tbuckley/cabot-search huggingface dataset:
The Na+/H+ exchanger regulator factor (NHERF-1) regulates Gefitinib capability to modulate EGFR-dependent cell growth and invasion
Authors: Stephan J. Reshkin, Antonia Bellizzi, Amalia Azzariti, Rosangela Cardone, Giovanni Busco, Stefania Tommasi, Angelo Paradiso
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1247 

Ectodomain-targeted antibodies and tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) family are in clinical use but show limited efficacy in monotherapy, underlining the necessity to identify new and appropiate predictive factors that will allow physicians to correctly choose patients that can benefit from these agents. In this study we confirmed that the Na+/H+ exchanger regulatory factor 1 (NHERF1) is an important molecular integrator of the downstream events involved in EGFR activation in breast cancer cell lines. It stabilizes the EGFR, ErbB1, at the cell surface restricting receptor downregulation. Overexpression of NHERF1 was achieved via transfection with full-length NHERF1 in the pCDNA vector through LipoTAXI reagent (Stratagene). Cell growth was measured with the MTT assay and cell migration with the wound-healing assay. The subcellular location of NHERF1 was studied with immunofluorescence microscopy. Preliminary results, in a metastatic breast cancer cell line, MDA-MB-435, demonstrated that the overexpression of NHERF1 induced an increased sensitivity to gefitinib (IRESSA) either as inhibition of cell growth (IC50 after 72h shift from >100μM to 46μM) or cell migration. Moreover, EGFR activation, by EGF exposure, which induced an increased of NHERF-1 expression, produced a temporial shift of NHERF1 expression to the plasma membrane, suggesting a feedback loop between this molecule and EGFR. Based on these data, we hypothesize that it may be possible to further improve TKI efficacy by studying NHERF-1 characteristics, and by utilising combinatorial approches targeting EGFR and NHERF-1. IRESSA is a trademark of the AstraZeneca group of companies. Supported by AIRC funds 2002 - 2005
Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation
Authors: Janine Schmidt, Joan Enric Ramis-Zaldivar, Ferran Nadeu, Blanca Gonzalez-Farre, Alba Navarro, Caoimhe Egan, Ivonne Aidee Montes-Mojarro, Teresa Marafioti, Jose Cabeçadas, Jon van der Walt, Stefan Dojcinov, Andreas Rosenwald, German Ott, Irina Bonzheim, Falko Fend, Elias Campo, Elaine S. Jaffe, Itziar Salaverria, Leticia Quintanilla-Martinez
Journal: Blood (2017)
Neurocognitive and somatic recovery curves following concussion in female interscholastic soccer players
Authors: Cameron Forbes, Joseph J Glutting, Thomas W Kaminski
Journal: British Journal of Sports Medicine (2017)

Objective To measure the acute effects of SRC on cognition and symptoms over a 7-day time course in interscholastic female soccer players. Design Prospective. Setting Soccer fields. Participants 36 interscholastic female soccer players were equally divided into concussed [CON] (age 16.3±1.4 yr.) and non-concussed [NOCON] (age 16.1±1.3 yr.) groups. Intervention A 17-item SRC-symptom checklist was completed resulting in a total symptom score (SX). Neurocognitive performance [ANAM] throughput scores [higher scores better] (SRT1, SRT2, MSP, MTH, CPT1, CPT2, ST6) was also measured. The CON and NOCON were evaluated on five occasions: baseline, day 1 [D1], day 3 [D3], day 5 [D5], and day 7 [D7]. Outcome measures Data from the 8 outcome variables were analysed using the multivariate approach to a repeated measures ANOVA Main results Significant (p&lt;0.05) deficits in throughput scores in the CON, including SRT1 (222.0 vs 200.3 – D7) and SRT2 (224.4 vs. 209.3 – D7), MSP (42.9 vs 38.8 – D7), and ST6 (83.8 vs. 75.1 – D5) as well as SX (9.1 vs. 12.8 – D5) existed across the 7 day recovery period. Differences between baseline and D1 existed for CPT and MTH scores but they surpassed the baseline on D3. Conclusions CON subjects exhibited robust symptoms and neurocognitive deficits in the days immediately following SRC. Similar to American football, our recovery curves represent an initial decline with gradual improvements in the days succeeding post-injury and reinforce the need for clinicians to be cautious in the 7-day period post-concussion and depend on cognitive rest to aid recovery. Competing interests None.
Abstract 159: Ablation of the Hypertension Candidate Gene <i>ATP2B1</i> Leads To Deficient Calcium Cycling, Systolic Dysfunction and Heart Failure Following Pressure Overload
Authors: Nicholas P Stafford, Min Zi, Ludwig Neyses, Elizabeth J Cartwright
Journal: Circulation Research (2014)

Mutations in ATP2B1 encoding the ubiquitous calcium extrusion pump Plasma Membrane Calcium ATPase 1 (PMCA1) have recently identified it as having the strongest association of any gene to hypertension, yet the role of PMCA1 in the pressure-overloaded heart is not known. To investigate this we generated a novel mouse line carrying cardiomyocyte-specific deletion of PMCA1 (PMCA1 cko ) and challenged them with transverse aortic constriction (TAC) alongside littermate ‘floxed’ controls (PMCA1 f/f ). After two weeks, echocardiographic analysis revealed signs of systolic dysfunction and left ventricular (LV) dilation in PMCA1 cko hearts as evidenced by reduced fractional shortening and increased diastolic diameter (both p&lt;0.05), whilst function in PMCA1 f/f TAC controls remained preserved. This was accompanied by an increase in normalised lung weight in PMCA1 cko mice compared to sham operated and TAC controls (p&lt;0.05) indicative of pulmonary congestion and a progression into LV failure, despite comparable hypertrophic growth amongst the two TAC cohorts. Hemodynamic analysis following LV catheterisation revealed contractility, as measured by left ventricular elastance (E es ), to be increased in controls after TAC (PMCA1 f/f TAC 12.69 ± 1.63 vs sham 7.02 ± 1.11 mmHg/μl, p&lt;0.05), a change which was not reciprocated in knockout hearts (PMCA1 cko TAC 7.70 ± 1.19 vs sham 7.22 ± 1.55 mmHg/μl). To examine whether altered calcium handling could be the underlying cause of the observed phenotype, cardiomyocytes were isolated following one week TAC and loaded with Indo-1, prior to the onset of failure in PMCA1 cko hearts. Compatible with an increase in E es , systolic calcium levels were higher in PMCA1 f/f myocytes following pressure overload compared to sham controls (p&lt;0.05), whilst PMCA1 cko TAC myocytes displayed equivalent peak calcium levels to their respective sham controls. These results suggest that PMCA1 may play a necessary role in enhancing calcium cycling during the early response to pressure overload, and that disrupting this gene may increase the susceptibility to heart failure under these conditions. This may provide first evidence of a novel genetic basis for the development of heart failure in a proportion of hypertensive patients.
Role of sport-related concussion on academic achievement among youth athletes
Authors: Kelly Russell, Erin Selci, Adrian Rozbacher, Michael Ellis
Journal: British Journal of Sports Medicine (2017)

Objective Determine change in report card grades in youth after sustaining an acute sport-related concussion. Design Prospective case-series. Setting Paediatric, multi-disciplinary concussion. Participants 48 youth athletes (mean age 14.3; SD: 0.9; male: 57.6%) who sustained a sport-related concussion during the school year. Overall, 3 youth were lost to follow-up and 12 youth submitted only one report card. Interventions (or assessment of risk factors) Subsequently developing Post-Concussion Syndrome (PCS: symptomatic after 30 days), initial concussion severity (Post Concussion Symptom Scale), self-reported concussion history, sex, age, and academic accommodations during recovery. Outcome measures The report card immediately before the concussion and the report card immediately after medical clearance were collected. Pre-concussion and post-concussion overall and core grade-point average was calculated from report cards. Core grade-point average (GPA) included math, sciences, social studies, English, and foreign languages. Main results Overall GPA was 82.9% (SD 8.5%) pre-concussion and 82.7% (SD 8.0%) after concussion recovery (difference: −0.2%, 95% CI: −1.6%, 1.1%). Core GPA was 80.0% (SD 10.1%) pre-concussion and 79.4% (SD 10.4%) after concussion recovery (difference: −0.6%, 95% CI: −2.8%, 1.6%). There were no significant differences in overall or core GPA when stratified by sex, age, initial concussion severity, previous concussion history, receiving adequate school accommodations during recovery, or subsequently developing PCS. Conclusions There were no statistically or clinically significant changes in overall or core GPA during concussion recovery. Further research is needed to determine if there are more subtle changes in academic performance during the recovery process. Competing interests None.
Smoking cessation and COPD: further evidence is more necessary than ever
Authors: Lucy Wood, Jennifer K. Quint, Joan B. Soriano
Journal: European Respiratory Journal (2017)

For twelve years I had been trying to give up smoking. As Mark Twain said–and who does not know the remark? –"It's nothing to stop. I've quit a hundred times." I used to feel I had said it myself, for certainly I had tried on ten times ten occasions, once for a year, once for nine months, once for four months. Over and over again I gave them up, a hundred times over the years, but always I went back. For in my dreams, sooner or later, I struck a match, brought flame to the tip, then took in all my hunger for existence with the first puff. I felt impaled on desire itself–those fiends trapped in my chest and screaming for one drag. Change the given! Smoking is bad for your lungs; quitting is good, anytime, anyhow <http://ow.ly/5KHL30b0YXL>
GERM-01. GENETIC AND EPIGENETIC LANDSCAPE OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
Authors: Koichi Ichimura, Yoshiko Nakano, Kai Yamasaki, Mai Kitahara, Kaishi Satomi, Hirokazu Takami, Shintaro Fukushima, Masao Matsutani, Ryo Nishikawa
Journal: Neuro-Oncology (2017)

Central nervous system germ cell tumors (CNS GCTs) are the second most common central nervous system tumors in patients under 14 in Japan. To elucidate molecular basis of CNS GCTs, tumor samples and patients’ data were collected from the Intracranial Germ Cell Tumor Genome Analysis Consortium, a nationwide multi-center collaborative body to study CNS GCTs established in 2012. Whole exome sequencing was carried out in 41 CNS GCTs and targeted sequencing for up to 93 genes are performed in more than 200 CNS GCTs of all subtypes as well as 65 testicular GCTs. The results showed that the genes involved either in the MAPK pathway (e.g., KIT, RAS, CBL) or the PI3K/MTOR pathway (e.g., MTOR, PTEN) were collectively mutated in more than 50% of all types of GCTs. All 3 selected mutant MTOR protein had increased kinase activity and conferred enhanced cell migration and colony formation in vitro, which were completely suppressed by a dual MTOR inhibitor. A 450K array DNA methylation analysis has showed that pure germinomas but not other types of GCTs had a massive global hypomethylation. A comparison of methylation profiles between GCTs and mouse primordial germ cells (PGCs) of different developmental stage showed a striking similarity between pure germinomas and immature mouse PGC. Microdissected germinoma or teratoma components from a mixed GCT shared an identical MAPK (CBL) or PI3K (MTOR) mutation while displaying distinct methylation profiles. These findings suggest that GCTs may develop from an immature PGC that acquired MAPK/PI3K pathway mutations, and that further differentiate into distinct subtypes through epigenetic mechanisms. Thus, our combined genetic and epigenetic study suggested that CNS GCTs may be originated from PGC by MAPK/PI3K mutation and epigenetically driven to differentiate into various subtypes.
Biomodulatory Metronomic Therapy Shows Remarkable Activity in Chemorefractory Multi-System Langerhans Cell Histiocytosis
Authors: Daniel Heudobler, Klaus Rehe, Juergen Foell, Selim Corbacioglu, Gerhard Hildebrandt, Wolfgang Herr, Albrecht Reichle, Martin Vogelhuber
Journal: Blood (2016)
Prevention activity can reduce catastrophic head injuries in judo players
Authors: Shinji Nagahiro, Yoshifumi Mizobuchi
Journal: British Journal of Sports Medicine (2017)

Objective To determine the features of catastrophic judo head injuries and the effects of prevention activities. Study Design Retrospective descriptive epidemiological study Methods We reviewed catastrophic head injuries in 44 judo players reported in the System for Compensation of Loss or Damage in the All Japan Judo Federation from 2003 to 2015. Prevention activities such as safety manual creation and enlightenment courses for judo instructors, including understanding of the consensus statement on concussion, were introduced in 2011. The incidences of death and poor outcomes before (Group A) and after (Group B) these prevention activities were compared. Results The majority of catastrophic head injuries were acute subdural hematoma. The average patient age was 16.5 years. Most of the injured patients were novices without fully developed physical stamina and skills. Furthermore, Ukemi, a protection technique applied while being thrown, had not been fully mastered. Among 36 Group A players, 8 (23%) had a prior history of judo-related head injury with posttraumatic headache. In 4 of these 8 patients, CT and/or MRI detected a thin subdural hematoma during evaluation for persistent headache. Annual rates of catastrophic head injury were 4.0 in Group A for 9 years and 2.0 in Group B for 4 years, and the annual respective mortality rates were 2.0 and 0.25. Both rates were reduced after the prevention action introduced in 2011, although the decreases were not statistically significant. Conclusions Continuous prevention activities can reduce catastrophic judo head injuries. Competing interests Authors have no conflicts of interest regarding this study.
Biosensors to assess performance status in cancer (BioAPS Study).
Authors: Arvind Manohar Shinde, Gillian K. Gresham, Andrew Eugene Hendifar, Richard Tuli, Brennan Spiegel, Robert A. Figlin
Journal: Journal of Clinical Oncology (2016)

TPS6631 Background: Oncologists assess patient (Pt) performance status (PS) to inform appropriate chemotherapy (Ct) decisions. Eastern Cooperative Oncology Group PS (ECOG-PS, range 0-5) and Karnofsky PS (KPS; range 0-100%), are subjective scales of function and ability for self-care, and are the primary scales used in oncologic research and practice. Higher ECOG-PS/Lower KPS scores are associated with poorer survival outcomes and Ct tolerance. Despite its prognostic importance, ECOG-PS/KPS have been criticized for being biased and incomplete resulting in inappropriate Ct decisions that are costly and potentially harmful. They also do not capture a Pts “free range” activity outside of the clinic. Wearable biometric sensors, such as Fitbit Charge HR (FC), can provide objective data regarding activity (number of steps, stairs climbed, heart rate (HR)) outside the the four walls of the clinic. Longitudinally collected patient reported outcomes (PROs) around function and activity may provide a better understanding of Pt PS. We hypothesize that combining objective data from FC with PROs could provide a more accurate assessment of patient PS. Furthermore, longitudinally collected biometric data may allow for real-time detection of Pt distress. Methods: We will recruit 30 Pts with stage 3/4 cancer, ≥ 18yrs, English speaking, ambulatory, with a smartphone, and prognosis of > 3 months. Subjects will wear a FC for 2 weeks, and complete online NIH PROMIS tools (Physical Function, Pain, Sleep, Fatigue, and Emotional Distress) on D1, 8, and 15. At Pt visits, MDs/RNs will score ECOG-PS/KPS History, physical exam and assessment for frailty phenotype will be completed at baseline. An exit interview will capture Pt experience with FC. Ct toxicity and survival will be recorded at 3- and 6-month follow-up. Primary Objective: Assess the association between FC data, and PROMIS PROs versus validated ECOG-PS/KPS scales. Secondary Objectives: Assess 1) the association between FC data and PROMIS indicators of distress, 2) the correlation of frailty phenotype with biosensor activity data, 3) the feasibility of collecting biometric data and PROMIS tools in cancer pts, and 4) the relationship between FC data and Ct toxicity and survival outcomes. Clinical trial information: NCT02659358.
MEDU-11. SONIC HEDGEHOG AND REACTIVE OXYGEN SPECIES INTERACT TO REGULATE MITOCHONDRIAL MORPHOLOGY IN MEDULLOBLASTOMA
Authors: Anshu Malhotra, Chad Potts, Abhinav Dey, Anna M. Kenney
Journal: Neuro-Oncology (2017)

Sonic hedgehog (Shh) signaling is closely coupled with the bioenergetics of medulloblastoma, the most common malignant pediatric solid tumor. We have reported earlier that Shh causes deregulation of mitochondrial biogenesis by suppressing mitofusins, leading to fragmented mitochondria in vitro as well as in SmoA1 mouse medulloblastomas (MB) in vivo. Ectopic expression of mitofusins restored mitochondrial fusion accompanied by a rescue in proliferation to the non-proliferative phenotype. In the present study, we report that a rescue in proliferation is also observed in organotypic slice cultures implanted with mitofusin overexpressing SmoA1 neurospheres. When mitofusin overexpressing tumor cells were injected into the cerebella of postnatal day 2 mice, tumor development was significantly delayed. We have significant evidence indicating that Shh induces high increases levels of Reactive Oxygen Species (ROS) in Cerebellar Granule Neuron Precursor cells (CGNPs). When total ROS in a cell was scavenged by treating with N-Acetyl Cytosine (NAC), the fragmented mitochondrial morphology was rescued to their fused morphology. NADPH Oxidase 4 (NOX4) is a known producer of ROS in cells. When we treated CGNPs with apocynin, an NADPH oxidase inhibitor, a significant reduction in proliferation was observed. NOX4 was also found to localise in the peri-vascular niche in SmoA1 tumors. This could have possible implications for a role of ROS in promoting the proliferation of tumor re-populating cells post irradiation. Our goal is to determine if manipulating ROS-mediated mitochondrial dynamics can restore the metabolic profile of tumor cells to that of non-transformed, non-proliferating cells. This would suggest a potential novel treatment paradigm for medulloblastoma that may reduce the requirement for high dose radiation.
Abstract 138: Thermo-Responsive, Self-Adhesive Injectable Heart Scaffold for Pluripotent Stem Cell-Derived Cardiomyocyte Delivery
Authors: Xintong Wang, Young Wook Chun, Lin Zhong, Charles Hong, Chee Lim, Simon Maltais, Hak-Joon Sung
Journal: Circulation Research (2013)

Introduction: Regeneration of heart tissue post-infarction is hampered by the limited proliferation of cardiomyocytes. Due to their expandability and pluripotency, human induced pluripotent stem cells (iPSCs) are considered an ideal cell source to produce cardiomyocytes and regenerate heart tissue. However, previous clinical trials revealed the quick loss of injected cells (&gt; 90%) after delivery in aqueous solutions (e.g. phosphate buffered saline, PBS), which significantly limited the clinical outcome. To enhance the retention of cells and promote tissue regeneration, we synthesized a temperature-responsive polymer which is water-soluble to encapsulate cardiomyocytes at room temperature, following injection into epicardium, it quickly forms a gel and holds the cells in situ at body temperature. Functional peptides can be conjugated to this material and facilitate its adhesion to cardiac tissue for optimal cell integration and cardiac regeneration. Materials and Methods: The polymers monomethoxypoly(ethylene glycol) (mPEG) and poly(ε-caprolactone) (PCL) were copolymerized to produce mPEG-PCL. The polymer was further modified with decorin-derived peptide, which can firmly bind to collagenous tissue. The solution-to-gel transition temperature (Ts) was determined by dissolving the polymer in PBS, slowly increasing the temperature from 4 to 40°C and checking the fluidity of the solution. The viability of cardiomyocytes encapsulated in polymer gel at 37°C for 2 weeks was determined by calcein AM. Peptide-modified polymer solution was injected to the epithelium of adult rat heart. Echocardiography was performed to evaluate the heart functions before and two weeks post injection. The tissue response to this material was studied by histological staining. Results and Conclusion: The material successfully underwent solution-to-gel transition at 37°C. Human iPSCs-derived cardiomyocytes encapsulated in the gel were still viable after 2 weeks. There was no heart dysfunction 2 weeks post-injection. No significant inflammatory response was induced in vivo. These demonstrate the safety and feasibility of this material to delivery cardiomyocytes to infarct heart.
Mutation profiling of <i>KRAS</i>, <i>BRAF</i>, and <i>PIK3CA </i>genes in colorectal cancer tissue.
Authors: S. McKeown, J. E. Doherty, M. P. Beaney, M. J. Latten, H. A. Murray, M. A. Crockard, J. V. Lamont, S. P. FitzGerald
Journal: Journal of Clinical Oncology (2012)

e14022 Background: Personalised cancer medicine based on mutation profiling of individual tumours is now a reality in the treatment of metastatic colorectal cancer (CRC) since the discovery of mutant KRAS status and resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. However, up to 65% of patients with KRAS wildtype tumours are resistant to anti-EGFR therapy. Mutations in other downstream effectors of the EGFR signaling pathway may also have a negative impact on patient response to anti-EGFR therapy. This study reportsthe analytical performance of a biochip array for the rapid simultaneous detection of 20 mutations within KRAS (including codons 12, 13, 61 and 146), BRAF and PIK3CA genes in CRC tissue samples. Methods: DNA from frozen CRC tissue samples was analysed using the Evidence Investigator KRAS/BRAF/PIK3CA Array. The assay is based on a combination of multiplex PCR and biochip array hybridisation, which enables high multiplexing detection. Innovative PCR priming technology permits high discrimination between multiple wildtype and mutant DNA regions. Providing there are enough copies of DNA present, approximately 1% of mutant can readily be detected in a background of wildtype genomic DNA. Analysis can be completed, from template DNA, through PCR (single reaction) to data readout in less than 3 hours. Confirmation of assay results was performed using Sanger sequencing and pyrosequencing. Results: Mutations were detected in 56% (14/25) of CRC tissue samples assessed. 6 samples were positive for KRAS, 3 for BRAF and 6 for PIK3CA with one sample harbouring both a KRAS and PIK3CA mutation. KRAS targets detected also included much rarer codon 61 and 13 mutations. Sanger sequencing confirmed all positive results apart from two, which were assessed via pyrosequencing. Conclusions: These findings demonstrate the applicability of the KRAS/BRAF/PIK3CA Array to rapidly simultaneously detect mutations within these genes in CRC tissue. The detection of additional markers besides KRAS and extending the profile of this gene to include other codons beyond 12 and 13 may aid in the selection of candidate patients to receive anti-EGFR therapy thereby maximising drug efficacy and minimising adverse patient effects.