tbuckley/cabot-search huggingface dataset:
The application of optical coherence tomography angiography in uveitis and inflammatory eye diseases
Authors: Francesco Pichi, David Sarraf, Sruthi Arepalli, Careen Y. Lowder, Emmett T. Cunningham, Piergiorgio Neri, Thomas A. Albini, Vishali Gupta, Kimberly Baynes, Sunil K. Srivastava
Journal: Progress in Retinal and Eye Research (2017)
P08.18 Replication stress as a driver of genomic instability in malignant gliomas
Authors: R. Rasmussen, M. Gajjar, L. Tuckova, K. Jensen, A. Maya-Mendoza, J. Bartek, P. Hamerlik
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM, WHO grade IV astrocytoma) is among the deadliest of solid tumors with median survival rates of only approximately 15 months. In spite of concerted efforts, molecular mechanisms/genes causing high recurrence and treatment resistance are poorly understood. The tumor suppressor BRCA1 plays a critical role in maintaining genomic stability, in general, and replication stress (RS), in particular. Numerous reports have demonstrated that wild type BRCA1 loss impairs the growth of several cancers (breast, ovarian, lung, prostate and colon). Our data show considerably higher level of RS in malignant gliomas compared to other solid tumors (breast, prostate ovarian) and identify a novel role for BRCA1, where high BRCA1 expression negatively associates with glioma patient survival. BRCA1 plays an unexpected tumor-promoting role in GBM, safeguarding a protective response to supraphysiological RS levels via transcriptional regulation of RRM2 expression. shRNA-mediated knockdown of BRCA1 or chemical inhibition of RRM2 both induce GBM cell death due to accumulation of RS-induced DNA damage in vitro and extend survival of tumor bearing mice in vivo, highlighting the clinical relevance of our findings. Acknowledgements: This work was supported by Danish Cancer Society Foundation.
P08.05 Irradiation of glioblastoma cells can promote enhanced motility and invasiveness, both in vitro and in vivo through activation of MRCK
Authors: J. L. Birch, L. D. Gilmore, K. Strathdee, H. McKinnon, M. Drysdale, M. Olson, A. Chalmers
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is one of the most common and aggressive forms of brain cancer. It is typically associated with poor survival rates, in part due to the characteristically infiltrative nature of GBM tumour cells. This allows GBM cells to disseminate through the brain via existing white matter tracts and perivascular spaces making complete surgical resection unachievable and contributing to high recurrence rates. For the majority of patients treatment of GBM includes radiotherapy. However, radiation resistance results in populations of surviving tumour cells with the potential for modified behaviour through radiation-induced alterations in signalling and gene expression profiles Myotonic dystrophy kinase-related CDC42- binding kinase (MRCK) is involved in regulating actin-myosin dynamics during cell migration through phosphorylation of its targets MLC2 and MYPT. Upon radiation of GBM cell lines in vivo we observed an increase in MRCK activity which was concomitant with a significant increase in GBM cell motility and invasion in in vitro and ex vivo assays. In support of these data we have observed increased MRCK activity at the invasive edges of both clinical GBM samples and an orthotopic GBM xenograft model that recapitulates key histological features of human GBM. Furthermore, therapeutic doses of irradiation were found to promote GBM invasion in vivo in this xenograft model. These observations suggest that MRCK activity may be required to promote invasion following irradiation and therefore may present a promising novel target for GBM treatment. To explore this further we performed MRCK RNAi on GBM cells and found we were able to reverse the radiation dependent promotion of GBM cell motility. We then used a novel MRCK selective inhibitor BDP-9066 to recapitulate this effect, observing dose dependent effects on both MRCK biomarkers, PMLC2 and PMYPT, and motility in vitro and ex vivo. These data suggest that MRCK activity is indeed required for GBM invasion and can be targeted effectively in multiple GBM cell lines. These observations provide evidence that glioblastoma cell migration may be enhanced following radiation therapy. As such, this might provide a substrate for therapy resistance and early recurrence in these tumours whilst offering a potential target for novel therapies in GBM management.
Discovery and Validation of STAT-3 and ERK1/2 Phosphorylation as Critical for the Function of Alloactivated T Cells in Acute Graft-Versus-Host-Disease Via a Novel Technique for Drug Discovery.
Authors: Sydney X. Lu, Onder Alpdogan, Roberto Campos, Xiao Wang, Guo-Jian Gao, Melanie Chow, Janine Lin, David Suh, Christopher King, Vanessa M. Hubbard, Johanne L. Bautista, Adam A. Kochman, Johannes L. Zakrzewski, O. Marsinay Smith, Jeremy Grubin, Andrew Chow, Neel Patel, Marcel R.M. van den Brink
Journal: Blood (2007)
Gastro-oesophageal reflux events: just another trigger in chronic cough?
Authors: L A Houghton, J A Smith
Journal: Gut (2017)

GORD is considered a common cause of chronic cough, either alone or in association with nasal disease and/or asthma.1 This, along with the fact that there are currently no specific therapies approved for the treatment of chronic cough, has led to extensive use of acid suppressants, such that one US study in patients with extraoesophageal manifestations of GORD, of which 50% had cough, estimated costs to be four to five times those associated with their use in typical GORD.2 Despite this widespread use, a significant proportion of patients with chronic cough thought to be due to GORD remain refractory to acid suppression. Indeed, multiple studies and meta-analyses have failed to document a therapeutic benefit of acid suppression in chronic cough.3

A growing number of studies suggest that in 30%–48% of patients, coughing episodes seem to be temporally linked to reflux events, irrespective of their acidity or the presence of other conditions contributing to coughing.1 ,4 ,5 Notably, patients exhibiting such associations, that is, a positive symptom association probability (SAP) for cough preceded by reflux (SAPR-C), appear to have no more erosive disease or oesophageal exposure to reflux, with little reaching the proximal oesophagus, than those with a negative SAPR-C.5 SAPR-C-positive patients, however, do have a heightened cough …
Abstract 264: TNFR2-Bmx Signaling in Cardiac Stem Cells and Cardiac Repair
Authors: Huanjiao J Zhou, Qunhua Huang, Wang Min
Journal: Circulation Research (2014)

While cytokine TNF via TNFR1 induces inflammation and apoptosis, it through its second receptor TNFR2 induces cell survival and migration by activating bone marrow non-receptor tyrosine kinase Bmx. Since Bmx has been implicated in self-renewal of stem cells, we hypothesize that TNF via TNFR2 activates Bmx in cardiac stem cells (CSCs) to mediate cardiac repair. We show that in human cardiac tissue affected by ischemia heart disease (IHD), TNFR2 is expressed on intrinsic CSCs, identified as c-kit(+) /CD45(-) /VEGFR2(-) interstitial round cells, which are activated as determined by entry to cell cycle and expression of Lin-28. Wild-type mouse heart organ cultures subjected to hypoxic conditions both increase cardiac TNF expression and show induced TNFR2 and Lin-28 expression in c-kit(+) CSCs that have entered cell cycle. These CSC responses are enhanced by exogenous TNF. TNFR2(-/-) mouse heart organ cultures subjected to hypoxia increase cardiac TNF but fail to induce CSC activation. Similarly, c-kit(+) CSCs isolated from mouse hearts exposed to hypoxia or TNF show induction of Lin-28, TNFR2, cell cycle entry, and cardiogenic marker, α-sarcomeric actin (α-SA), responses more pronounced by hypoxia in combination with TNF. Knockdown of Lin-28 by siRNA results in reduced levels of TNFR2 expression, cell cycle entry, and diminished expression of α-SA (references: Stem Cells 2013;31:1881-1892). In the present study, we detect the c-kit(+)Lin28(+) CSCs populations in a mouse coronary artery ligation ischemic model. Furthermore, the c-kit(+) CSCs are reduced in TNFR2-KO and Bmx-KO mice. Mechanistically, we show a crosstalk between the TNFR2-Bmx and the c-Kit signaling pathways to mediate CSC proliferation, survival and migration. These observations suggest that TNFR2-Bmx signaling in c-kit(+) CSCs induces cardiac repair, providing a potential strategy to stimulate cardiac regeneration by TNFR2-specific agonists.
RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization (vol 65, pg 7743, 2005)
Authors: K. Ito, Q. Liu, Manuel Salto-Tellez, T. Yano, K. Tada, H. Ida, C. Huang, N. Shah, M. Inoue, A. Rajnakova, K.C. Hiong, B.K. Peh, H.C. Han, T. Ito, M. Teh, K.G. Yeoh, Y. Ito
Journal: Cancer Research (2006)
Epistatic and allelic interactions control expression of ribosomal RNA gene clusters in Arabidopsis thaliana
Authors: Fernando A. Rabanal, Terezie Mandáková, Luz M. Soto-Jiménez, Robert Greenhalgh, David L. Parrott, Stefan Lutzmayer, Joshua G. Steffen, Viktoria Nizhynska, Richard Mott, Martin A. Lysak, Richard M. Clark, Magnus Nordborg
Journal: Genome biology (2017)

Ribosomal RNA (rRNA) accounts for the majority of the RNA in eukaryotic cells, and is encoded by hundreds to thousands of nearly identical gene copies, only a subset of which are active at any given time. In Arabidopsis thaliana, 45S rRNA genes are found in two large ribosomal DNA (rDNA) clusters and little is known about the contribution of each to the overall transcription pattern in the species.
P09.14 The National Institute of Health stroke scale (NIH-SS) does not predict RANO-MRI findings in the follow up assessment of glioma patients: a monocentric, retrospective analysis
Authors: V. Tobe, M. Desax, R. Sauter, M. Hollenstein, P. M. Putora, T. Hundsberger
Journal: Neuro-Oncology (2017)

Abstract: Treatment evaluation of gliomas is performed by using the RANO criteria. They are based on cerebral MRI, steroid use, and neurological function. However, assessment of neurological function is neither defined nor standardized due to the lack of a validated measure. We used the NIH-SS to measure neurological function at baseline and follow-up in glioma patients in a standardized manner and compared the results with outcomes on MRI using the RANO criteria. Methods: Retrospective analysis of glioma patients (WHO grade II-IV; > 18 years) treated from 2008 to 2015 at the cantonal hospital St. Gallen with at least one follow up MRI including an NIH-SS assessment (0-42 points). Patients were identified by chart review. Results: We identified 61 patients (36 males, median age 52 years) with WHO grade II (10), grade III (21) and grade IV (30) gliomas who met the minimal inclusion criteria. During the observation period 45 (74%) patients progressed and 27 (44%) died. Median PFS and OS was 1.70 and 3.22 years, respectively. We evaluated 471 baseline and follow up assessments, with a median of 6 per patient (range, 2-22).Median baseline NIH-SS was 0 points (range, 0 to 7) and median change in NIH-SS was also 0 points (range,-4 to 9). Statistical analysis (Cohen’s kappa, Stuart-Maxwell-test) did not reveal an agreement of changes in NIH-SS and MRI-RANO criteria. Conclusion: Neurological follow up assessment using the NIH-SS was not a useful predictor of MRI findings in this retrospective cohort of glioma patients.
Antimalarial efficacy of MMV390048, an inhibitor of <i>Plasmodium</i> phosphatidylinositol 4-kinase
Authors: Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P. Henrich, Tara S. Abraham, Marcus C. S. Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M. Blagborough, Sara E. Zakutansky, Anne-Marie Zeeman, Karen L. White, David M. Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J. Dechering, Robert W. Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J. Witty, Kennan C. Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M. Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A. Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K. Hanson, Gerard Drewes, Clemens H. M. Kocken, Michael J. Delves, Didier Leroy, David A. Fidock, David Waterson, Leslie J. Street, Kelly Chibale
Journal: Science Translational Medicine (2017)

MMV390048, a member of a new class of inhibitors of the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis.
ECCENTRIC KNEE FLEXOR STRENGTH AND HAMSTRING INJURY RISK IN ATHLETES WITH HISTORY OF ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION
Authors: Daniel Messer, Matthew Bourne, Ryan Timmins, David Opar, Morgan Williams, Anthony Shield
Journal: British Journal of Sports Medicine (2017)

Background Hamstring strain injuries (HSIs) are the most common cause of time loss from training and competition in elite football. Anterior cruciate ligament (ACL) ruptures are also prevalent and typically require surgery from hamstring grafts, which often results in chronic deficits in eccentric knee flexor strength, a known risk factor for HSI. Objective We aimed to determine the effect of prior ACL reconstruction (ACLR) on 1) eccentric knee flexor strength during the Nordic hamstring exercise (NHE) and; 2) the risk of future HSI. We hypothesised that athletes with a prior ACLR would display 1) lower levels of eccentric knee flexor strength than athletes without such history and; 2) an increased risk of future HSI. Design Prospective study. Setting Secondary analysis of 3 studies previously completed in Australian sport. Patients (or Participants) 541 elite to sub-elite male footballers had their eccentric knee flexor strength assessed using the NHE. Reports of HSIs and any history of ACL injuries were obtained. All participants were categorized into injury history groups. Interventions (or Assessment of Risk Factors) Injury history, eccentric strength. Main Outcome Measurements Prospective HSI occurrence. Results Athletes with history of ACLR were 39N (95% CI, 14.2–67.1; P&lt;0.005) weaker in the injured limb compared to the contralateral limb. Athletes with history of ACLR had a 3.18-fold (95% CI, 1.9–5.2; P&lt;0.001) greater risk of subsequent HSI than athletes without such history and was augmented to 5.69 (95% CI, 3.2–9.5; P&lt;0.001) if they had suffered HSI in the previous 12 months. Conclusions ACLR injured limbs are significantly weaker than uninjured limbs. Athletes with prior ACLR are significantly more likely to suffer future HSI, particularly if they have a recent history of HSI. This is the first adequately powered study to have assessed the effect of prior ACLR on future HSI risk.
Erratum: Corrigendum: Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
Authors: Angelika Bierhaus, Thomas Fleming, Stoyan Stoyanov, Andreas Leffler, Alexandru Babes, Cristian Neacsu, Susanne K Sauer, Mirjam Eberhardt, Martina Schnölzer, Felix Lasischka, Winfried L Neuhuber, Tatjana I Kichko, Ilze Konrade, Ralf Elvert, Walter Mier, Valdis Pirags, Ivan K Lukic, Michael Morcos, Thomas Dehmer, Naila Rabbani, Paul J Thornalley, Diane Edelstein, Carla Nau, Josephine Forbes, Per M Humpert, Markus Schwaninger, Dan Ziegler, David M Stern, Mark E Cooper, Uwe Haberkorn, Michael Brownlee, Peter W Reeh, Peter P Nawroth
Journal: Nature Medicine (2012)
EPIDEMIOLOGY OF SPORTS INJURIES AMONG HIGHLY TRAINED YOUTH MULTISPORT ATHLETES
Authors: Abdallah Rejeb, Amanda Johnson, Cosmin Horobeanu, Roel Vaeyens, Erik Witvrouw
Journal: British Journal of Sports Medicine (2017)

Background Injury epidemiology is imperative for the development of prevention strategies. Apart from football, little is known about injury characteristics on young elite athletes. Objective The aim of the present study is to examine the incidence of injuries sustained by adolescent highly trained multisport athletes. Design Longitudinal prospective study. Setting Aspire Academy for sport. Patients (or Participants) 166 male adolescent athletes (mean age 15.1+/−1.85) enrolled in the academy for both school and training. Interventions (or Assessment of Risk Factors) Using an injury surveillance system and record of training exposure (hours) during 5 consecutive seasons according to injury, body part, severity and mechanism. An injury was recorded as physical complaint requiring the attention of the medical staff. Overuse injuries were defined as injuries resulting from repetition of micro-trauma and with insidious onset. The severity of an injury was based on time loss (TL) criterias (Timpka et al . 2014). Main Outcome Measurements The incidence of overall injuries (per 1000 training Hours), injuries with TL, and no time loss (NTL), growth and overuse injuries were computed. Results Altogether 643 injuries were documented. Of these injuries, 87% were TL injuries with an incidence of 4.8 per 1000 hours; (95% confidence interval [CI], 4.4–5.2). Overuse injuries represented 50.3%. The prevalence of growth related injuries accounted for 20%. Exposure to training was associated with an increase of overuse injuruies (relative risk [1.03]). The most commonly diagnosed type of injury was muscle and tendon injuries (30.1%). Most injuries were located at the lower extremities (67%), with the majority affecting the foot and ankle (22%). There were only 13% serious injuries. Conclusions This study revealed high rates of overuse injuries and growth related conditions. Most injuries were minor. Our findings were consistent with similar studies on youth soccer. Further investigation is required to define injury potential risk factors.
Association of Mortality With the Death of a Sibling in Childhood
Authors: Yongfu Yu, Zeyan Liew, Sven Cnattingius, Jørn Olsen, Mogens Vestergaard, Bo Fu, Erik Thorlund Parner, Guoyou Qin, Naiqing Zhao, Jiong Li
Journal: JAMA Pediatrics (2017)

The death of a close relative is associated with an increased mortality risk among the bereaved, but much less is known about the potential association of the death of a sibling in childhood with mortality in this population.To examine the association between sibling death in childhood and subsequent mortality risk.This population-based cohort study of 5 005 029 participants evaluated linked national registers in Denmark (January 1, 1973, through December 31, 2009) and Sweden (January 1, 1973, through December 31, 2008). A total of 2 060 354 Danish and 2 944 675 Swedish children who survived the first 6 months of their life were included. We excluded 14 children who died of the same external cause as their siblings within 30 days. Data were analyzed from November 2, 2015, through October 14, 2016.Participants were classified as exposed if a sibling died in childhood (age <18 years).Poisson regression was used to estimate mortality rate ratio (MRR) with the exposure as a time-varying variable.Among the 55 818 participants who experienced sibling death in childhood (51.5% male and 48.5% female; median age at loss, 7.0 [interquartile range, 3.3-12.1] years), all-cause mortality risk was increased by 71% (MRR, 1.71; 95% CI, 1.57-1.87) during the follow-up of 37 years. The excess mortality risk was observed for groups with specific causes of death, and the higher MRRs were found when the sibling pairs died of the same cause (death due to disease [MRR, 2.16; 95% CI, 1.87-2.49]; death due to external cause [MRR, 1.91; 95% CI, 1.54-2.37]). The increased mortality risk after sibling death was seen across the follow-up period, regardless of the age at bereavement and the type of death among bereaved siblings, but the magnitude of association was stronger during the first year after sibling death (MRR, 2.51; 95% CI, 1.79-3.54). Higher MRRs were found among sibling pairs with the same sex (MRR, 1.92; 95% CI, 1.70-2.18) and close age (MRR, 1.94; 95% CI, 1.58-2.37).Bereavement in childhood because of the death of a sibling was associated with an increased risk for mortality in the short and long term. Health care professionals should be aware of individuals' vulnerability due to sibling death, especially for sibling pairs of close age or the same sex. Social and health care support may help to minimize the potential adverse effects on the bereaved sibling.
P09.45 Impact of extent of resection for long-term survival in patients with glioblastoma
Authors: T. Roh, E. Kim, S. Kang, J. Cho, C. Suh, S. Kim, J. Chang
Journal: Neuro-Oncology (2017)

OBJECTIVES: Survivors who live more than three years after diagnosis of glioblastoma (GBM), are referred as long-term survivors. Only 3-5% of glioblastoma patients are reported to survive longer than three years. However, we are having an increasing number of long-term survivors owing to advances in treatment. Our study explored the efficiency of the currently identified prognostic factors on the long-term survival of GBM patients. Materials and Methods: The authors reviewed all patients with newly diagnosed brain GBM who underwent surgery followed by combined chemoradiotherapy between 2005 and 2013, with a minimum of 3 years of follow-up. Clinical information was compared between long-term and short-term survivors. Results: Fifty-two (26.8%) patients survived more than three years. When gross total resection was achieved, 34.6% (44/127) of the patients survived more than three years, compared to 16.0% (20/125) patients survived more than three years when gross total resection was not achieved (p < 0.001). The median overall survival was 20.8 (95% confidence interval [CI] 17.7-23.9) months, and progression-free survival was 12.7 months. In univariate analysis, patients who are younger than 50 years, underwent gross total resection in initial surgery, with tumors smaller than 3.5cm, 1p/19q co-deleted, Isocitrate dehydrogenase (IDH) mutated, o6-DNA-methylguanine methyltransferase (MGMT) promoter methylated, Karnofsky performance scale more than 70, without cerebrospinal dissemination were significantly related to long-term survivors. In multivariate analysis, Age (<50), MGMT methylation, gross total resection were significant factors for long-term survival. Conclusions: In GBM patients who received current best treatment with temozolomide, more than one-fourth of patients survived more than three years. The extent of resection is a powerful predictor of long-term survival which can be controlled by the surgeon.