018) reveals that direct modulation of neural dynamics using a brain-computer interface can also modify physical movements. The study further demonstrates that “mental practice” and physical movements share a common neural subspace. Teaser Previous research has shown that mental rehearsal can improve performance. A new study by Vyas et al. (2018) reveals that direct modulation of neural dynamics using a brain-computer interface can also modify physical movements. The study further demonstrates that “mental practice” and physical movements share a common neural subspace.
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  • 45
    Publication Date: 2018-03-09
    Description: Publication date: 7 March 2018 Source: Neuron, Volume 97, Issue 5 Author(s): C.Y. Daniel Lee, Anthony Daggett, Xiaofeng Gu, Lu-Lin Jiang, Peter Langfelder, Xiaoguang Li, Nan Wang, Yingjun Zhao, Chang Sin Park, Yonatan Cooper, Isabella Ferando, Istvan Mody, Giovanni Coppola, Huaxi Xu, X. William Yang Variants of TREM2 are associated with Alzheimer’s disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models. Teaser Augmenting TREM2 gene dosage in AD mouse models leads to reduced amyloid burden and neuropathology and improved memory performance. Gene expression profiling reveals a reprogrammed disease-associated microglial response that may underlie the phenotypic improvement in AD models.
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  • 46
    Publication Date: 2018-03-09
    Description: Publication date: 7 March 2018 Source: Neuron, Volume 97, Issue 5 Author(s): Dyan MacWilliam, Joel Kowalewski, Arun Kumar, Crystal Pontrello, Anandasankar Ray Odor detection involves hundreds of olfactory receptors from diverse families, making modeling of hedonic valence of an odorant difficult, even in Drosophila melanogaster where most receptors have been deorphanised. We demonstrate that a broadly tuned heteromeric receptor that detects CO 2 (Gr21a, Gr63a) and other odorants is a key determinant of valence along with a few members of the Odorant receptor family in a T-maze, but not in a trap assay. Gr21a and Gr63a have atypically high amino acid conservation in Dipteran insects, and they use both inhibition and activation to convey positive or negative valence for numerous odorants. Inhibitors elicit a robust Gr63a- dependent attraction, while activators, strong aversion. The attractiveness of inhibitory odorants increases with increasing background CO 2 levels, providing a mechanism for behavior modulation in odor blends. In mosquitoes, valence is switched and activation of the orthologous receptor conveys attraction. Reverse chemical ecology enables the identification of inhibitory odorants to reduce attraction of mosquitoes to skin. Teaser Insects sense a variety of odors using numerous transmembrane receptors and instantaneously like or dislike them. MacWilliam et al. find that only a few receptors explain instantaneous behavior in a T-maze, including a key conserved receptor that detects several odorants and CO 2 .
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  • 47
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    Elsevier
    Publication Date: 2018-03-09
    Description: Publication date: Available online 9 March 2018 Source: Seminars in Cell & Developmental Biology Author(s): Jonathan P. Richardson, David L. Moyes, Jemima Ho, Julian R. Naglik The tremendous diversity in microbial species that colonise the mucosal surfaces of the human body is only now beginning to be fully appreciated. Distinguishing between the behaviour of commensal microbes and harmful pathogens that reside at mucosal sites in the body is a complex, and exquisitely fine-tuned process central to mucosal health. The fungal pathobiont Candida albicans is frequently isolated from mucosal surfaces with an asymptomatic carriage rate of approximately 60% in the human population. While normally a benign member of the microbiota, overgrowth of C. albicans often results in localised mucosal infection causing morbidity in otherwise healthy individuals, and invasive infection that often causes death in the absence of effective immune defence. C. albicans triggers numerous innate immune responses at mucosal surfaces, and detection of C. albicans hyphae in particular, stimulates the production of antimicrobial peptides, danger-associated molecular patterns and cytokines that function to reduce fungal burdens during infection. This review will summarise our current understanding of innate immune responses to C. albicans at mucosal surfaces.
    Print ISSN: 1084-9521
    Electronic ISSN: 1096-3634
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  • 48
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    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Seminars in Cell & Developmental Biology Author(s): Ana V. Marin, Paula P. Cárdenas, Anaïs Jiménez-Reinoso, Miguel Muñoz-Ruiz, Jose R. Regueiro We address current data, views and puzzles on the emerging topic of regulation of lymphocytes by complement proteins or fragments. Such regulation is believed to take place through complement receptors (CR) and membrane complement regulators (CReg) involved in cell function or protection, respectively, including intracellular signalling. Original observations in B cells clearly support that complement cues through CR improve their performance. Other lymphocytes likely integrate complement-derived signals, as most lymphoid cells constitutively express or regulate CR and CReg upon activation. CR-induced signals, particularly by anaphylatoxins, clearly regulate lymphoid cell function. In contrast, data obtained by CReg crosslinking using antibodies are not always confirmed in human congenital deficiencies or knock-out mice, casting doubts on their physiological relevance. Unsurprisingly, human and mouse complement systems are not completely homologous, adding further complexity to our still fragmentary understanding of complement-lymphocyte interactions.
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  • 49
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    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Seminars in Immunology Author(s): Owen A. Hawksworth, Liam G. Coulthard, Susanna Mantovani, Trent M. Woodruff From its discovery in the late nineteenth century, as a ‘complement’ to the cellular immune response, the complement system has been widely affirmed as a powerful controller of innate and adaptive immune responses. In recent decades however, new roles for complement have been discovered, with multiple complement proteins now known to function in a broad array of non-immune systems. This includes during development, where complement exerts control over stem cell populations from fertilization and implantation throughout embryogenesis and beyond post-natal development. It is involved in processes as diverse as cell localisation, tissue morphogenesis, and the growth and refinement of the brain. Such physiological actions of complement have also been described in adult stem cell populations, with roles in proliferation, differentiation, survival, and regeneration. With such a broad range of complement functions now described, it is likely that current research only describes a fraction of the full reach of complement proteins. Here, we review how complement control of physiological cell processes has been harnessed in stem cell populations throughout both development and in adult physiology.
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    Electronic ISSN: 1096-3618
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  • 50
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Radiotherapy and Oncology Author(s): K.P. Rooney, A.B. Miah, S.A. Bhide, M.T. Guerrero-Urbano, M.T. Sharabiani, K.L. Newbold, L. Grove, K.J. Harrington, C.M. Nutting Background and purpose To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. Materials and methods A sequential Phase I dose-escalation design was used. Dose level one ( DL1 ) received 58.8  Gy /2 8F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels . Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment. Results Fifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.
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  • 51
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    Publication Date: 2018-03-09
    Description: Publication date: February 2018 Source: Radiotherapy and Oncology, Volume 126, Issue 2
    Print ISSN: 0167-8140
    Electronic ISSN: 1879-0887
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  • 52
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Radiotherapy and Oncology Author(s): Vikas Gupta, Yibing Wang, Alejandra Méndez Romero, Andriy Myronenko, Petr Jordan, Calvin Maurer, Ben Heijmen, Mischa Hoogeman Purpose To validate a novel deformable image registration (DIR) method for online adaptation of planning organ-at-risk (OAR) delineations to match daily anatomy during hypo-fractionated RT of abdominal tumors. Materials and methods For 20 liver cancer patients, planning OAR delineations were adapted to daily anatomy using the DIR on corresponding repeat CTs. The DIR’s accuracy was evaluated for the entire cohort by comparing adapted and expert-drawn OAR delineations using geometric (Dice Similarity Coefficient (DSC), Modified Hausdorff Distance (MHD) and Mean Surface Error (MSE)) and dosimetric ( D max and D mean ) measures. Results For all OARs, DIR achieved average DSC, MHD and MSE of 86%, 2.1 mm, and 1.7 mm, respectively, within 20 s for each repeat CT. Compared to the baseline (translations), the average improvements ranged from 2% (in heart) to 24% (in spinal cord) in DSC, and 25% (in heart) to 44% (in right kidney) in MHD and MSE. Furthermore, differences in dose statistics ( D max , D mean and D 2% ) using delineations from an expert and the proposed DIR were found to be statistically insignificant ( p  > 0.01). Conclusion The validated DIR showed potential for online-adaptive radiotherapy of abdominal tumors as it achieved considerably high geometric and dosimetric correspondences with the expert-drawn OAR delineations, albeit in a fraction of time required by experts.
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  • 53
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    Publication Date: 2018-03-09
    Description: Publication date: February 2018 Source: Radiotherapy and Oncology, Volume 126, Issue 2
    Print ISSN: 0167-8140
    Electronic ISSN: 1879-0887
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  • 54
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Structure Author(s): Yan Xia, Axel W. Fischer, Pedro Teixeira, Brian Weiner, Jens Meiler While great progress has been made, only 10% of the nearly 1,000 integral, α-helical, multi-span membrane protein families are represented by at least one experimentally determined structure in the PDB. Previously, we developed the algorithm BCL::MP-Fold, which samples the large conformational space of membrane proteins de novo by assembling predicted secondary structure elements guided by knowledge-based potentials. Here, we present a case study of rhodopsin fold determination by integrating sparse and/or low-resolution restraints from multiple experimental techniques including electron microscopy, electron paramagnetic resonance spectroscopy, and nuclear magnetic resonance spectroscopy. Simultaneous incorporation of orthogonal experimental restraints not only significantly improved the sampling accuracy but also allowed identification of the correct fold, which is demonstrated by a protein size-normalized transmembrane root-mean-square deviation as low as 1.2 Å. The protocol developed in this case study can be used for the determination of unknown membrane protein folds when limited experimental restraints are available. Teaser Xia et al. developed a computational structure prediction pipeline to utilize multiple experimental restraints to fold membrane proteins in BCL and Rosetta. The pipeline described herein could determine structures to an accuracy of 1.2 Å RMSD relative to the experimentally determined structural model.
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  • 55
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    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Structure Author(s): Benjamin C. McIlwain, Simon Newstead, Randy B. Stockbridge Crystallization of dual-topology fluoride (Fluc) channels requires small, soluble crystallization chaperones known as monobodies, which act as primary crystal lattice contacts. Previous structures of Flucs have been solved in the presence of monobodies that inhibit fluoride currents in single-channel electrophysiological recordings. These structures have revealed two-fold symmetric, doubly bound arrangements, with one monobody on each side of the membrane. The combined electrophysiological and structural observations raise the possibility that chaperone binding allosterically closes the channel, altering the structure from its conducting form. To address this, we identify and solve the structure with a different monobody that only partially blocks fluoride currents. The structure of the channel-monobody complex is asymmetric, with monobody bound to one side of the channel only. The channel conformation is nearly identical on the bound and uncomplexed sides, and to all previously solved structures, providing direct structural evidence that monobody binding does not induce local structural changes. Graphical abstract Teaser McIlwain et al. present the structure of a fluoride channel bound to an inhibitory chaperone (monobody) on one side. Comparing to previous structures with chaperones on both sides, the authors show that monobody binding does not affect the structure of the channel, likely using physical occlusion to block the channel.
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  • 56
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Structure Author(s): André Schiefner, Michaela Gebauer, Antonia Richter, Arne Skerra We describe the comparative X-ray structural analysis of three Anticalin proteins directed against the extra-domain B (ED-B) of oncofetal fibronectin (Fn), a validated marker of tumor neoangiogenesis. The Anticalins were engineered from the human lipocalin 2 (Lcn2) scaffold via targeted randomization of the structurally variable loop region and selection by phage display, resulting in 15–19 exchanged residues. While the four reshaped loops exhibit diverse conformations (with shifts in Cα positions up to 20.4 Å), the β-barrel core of the lipocalin remains strongly conserved, thus confirming the extraordinary robustness of this scaffold. All three Anticalins bind the cc' hairpin loop of ED-B, the most exposed motif in the context of its neighboring Fn domains, but reveal entirely different binding modes, with orientations differing by up to 180°. Hence, each Anticalin recognizes its molecular target in an individual manner, in line with the distinct epitope specificities previously seen in binding experiments. Graphical abstract Teaser Anticalin proteins are engineered lipocalin-like molecules that, like antibodies, show specific binding ability for different molecular targets. Schiefner et al. analyze three distinct Anticalin complexes, bound to an oncogenic domain of fibronectin. These structures confirm the high paratope plasticity and scaffold robustness of engineered lipocalins.
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  • 57
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Structure Author(s): Santiago Martínez-Lumbreras, Caterina Alfano, Nicola J. Evans, Katherine M. Collins, Kelly A. Flanagan, R. Andrew Atkinson, Ewelina M. Krysztofinska, Anupama Vydyanath, Jacquelin Jackter, Sarah Fixon-Owoo, Amy H. Camp, Rivka L. Isaacson Global changes in bacterial gene expression can be orchestrated by the coordinated activation/deactivation of alternative sigma (σ) factor subunits of RNA polymerase. Sigma factors themselves are regulated in myriad ways, including via anti-sigma factors. Here, we have determined the solution structure of anti-sigma factor CsfB, responsible for inhibition of two alternative sigma factors, σ G and σ E , during spore formation by Bacillus subtilis . CsfB assembles into a symmetrical homodimer, with each monomer bound to a single Zn 2+ ion via a treble-clef zinc finger fold. Directed mutagenesis indicates that dimer formation is critical for CsfB-mediated inhibition of both σ G and σ E , and we have characterized these interactions in vitro . This work represents an advance in our understanding of how CsfB mediates inhibition of two alternative sigma factors to drive developmental gene expression in a bacterium. Graphical abstract Teaser Martínez-Lumbreras, Alfano et al. have solved the structure of the anti-sigma factor CsfB and explored its role in inhibiting two alternative sigma factors during Bacillus subtilis spore formation. The results provide insight into the molecular mechanism underlying a gene expression switch in bacteria.
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  • 58
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    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Structure Author(s): Natalia Stach, Magdalena Kalinska, Michal Zdzalik, Radoslaw Kitel, Abdulkarim Karim, Karol Serwin, Wioletta Rut, Katrine Larsen, Abeer Jabaiah, Magdalena Firlej, Benedykt Wladyka, Patrick Daugherty, Henning Stennicke, Marcin Drag, Jan Potempa, Grzegorz Dubin Staphylococcus aureus is a dangerous human pathogen characterized by alarmingly increasing antibiotic resistance. Accumulating evidence suggests the role of Spl proteases in staphylococcal virulence. Spl proteases have restricted, non-overlapping substrate specificity, suggesting that they may constitute a first example of a proteolytic system in bacteria. SplA, SplB, and SplD were previously characterized in terms of substrate specificity and structural determinants thereof. Here we analyze the substrate specificity of SplE documenting its unique P1 preference among Spl proteases and, in fact, among all chymotrypsin-like (family S1) proteases characterized to date. This is interesting since our understanding of the general aspects of proteolysis is based on seminal studies of S1 family members. To better understand the molecular determinants of the unusual specificity of SplE, the crystal structure of the protein is determined here. Conclusions from structural analysis are evaluated by successful grafting of SplE specificity on the scaffold of SplB protease. Graphical abstract Teaser Serine proteases of the chymotrypsin family provide a textbook example of enzyme-substrate recognition. Stach et al. analyze the unique specificity of SplE protease for histidine residues and characterize the structural basis guiding this specificity. Successful rational grafting of SplE specificity onto a protease of different initial substrate preference supports the conclusions.
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  • 59
    Publication Date: 2018-03-09
    Description: Publication date: Available online 7 March 2018 Source: Stem Cell Research Author(s): Frank Griscelli, Hélène Ezanno, Mathis Soubeyrand, Olivier Feraud, Noufissa Oudrhiri, Amélie Bonnefond, Ali G. Turhan, Philippe Froguel, Annelise Bennaceur-Griscelli Heterozygous non-synonymous (p.S142F) mutation in HNF1A leads to maturity-onset diabetes of the young (MODY) type 3, which is a subtype of dominant inherited young-onset non-autoimmune diabetes due to the defect of insulin secretion from pancreatic beta cells. We generated induced pluripotent stem cells (iPSCs) from a patient with HNF1A p.S142F mutation. Cells from this patient, which were reprogrammed by non-integrative viral transduction had normal karyotype, harboured the HNF1A p.S142F mutation, expressed pluripotency hallmarks.
    Print ISSN: 1873-5061
    Electronic ISSN: 1876-7753
    Topics: Biology
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  • 60
    Publication Date: 2018-03-09
    Description: Publication date: Available online 28 February 2018 Source: Urology Author(s): Jeffrey Spencer, Joseph Mahon, Michael Daugherty, Laura Chang-Kit, Stephen Blakely, Andrew McCullough, Timothy Byler, Dmitriy Nikolavsky Objective To assess the association of hypoandrogenism (HA) with urethral stricture disease in a series of patients undergoing urethroplasty at 2 institutions. HA has recently been associated with increased urethral atrophy in artificial sphincter failures and decreased androgen receptors and periurethral vascularity. HA might be an etiologic factor in urethral stricture disease. Methods We reviewed the charts in 202 men with anterior urethral strictures between 2011 and 2017. We excluded patients with radiation-induced stricture, previous prostatectomy, previous urethroplasty, pelvic fracture-related strictures, or those on testosterone replacement. We defined HA by a total testosterone of less than 300 ng/dL. We used as age-matched cohort from a national database (National Health and Nutrition Examination Survey), as a reference. Stricture characteristics, such as length, location, and etiology were compared in HA and eugonadal groups. Results Of 202 men with anterior urethral strictures, we excluded 45. Of the remaining 157 patients, 115 (73%) had preoperative testosterone measurements. Overall, hypoandrogenism (HA) was found in 65 of 115 (57%) men in the urethral stricture group compared with 28% of age-matched men in the national database. Mean stricture length in HA and eugonadal men was 7.2 cm and 4.8 cm, respectively ( P  = .02). Conclusion HA may be more prevalent and associated with increased disease severity in men with anterior urethral strictures. The relationship between HA and stricture formation and its potential impact on therapeutic outcomes merit further prospective investigation.
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  • 61
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    In: Urology
    Publication Date: 2018-03-09
    Description: Publication date: Available online 28 February 2018 Source: Urology Author(s): Gregory T. Bales
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  • 62
    Publication Date: 2018-03-09
    Description: Publication date: Available online 27 February 2018 Source: Urology Author(s): Alkan Cubuk, Akif Erbin
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  • 63
    Publication Date: 2018-03-09
    Description: Publication date: Available online 21 February 2018 Source: Urology Author(s): Lathem Wojno, Caitlyn Minutella, Donald Moylan, Arla Bush, Kirk Wojno Objectives To determine if tissue contamination in histologic specimens can significantly affect the results of prognostic molecular markers that are routinely used as confirmatory tests to safely assign appropriate candidates to prostate cancer active surveillance protocols. Materials and Methods This study evaluates 2,134 cases from a single, large urology practice that were successfully tested for DNA specimen provenance verification using short tandem repeat analysis for the presence of a significant level of contaminating DNA. After removal of the contamination, five of the samples were retested, and the results of the molecular diagnostic test were compared. Results 49 of the 2,134 cases (2.3%) sent for DNA provenance analysis were found to possess significant levels of contamination. Of these 49 cases, seven of them were resent for a repeat molecular diagnostic test after being decontaminated. Five of these prostate cancer specimens had sufficient tissue and RNA to give a more accurate cell cycle progression (CCP) score. The average absolute change in these patient's CCP scores was 0.48, with a low of a 0.1-unit and a high of a 1.0-unit difference. These changes in CCP scores are significant enough to cause meaningful alterations in a patient's calculated 10-year mortality rate, as defined by their combined risk score (CRS). Conclusions DNA contamination in unstained tissue sections sent for prognostic prostate cancer molecular diagnostic testing occurs on 2.3% of cases, and can be of a magnitude that affects the results and subsequent clinical decision of appropriateness for active surveillance.
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  • 64
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    In: Urology
    Publication Date: 2018-03-09
    Description: Publication date: Available online 13 February 2018 Source: Urology Author(s): Daryl J. McLeod
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  • 65
    Publication Date: 2018-03-09
    Description: Publication date: Available online 9 February 2018 Source: Urology Author(s): Amy Lehman, Marilly Palettas
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  • 66
    Publication Date: 2018-03-09
    Description: Publication date: Available online 8 March 2018 Source: Urology Author(s): Stefan Heidler, Martin Drerup, Lukas Lusuardi, Ursula Bannert, Katharina Bretterbauer, Johannes Bures, Franz Dietersdorfer, Eva Dlouhy-Schütz, Clemens Hessler, Rainer Karpf, Lie-Anna Mittellehner, Barbara Mitlöhner, Stephan Schwarz, Günther Thomay, Georg Lösch, Christa Freibauer, Walter Albrecht Objective To compare prostate volume and PSA levels with bacterial growth in prostate tissue cultures. Methods 50 male patients who underwent transuretheral prostate resection (TURP) were investigated prospectively. Resection chips from the prostate gland were added to Brain Heart Infusion Medium and incubated. PSA levels were determinded preoperatively at our urology ward. The prostate gland volume was estimated by transabdominal ultrasound (TAUS) examination preoperatively. Results Persons with positive bacterial prostate tissue cultures have a greater prostate volume. This is significant in patients with and without histopathological signs of prostatitis. Persons with positive bacterial prostate tissue cultures have higher PSA values. This is significant in patients without histopathological signs of prostatitis. Conclusions People with positive bacterial prostatic tissue culture have a higher prostate volume in comparison to patients with negative culture findings and show a tendency towards increased PSA levels as well.
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  • 67
    Publication Date: 2018-03-09
    Description: Publication date: Available online 6 March 2018 Source: Urology Author(s): Carla Pérez-Tomás, Luis Gómez-Pérez, Jesús Romero-Maroto, Antonio Palazón-Bru, Felipe Navarro-Cremades, Ernesto Cortés-Castell Objectives To assess the sexuality and quality of life of sexually active women with stress or mixed urinary incontinence (SUI/MUI) after surgery with adjustable tension-free suburethral mesh system (TOA/TVA). Methods This intervention study with two years of follow-up (visits at three months, one year and two years) involved 60 women with SUI/MUI who underwent surgery using TOA/TVA during 2008-2014 in a Spanish region. The variables of interest measured pre- and post-intervention were the global scores on the following questionnaires: 1) Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire-12 (PISQ-12), the International Consultation on Incontinence Questionnaire (ICIQ-SF) and the Incontinence Quality of Life Questionnaire (I-QOL). Mixed linear models were constructed to determine the effect of the intervention on the outcome variables. Results : A significant improvement (p〈0.001) was seen over time in all the questionnaires, although between the one- and two-year visits there was a slight deterioration in all of them. Conclusions The technique provided an improved quality of life and sexuality, which was maintained at all the postoperative visits compared to baseline.
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  • 68
    Publication Date: 2018-03-09
    Description: Publication date: Available online 6 March 2018 Source: Urology Author(s): Chalairat Suk-Ouichai, Jitao Wu, Wen Dong, Hajime Tanaka, Yanbo Wang, J.J. H. Zhang, Elvis Caraballo, Erick Remer, Jianbo Li, Sudhir Isharwal, Steven C. Campbell Objectives To evaluate contact surface area (CSA) between the tumor and parenchyma as a predictor of ipsilateral parenchyma and function preserved after partial nephrectomy (PN). Previous studies suggested that CSA is a strong predictor of functional outcomes but the limitations of CSA have not been adequately explored. Patients/Methods 419 patients managed with standard PN for solitary tumor with necessary studies to evaluate ipsilateral preoperative/postoperative parenchymal mass/function were analyzed. Parenchymal mass and CSA were measured using contrast-enhanced CT 〈2months prior and 3-12months after PN. CSA was calculated: 2πrd, where r=radius and d=intraparenchymal depth. Pearson-correlation evaluated relationships between CSA and ipsilateral parenchymal mass or function preserved. Multivariable regression assessed predictors of function preserved. Conceptually, the CSA paradigm should function better for exophytic tumors than endophytic ones. Results Median tumor size was 3.5cm and R.E.N.A.L. was 8. Median global and ipsilateral GFR preserved were 89%/79%, respectively. Median ipsilateral parenchymal mass preserved was 85% and significantly higher for exophytic masses (p=0.001). Median CSA was 22.8cm 2 and significantly less for exophytic masses (p=0.02). CSA associated with both ipsilateral function and mass preserved (both p〈0.05), but the correlations were only modest ( r =0.25 and 0.36, respectively). On multivariable analysis, CSA associated with function preserved for exophytic masses(p=0.01), but not for endophytic ones(p=0.27). Conclusion CSA associates with functional outcomes after standard PN, although the strength of the correlations were modest, unlike previous studies, and CSA was not an independent predictor for endophytic tumors. Further study will be required to evaluate the utility of CSA in various clinical settings.
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  • 69
    Publication Date: 2018-03-09
    Description: Publication date: Available online 1 March 2018 Source: Urology Author(s): Emilio Sacco, Carlo Gandi, Luigi Vaccarella, Salvatore Recupero, Marco Racioppi, Francesco Pinto, Angelo Totaro, Nazario Foschi, Giuseppe Palermo, Francesco Pierconti, Pierfrancesco Bassi Objective To evaluate prospectively midterm outcomes of a new titanium-coated fixed polypropylene sling for male stress urinary incontinence. Materials and methods From 01/2013 to 06/2016, 44 consecutive patients with incontinence caused by radical prostatectomy (39) or TURP (5) underwent transobturator two-arm titanium-coated sling (TiLOOP Male ® ) implantation with an inside-out, single-incision technique, leaving the bulbourethral muscle in place. Patients have been assessed postoperatively with uroflowmetry, pad count, ICIQ-SF, IIQ-7, PGI-I, OABq, IPSS, satisfaction (yes/no). Successful outcome included cure (no pad use or one dry “security” pad) or improvement (reduction of at least 50% of the pad count). Results Evaluated patients were suffering from mild (11/44, 25%), moderate (26/44, 59%) or severe (7/44, 16%) incontinence. After a median follow-up of 25 months (range 12-55, minimum 12 months), 24(54.6%) patients were cured and 10(22.7%) were improved, which was a global success rate of 77.3%. There were 10(22.7%) failures in the first 6 months. Zero pad rate was 50%. Subjective success (PGI-I very much/much improved) was achieved in 33(75%) patients. Mean scores of ICIQ-SF, ICIQ-QoL and IIQ-7 improved to a statistical significant extent. Satisfaction was reported by 33(75%) patients. Uroflowmetry parameters were unchanged postoperatively, and most of complications were Clavien-Dindo grade I. BMI≥30 and previous irradiation/HIFU were independent predictors of failure. Conclusions TiLOOP Male ® provided favourable and stable midterm continence outcomes. The inside-out approach was safe, and the tolerability of the sling and the single-incision technique was satisfactory. Patients with obesity and previous irradiation/HIFU should be aware of their higher risk of failure.
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  • 70
    Publication Date: 2018-03-09
    Description: Publication date: Available online 28 February 2018 Source: Urology Author(s): Christina P. Carpenter, Ashley Rawson, David S. Hains, Dana W. Giel Nephrogenic diabetes insipidus (NDI), a rare cause of polyuria and polydipsia in children, is usually managed with medications and careful monitoring of water intake. We present a child who was incidentally found to have right hydronephrosis secondary to ureteropelvic junction obstruction, and was subsequently also diagnosed with NDI. After being medically managed, he underwent open right pyeloplasty. His polydipsia abated within one month of surgery, and he has done well off of medications since that time. NDI resolution after correction of obstructive uropathy in adults has been reported, but this represents a novel case in pediatrics.
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  • 71
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    In: Urology
    Publication Date: 2018-03-09
    Description: Publication date: Available online 27 February 2018 Source: Urology Author(s): Aldo Brassetti, Gianluca D'Elia
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  • 72
    Publication Date: 2018-03-09
    Description: Publication date: Available online 9 February 2018 Source: Urology Author(s): Heather J. Chalfin, Max Kates, Emma E. van der Toom, Stephanie Glavaris, James E. Verdone, Noah M. Hahn, Kenneth J. Pienta, Trinity J. Bivalacqua, Michael A. Gorin Objective To investigate circulating tumor cells (CTCs) as biomarkers of urothelial carcinoma (UC). The majority of this work to date has utilized the CellSearch test, which has limited sensitivity due to reliance on positive selection for the cell surface protein EpCAM. We used a novel selection-free method to enumerate and characterize CTCs across a range of UC stages. Materials and Methods Blood samples from 38 patients (9 controls, 8 non-muscle invasive bladder cancer [NMIBC], 12 muscle-invasive bladder cancer [MIBC] and 9 metastatic UC) were processed with the AccuCyte-CyteFinder system. Slides were stained for the white blood cell (WBC) markers CD45 and CD66b and the epithelial markers EpCAM and pancytokeratin (CK). CTCs were defined as any CK+/WBC- cell. Separately, the more restrictive CellSearch definition was applied, with the additional requirement of EpCAM positivity. The Kruskal-Wallis ANOVA test compared CTC counts by stage. Results ≥1 CTC was detected in 2/8(25%) patients with NMIBC, 7/12(58%) with MIBC, and 6/9(67%) with metastatic disease. No control had CTCs. Comparing CTC counts between groups, the only statistically significant comparison was between controls and patients with metastatic UC (p=0.009). With EpCAM positivity as a CTC requirement, no CTCs were detected in any NMIBC patient, and only 2(17%) MIBC patients had CTCs. CTCs tended to be larger in metastatic patients. Conclusions CTCs were detected at all UC stages and exhibited phenotypic diversity of cell size and EpCAM expression. EpCAM negative CTCs that would be missed with the CellSearch test were detected in NMIBC and MIBC patients.
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  • 73
    Publication Date: 2018-03-09
    Description: Publication date: Available online 19 February 2018 Source: Urology Author(s): Federico Soria, Esther Morcillo, Alvaro Serrano, Alberto Budia, Inmaculada Fernández, Tomás Fernández-Aparicio, Francisco M. Sanchez-Margallo Objectives The purpose is to determine the effects in urinary tract of a new antireflux biodegradable ureteral stent. Material and methods Thirty six ureters belonging to 24 pigs were used. The study began with an endoscopic, nephrosonographic and fluoroscopic assessment. Three study groups of n=12 ureters were then specified. In Group I, a biodegradable antireflux stent (BDG-ARS) was inserted in the right ureter of 12 pigs. Group II was comprised by the left ureter of the same animals, in which a double pigtail stent was placed for 6 weeks. Group III ureters, belonging to 12 additional animals, were subjected to a ureteropelvic junction obstruction model, that was then treated by endopyelotomy and stenting with BDG-ARS. Follow-ups were performed at 3-6 weeks and 5 months. Results None of the ureters receiving the BDG-ARS showed any evidence of vesicoureteral reflux. BDG-ARS degradation took place in a controlled and predictable fashion from the 3 rd -6 th weeks, and no obstructive fragments appeared. No differences were found between Groups I and II regarding passive ureteral dilatation, but significant differences were found regarding vesicoureteral reflux and ureteral orifice damage. BDG-ARS always maintained distal ureteral peristalsis. BDG-ARS in Group-III showed a 50% positive urine culture rate and a 16.6% migration rate in both BDG-ARS groups. Conclusions ARS biodegradable stent avoided vesicoureteral reflux and bladder trigone irritation. In addition, this polymer combination and stent-braided design achieved a consistent biodegradation rate with no obstructive fragments and with uniformly degradation between 3 rd -6 th weeks. Consequently, morbidity associated with ureteral stents might be reduced.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
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  • 74
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    Elsevier
    In: Urology
    Publication Date: 2018-03-09
    Description: Publication date: Available online 9 February 2018 Source: Urology Author(s): Francesco Petrocelli, Giulio Bovio, Alice Utili, Nicola Camisassi Varicocele consists of abnormally dilated and tortuous veins within the pampiniform plexus, usually in the left scrotum. We reported a rare case of right varicocele due to post traumatic arteriovenous fistula successfully treated by percutaneous embolization.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
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  • 75
    Publication Date: 2018-03-09
    Description: Publication date: Available online 9 February 2018 Source: Urology Author(s): Dong Hyuk Kang, Joo Yong Lee, Dae Chul Jung, Young Taik Oh, Eun Suk Cho, Sung Yoon Park, Ki Soo Lee, Kang Su Cho Objective To review the tertiary referral hospital experiences of men presenting with painless post-coital gross hematuria (PCGH) and suggest the management algorithm. Materials and Methods We reviewed clinical data from 19 male patients who first visited a clinic because of PCGH between 2009 and 2016. The patients were evaluated according to our tentative management algorithm for painless PCGH. First, a general work-up for painless gross hematuria (GH) was performed. If the cause of the PCGH was not identified, a vascular work-up of the pelvic vasculatures for PCGH was performed, including transrectal and penile ultrasonography (USG) with Doppler study. Pelvic angiography and subsequent angioembolization were recommended at the physician's discretion. Results The median age of the patients was 47 (range: 30–67) years. The tentative management algorithm led to no abnormal findings in seven patients and identified urological malignancies in two patients. Urethrocystoscopy revealed urethral hemangioma in three patients. Doppler USG revealed pelvic varicosities in three patients, complicated cyst of Cowper's glands in one patient, and pelvic arteriovenous malformation in three patients. Pelvic angiography was recommended for the three patients with pelvic arteriovenous malformation, and two of those patients were successfully treated by angioembolization. Conclusions The clinical approach to painless PCGH should be different than that to painless GH. Both the general and the vascular work-up for the pelvic vasculatures for painless GH are mandatory for the evaluation of patients with painless PCGH.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
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  • 76
    Publication Date: 2018-03-09
    Description: Publication date: Available online 9 February 2018 Source: Urology Author(s): Gajanan S. Bhat, S. Anuradha Objective To evaluate the proposed novel tools, namely, Arousal to Ejaculation Time Interval (AETI) and Erection to Ejaculation Time Interval (EETI), to measure ejaculatory latency during different types of sexual encounters, in a pilot study. Methods The study period was from September 2016 to December 2016. After obtaining informed consent and institutional review board approval, the medical practitioners without any co-morbidity, who volunteered to participate, were asked to report the self assessed time taken to ejaculate following sexual arousal (AETI) and also following a sustained erection (EETI) during a sexual activity. They were also asked to opine as to whether they consider themselves as normal ejaculators, delayed ejaculators or premature ejaculators. Statistical data including mean, standard deviation and p value were obtained. Results The sample size was 60 with the mean age of 48.9±10.8 years. 48 participants reported themselves as normal. Their mean AETI was 624.8±83.6 seconds, 700±79.1 seconds, 420±57.7 seconds and mean EETI was 355±82.6 seconds, 442.5±46.6 seconds, 240±38.6 seconds during heterosexual vaginal intercourse, masturbation and oral sex respectively. 12 participants reported premature ejaculation and their mean AETI was 122±11.6 seconds, 73.33±11.2 seconds, 74±12.3 seconds and mean EETI was 106.7±21.6 seconds, 70±13.7 seconds, 60±11.8 seconds during heterosexual vaginal intercourse, masturbation and oral sex respectively. None of the participants reported themselves as delayed ejaculators. The differences between the means were statistically significant (p≤0.0001). Conclusions AETI and EETI can be used to measure ejaculatory latency in different types of sexual encounters.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
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  • 77
    Publication Date: 2018-03-12
    Description: Publication date: Available online 8 March 2018 Source: The American Journal of Human Genetics Author(s): Silvia Albert, Alejandro Garanto, Riccardo Sangermano, Mubeen Khan, Nathalie M. Bax, Carel B. Hoyng, Jana Zernant, Winston Lee, Rando Allikmets, Rob W.J. Collin, Frans P.M. Cremers Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep-intronic ABCA4 variants (c.4539+2001G>A and c.4539+2028C>T) result in a retina-specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs ∗ 36), likely due to the creation of exonic enhancers. Administration of antisense oligonucleotides (AONs) targeting the 345-nt pseudoexon can significantly rescue the splicing defect observed in PPCs of two individuals with these mutations. Intriguingly, an AON that is complementary to c.4539+2001G>A rescued the splicing defect only in PPCs derived from an individual with STGD1 with this but not the other mutation, demonstrating the high specificity of AONs. In addition, a single AON molecule rescued splicing defects associated with different neighboring mutations, thereby providing new strategies for the treatment of persons with STGD1. As many genes associated with human genetic conditions are expressed in specific tissues and pre-mRNA splicing may also rely on organ-specific factors, our approach to investigate and treat splicing variants using differentiated cells derived from individuals with STGD1 can be applied to any tissue of interest.
    Print ISSN: 0002-9297
    Electronic ISSN: 1537-6605
    Topics: Biology , Medicine
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  • 78
    Publication Date: 2018-03-12
    Description: Publication date: Available online 8 March 2018 Source: The American Journal of Human Genetics Author(s): Christina Zarouchlioti, Beatriz Sanchez-Pintado, Nathaniel J. Hafford Tear, Pontus Klein, Petra Liskova, Kalyan Dulla, Ma’ayan Semo, Anthony A. Vugler, Kirithika Muthusamy, Lubica Dudakova, Hannah J. Levis, Pavlina Skalicka, Pirro Hysi, Michael E. Cheetham, Stephen J. Tuft, Peter Adamson, Alison J. Hardcastle, Alice E. Davidson Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.
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  • 79
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    Elsevier
    Publication Date: 2018-03-12
    Description: Publication date: Available online 9 March 2018 Source: The American Journal of Medicine Author(s): Joseph S. Alpert
    Print ISSN: 0002-9343
    Electronic ISSN: 1555-7162
    Topics: Medicine
    Published by Elsevier