tbuckley/cabot-search huggingface dataset:
Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome
Authors: Neil A. J. Ryan, Julie Morris, Kate Green, Fiona Lalloo, Emma R. Woodward, James Hill, Emma J. Crosbie, D. Gareth Evans
Journal: JAMA Oncology (2017)

Lynch syndrome is caused by dominantly inherited germline mutations that predispose individuals to colorectal, endometrial, ovarian, and other cancers through inactivation of the cellular mismatch repair system. Lynch syndrome–associated cancers are amenable to surveillance strategies that may improve survival. The age at which surveillance should start is disputed.To determine whether mutated gene and type of mutation influence age at onset of Lynch syndrome–associated cancers.A retrospective cohort study of individuals with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancers whose medical records were included in the clinical database of a large quaternary referral center for genomic medicine in the Northwest of England.Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or large rearrangement).Age at cancer diagnosis.A total of 1063 individuals with proven Lynch syndrome were included, 495 male and 568 female (mean age 52 years; age range, 10-93 years [children were included in the database, but no children developed cancer]). There were 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer; mean follow-up was 68.2 months. Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women. Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most commonly associated with female-specific cancers: endometrial cancer in 83 (30%) of 279 women; ovarian cancer in 28 (10%) of 279 women; and colorectal cancer in 239 (50%) 479 men and women. Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1. When stratified by mutation type, women with truncating MLH1 mutations had later ages of onset of endometrial cancer than those with nontruncating mutations (median difference, 6.6 years; 95% CI, 2.7-10.4; P = .002). Carriers of truncating MLH1 mutations presented with colorectal cancer at later ages than those with other mutations, but the difference was not statistically significant.Individuals with known Lynch syndrome could be risk stratified by mutated gene and mutation type in tailored surveillance programs. Specifically, individuals with MSH6 mutations could be offered cancer surveillance from a later age. Furthermore, those with truncating MLH1 mutations could begin endometrial cancer surveillance later than those with nontruncating mutations.
GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity
Authors: Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart Abbot, Daniel Shoemaker, Yenan T. Bryceson, Bruce R. Blazar, Scott Wolchko, Sarah Cooley, Jeffrey S. Miller
Journal: Cancer Research (2017)

Maturation of human natural killer (NK) cells as defined by accumulation of cell-surface expression of CD57 is associated with increased cytotoxic character and TNF and IFNγ production upon target-cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacologic inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK-cell maturation including T-BET, ZEB2, and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFNγ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity. In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy. Cancer Res; 77(20); 5664-75. ©2017 AACR.
Co-occurrence of colistin-resistance genes mcr-1 and mcr-3 among multidrug-resistant Escherichia coli isolated from cattle, Spain, September 2015
Authors: Marta Hernández, M Rocío Iglesias, David Rodríguez-Lázaro, Alejandro Gallardo, Narciso Quijada, Pedro Miguela-Villoldo, Maria Jorge Campos, Segundo Píriz, Gema López-Orozco, Cristina de Frutos, José Luis Sáez, María Ugarte-Ruiz, Lucas Domínguez, Alberto Quesada
Journal: Eurosurveillance (2017)

Colistin resistance genes mcr-3 and mcr-1 have been detected in an Escherichia coli isolate from cattle faeces in a Spanish slaughterhouse in 2015. The sequences of both genes hybridised to same plasmid band of ca 250 kb, although colistin resistance was non-mobilisable. The isolate was producing extended-spectrum beta-lactamases and belonged to serotype O9:H10 and sequence type ST533. Here we report an mcr -3 gene detected in Europe following earlier reports from Asia and the United States.
JUMPER'S KNEE: A PROSPECTIVE EVALUATION OF RISK FACTORS IN VOLLEYBALL PLAYERS USING AN OVERUSE MEASURE OF INJURY
Authors: Kerry MacDonald, Luz Palacios-Derflingher, Sarah Kenny, Carolyn Emery, Willem H. Meeuwisse
Journal: British Journal of Sports Medicine (2017)

Background A multitude of risk factors have been reported to increase an athlete's risk of developing jumper's knee. An overuse injury definition has been cited as more sensitive in capturing knee injuries when compared to a time-loss injury definition. To date, risk factors for jumper's knee have not been assessed for the development of knee problems captured by an overuse injury definition. Objective To assess a multitude of potential intrinsic risk factors for jumper's knee in volleyball players. Design Prospective Cohort. Setting Collegiate and national team training facilities. Patients (or Participants) Sixty elite adult male volleyball players were recruited from collegiate and national team programs in Canada. Interventions (or Assessment of Risk Factors) Participants completed risk factor assessments at the commencement of the season including: vertical jump ability (cm), weight bearing ankle dorsiflexion range (degrees), dynamic balance (cm), dynamic knee alignment (degrees) and landing mechanics (degrees). Main Outcome Measurements Self-reporting knee problems utilizing an overuse injury questionnaire collected via short message service (SMS) was completed prospectively over one season. Substantial knee problems were identified and logistic regression was used to estimate odds ratios for each risk factor independently. Results The season prevalence of knee problems was 75.0% (95% CI: 62.2 to 84.6) and the incidence proportion of those rated as substantial was 30.0% (95% CI: 19.5 to 43.1). The SMS system of tracking overuse injuries demonstrated 98.2% completeness. No single risk factor was found to predict substantial knee problems. All odds ratios were close to unity with narrow confidence intervals (0.91–1.07) and p&gt;0.05. Conclusions A more sensitive capture of overuse knee injuries did not result in the identification of distinct risk factors for the development of jumper's knee. These findings bring question to the utility of field based pre-season risk factor assessment for the identification of at risk athletes.
腫瘍細胞溶解物負荷キトサンナノ粒子ワクチン標的化樹状細胞により強化された抗腫瘍免疫【Powered by NICT】
Authors: Shi Gao-Na, Zhang Chuang-Nian, Xu Rong, Niu Jin-Feng, Song Hui-Juan, Zhang Xiu-Yuan, Wang Wei-Wei, Wang Yan-Ming, Li Chen, Wei Xiao-Qing, Kong De-Ling
Journal: Biomaterials (2017)
Abstract P096: Eya4, a Transcription Cofactor Crucial in Acquired Heart Disease
Authors: Tatjana Williams, Jost Schoenberger, Moritz Hundertmark, Martin Czolbe, Franziska Panther, Oliver Ritter
Journal: Circulation Research (2011)

Introduction: We previously identified a mutation in the human transcriptional cofactor Eya4 (E193) as cause of familial dilated cardiomyopathy (DCM) and heart failure. Upon interaction with real transcription factors such as Six family members, Eya4 is recruited to and interacts with target genes. One of the few known Eya-Six targets expressed in the heart is the cyclin-dependent kinase inhibitor p27kip1, which has been shown to inhibit hypertrophic growth in adult cardiomyocytes, is. We therefore hypothesize that Eya4/Six1 regulates targets relevant in normal cardiac function. Methods and results: We examined p27 expression in response to Eya4 in permanent mammalian cell lines. Western blot analysis demonstrated that an overexpression of Eya4 led to a significant downregulation of p27, whereas the overexpression of E193 had no effect on p27 levels. Studies using a p27 promoter fragment including Six1 consensus sites cloned in front of a Luciferase reporter gene proved Eya4 acts as a suppressor of p27 already at the transcriptional level, whereas E193 could not sufficiently inhibit p27 expression. Further transfection and knockdown experiments revealed that under basal conditions an Eya4 overexpression decreased protein synthesis in primary cardiac myocytes. We constructed transgenic mouse models with a constitutive myocardial overexpression of E193 and Eya4 to study the precise role of Eya4 in the heart. First analysis of these animals using magnetic resonance imaging to visualize cardiac structures in detail show that an overexpression of E193 leads to an age related onset of DCM as seen in an increase in LVEDV, whereas Eya4 overexpressing mice show no signs of heart disease. Conclusion: In summary, we identified a mutation in Eya4 to cause DCM. We now provide evidence that the Eya4/Six1 signalling cascade is also relevant in more common forms of acquired heart disease. Eya4/Six1 seems to regulate the expression of p27kip1, an important inhibitor of the development of hypertrophy in postmitotic cardiomyocytes. Studies using E193 overexpressing mice support our hypothesis whereas tempering the Eya4/Six1 signalling cascade disturbs cardiac physiology.
<i>SIRT1</i> activates the expression of fetal hemoglobin genes
Authors: Yan Dai, Tyngwei Chen, Heba Ijaz, Elizabeth H. Cho, Martin H. Steinberg
Journal: American Journal of Hematology (2017)

Abstract High fetal hemoglobin (HbF, α 2 γ 2 ) levels ameliorate the clinical manifestations of sickle cell disease and β thalassemia. The mechanisms that repress HbF expression and silence γ‐globin genes in adults are incompletely characterized and only a single HbF inducer, hydroxyurea, is approved for treatment, and only in patients with sickle cell disease. We identified SIRT1, a protein deacetylase, as a new inducer of γ‐globin. SIRT1 knockdown decreased, while SIRT1 ectopic expression upregulated γ‐globin gene ( HBG ) expression in primary human erythroid cells and in K562 cells. The small molecule SIRT1 activators SRT2104 and SRT1720 enhanced HBG expression in cord blood human erythroblasts and reactivated silenced HBG in adult human erythroblasts. Furthermore, SIRT1 binds in the β‐globin gene cluster locus control region (LCR) and HBG promoters, promotes the looping of the LCR to HBG promoter, and increases the binding of RNA polymerase II and H4K16Ac in the HBG promoter. SIRT1 suppressed the expression of the HBG suppressors BCL11A , KLF1 , HDAC1 and HDAC2 . Lastly, SIRT1 did not change the proliferation of human erythroid progenitor cells or the expression of differentiation marker CD235a. These data suggest that SIRT1 activates HBG expression through facilitating LCR looping to the HBG promoter, inhibiting the expression of transcriptional suppressors of HBG, and indirectly increasing histone acetylation in the HBG promoter. SIRT1 is a potential therapeutic target for γ‐globin gene induction, and small molecule SIRT1 activators might serve as a lead compound for the development of new HbF inducers.
AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy
Authors: Giuseppe Morabito, Serena G. Giannelli, Gabriele Ordazzo, Simone Bido, Valerio Castoldi, Marzia Indrigo, Tommaso Cabassi, Stefano Cattaneo, Mirko Luoni, Cinzia Cancellieri, Alessandro Sessa, Marco Bacigaluppi, Stefano Taverna, Letizia Leocani, José L. Lanciego, Vania Broccoli
Journal: Molecular Therapy (2017)

The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of α-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV-PHP.B-GBA1 restored physiological levels of the enzyme, reduced α-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies.Graphical abstract
02.14 Small ubiquitin related modifier-1 (sumo-1) regulates osteoclast differentiation
Authors: Svetlana Frank, David JJ de Gorter, Daniel Umlauf, Olli A Jänne, Berno Dankbar, Thomas Pap
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis is a common autoimmune disease characterised by the hyperplastic transformation of synovium, its infiltration with γ inflammatory cells and by stimulation of bone resorption through osteoclast activation leading to joint destruction. Posttranslational modification by SUMOylation has been described for various proteins and is involved in a wide variety of cellular processes, including protein localization and stability, transcriptional regulation, cell survival and death. Here, we investigated the role of SUMO-1 in osteoclastogenesis and studied the skeletal phenotype of <i>SUMO-1<sup>-/-</sup></i> mice. <h3>Materials and methods</h3> The skeletal phenotype of 8-week old <i>SUMO-1<sup>-/-</sup></i> and wild- type (WT) mice was investigated by µCT-analysis and by van Kossa and TRAP stainings. For <i>in vitro</i> experiments, bone marrow-derived macrophages (BMMs) were isolated from <i>SUMO-1<sup>-/-</sup></i> and WT mice, and differentiated into osteoclasts in presence of M-CSF and RANKL. Osteoclast differentiation was characterised by TRAP staining and by real-time PCR analysis of osteoclast marker genes. Activation of p38 and p44/42 MAPK as well as NF-κB signalling was investigated by western blotting. The osteoclast resorption capacity was determined using a calcium phosphate bone resorption assay. Cell motility was analysed by live cell imaging. <h3>Results</h3> <i>SUMO-1<sup>-/-</sup></i> mice demonstrated 20% higher trabecular bone volume compared with WT mice. Moreover, trabecular thickness was increased and trabecular separation was decreased in <i>SUMO-1<sup>-/-</sup></i> mice. In addition, <i>SUMO-1<sup>-/-</sup></i> mice display a significant reduction in osteoclasts. Of note, SUMO-1 loss was associated with impaired <i>in vitro</i> osteoclast differentiation and resorption capacity. Expression of DC-STAMP, cathepsin K and integrin ß3 was decreased in <i>SUMO-1<sup>-/-</sup></i> osteoclasts compared to WT osteoclasts. However, no differences in activation of p38 and p44/42 MAPK as well as the NF-κB signalling pathway in BMMs and osteoclasts of <i>SUMO-1<sup>-/-</sup></i> and WT mice was observed. Conversely, cell migration and fusion seemed to be affected in <i>SUMO-1<sup>-/-</sup></i> osteoclasts. <h3>Conclusions</h3> We found that <i>SUMO-1<sup>-/-</sup></i> mice have a higher bone mass owing to a decreased number of functional osteoclasts. Our data suggest that SUMO-1 is involved in the regulation of bone mass by osteoclast formation and activity, and therefore may be an interesting target for treating diseases associated with bone loss.
SP0037 How to assess us elementary lesions in cppd
Authors: G Filippou
Journal: Annals of the Rheumatic Diseases (2017)

Ultrasonography has been increasingly used the last years for the identification of calcium pyrophosphate dihydrate crystal deposition (CPPD) in joints and on 2011 has been considered by the EULAR task force on CPPD as a promising tool for the diagnosis of the disease. However, it is common experience between sonographers that in daily clinical practice CPP identification by US is rather challenging as crystal deposits are not always numerous and diffuse. Furthermore, other conditions can mimic CPP deposition leading to a wrong diagnosis. The recently created OMERACT US for CPPD subtask force has created for the first time a set of criteria for identification of CPP deposition and assessed their reliability trying to address some of the issues that impede a wider use of US for CPPD diagnosis. During this section will be exposed the main US features of CPP deposition according to the new criteria as well as the principal pitfals that could mislead diagnosis. The scanning techique and some tips and tricks that could help sonographers to identify correctly CPP deposition will also be explained. <h3>Disclosure of Interest</h3> None declared
FLOORBALL INJURIES DURING INTERNATIONAL TOURNAMENTS
Authors: Kati Pasanen, Merita Bruun, Tommi Vasankari, Minna Nurminen, Walter Frey
Journal: British Journal of Sports Medicine (2017)

Background Little is known about sports injuries in international floorball competition. Objective To investigate the incidence and pattern of injuries among adult female and male floorball players during the major international floorball events (World Championships and Champions Cups). Design Prospective study. Setting International Floorball Federation (IFF) events 2012–2015. Participants In total, 112 teams with 2179 athletes (mean age 24.6±4.8) took part in the twelve IFF events. Main Outcome Measurements The team medical persons were requested to report all new injuries during matches and practices throughout the events by using a structured injury form. The time of exposure was calculated for entire teams based on the IFF statistics. Results Sixty-eight injuries were registered among 67 players. The overall rate of injury (per 1000 match and practice hours) was 3.07 (95% CI 2.35 to 3.80). Injury incidence during match play was 21.24 (95% CI 16.13 to 26.35). All except one of the injuries were acute traumas. The ankle was the most commonly injured body part (26%), followed by the head/face (18%) and the knee (18%). The most frequently reported injury types were sprain (46%), contusion (26%) and strain (16%). Five ACL injuries occurred and four of them in females. Injuries to the head/face included five lacerations, four contusions, two eye injuries and a concussion. Conclusions Three percent of floorball players suffered from an injury during the twelve IFF events. Ankle sprain was the most common injury type. More data of floorball injuries on the international level is needed to enable more accurate knowledge of injuries and their risk factors.
68Ga-PSMA Uptake in Combined Hepatocellular Cholangiocarcinoma With Skeletal Metastases
Authors: Ramin Alipour, Sandeep Gupta, Scott Trethewey
Journal: Clinical Nuclear Medicine (2017)

Ga-PSMA PET is a rapidly evolving imaging modality for whole-body staging of prostate cancer. We report a case of a 70-year-old man with mildly elevated prostate-specific antigen (8.1 μg/L) and clinical suspicion of prostate cancer (osteoblastic metastases on radionuclide bone scan) who was referred for Ga-PSMA PET/CT for primary staging. Multiple Ga-PSMA-avid skeletal foci, mostly associated with lytic changes on low-dose CT, as well as hepatic foci of avid Ga-PSMA uptake, were identified. No abnormal focus of avid Ga-PSMA uptake was identified in the prostate. On histopathological examination, the liver lesion proved to be combined hepatocellular cholangiocarcinoma.