tbuckley/cabot-search huggingface dataset:
Abstract A17: TRPM7 kinase domain is involved in breast tumor cell metastasis
Authors: Tamer S. Kaoud, Xuemei Xie, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Mohamed F. Radwan, Chandra Bartholomeusz, Kevin N. Dalby
Journal: Cancer Research (2016)

Abstract Introduction: TRPM7 (transient receptor potential melastatin 7) is a non-selective cation channel fused to protein kinase domain at the C-terminal whose activity is linked to the control of actomyosin contractility. TRPM7 mediates adhesion and migration of breast cancer cells and promotes breast tumor metastasis. The lack of cell-permeable inhibitors of the kinase domain represents a barrier to understand the kinase function. Methods: Herein, we discover the first small molecule (KD-1) that targets TRPM7 kinase activity and characterize its mechanism of action in-vitro, in-cells and in-vivo. By using this inhibitor, we are investigated the involvement of TRPM7 kinase domain in breast tumor cell metastasis. Results: Mg2+ starvation, which promotes TRPM7 kinase activity, induces phosphorylation of eEF2. Treatment of Mg2+-starved HEK293 cells with KD-1 decreased eEF2 phosphorylation, consistent with TRPM7 kinase activity suppression in-cells. KD-1 decreased the binding of Myosin IIB to TRPM7 in HEK293 and MDA-MB-231 cells. And when MDA-MB-231 and BT 549 cells were treated with increasing doses of KD-1, no change in cell viability was seen. Interestingly, KD-1 inhibited migration and invasion in the MDA-MB-231 and BT 549 cells that is reportedly regulated by TRPM7 kinase activity. Finally, the bioluminescent signals (to assess lung metastasis) were significantly lower in KD-1-treated mice (25 and 50 mg/kg/day) than in mice treated with vehicle control (P ≤0.05, 2-sided t-test.). Conclusion: The discovered compound represents the first inhibitor that targets the kinase activity of transient receptor potential melastatin 7 (TRPM7). Inhibition of TRPM7 kinase activity may reduce or block breast tumor progression and/or metastasis. Citation Format: Tamer S. Kaoud, Xuemei Xie, Jihyun Park, Clint D.J. Tavares, Shreya Mitra, Micael Cano, Mohamed F. Radwan, Chandra Bartholomeusz, Kevin N. Dalby. TRPM7 kinase domain is involved in breast tumor cell metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A17.
TMOD-02. PEDIATRIC MEDULLOBLASTOMA XENOGRAFT GROWTH LOCATION TRANSFORMS TRANSCRIPTOMIC BUT NOT PHENOTYPIC PROFILES AND ALTERS SENSITIVITY TO RADIATION
Authors: Tina Etminan, Li Nan, Blake Moore, Brent Orr, Anita Hjelmeland, Eric Ring, Elizabeth Beierle, James Markert, Joseph Chewning, David Crossman, Yancey Gillespie, Gregory Friedman
Journal: Neuro-Oncology (2017)

Patient-derived xenograft models maintained in immunodeficient mice provide a powerful preclinical tool for testing oncologic therapies. Xenograft response to treatment informs which agents advance to human clinical trials. Frequently, pediatric brain tumor models are grown and tested heterotopically in the flank. We sought to determine if growing a Group 3 medulloblastoma xenograft in the flank compared to the brain altered the tumor profile. D341 Flank tumors were harvested and tumor pieces were injected into the flank or dissociated and 5x105 cells injected into the cerebrum. After tumor regrowth, tumors were harvested, prepared for routine histological examination, and duplicate biological samples were prepared for mRNA-sequencing (Illumina HiSeq2500). TopHat and Cufflinks were used to determine gene differences between each location (fold change ≥ ±2 and q-value <0.05). To compare location sensitivity to radiation, 10–20 mice were inoculated with 4x106 or 5x105 bioluminescently-enabled D341cells in the flank or cerebrum, respectively. Half of each group received 2 Gy of radiation 3 days/week for 6 doses. Bioluminescence was measured twice weekly. Tumor growth in the brain versus flank resulted in 348 significant gene differences. 90% of differences involved gene upregulation in the brain despite tumors appearing histologically similar. When normalized relative to their respective controls, mice lived 1.5x longer after tumor radiation in the flank compared to the brain. Average time for bioluminescence to recover back to baseline level after radiation was significantly greater (p<0.0001) in the flank (54.2 ± 10.7 days) versus brain (10.0 ± 2.1). Once tumors recovered from radiation (returned to baseline), they grew significantly faster (p=0.0021) in brain (time to 10-fold increase in bioluminescence: flank, 21.6 ± 11.0 days; brain 6.5 ± 0.5). These results suggest that significant genetic changes occur when a medulloblastoma xenograft is implanted in the flank compared to the brain and treatment sensitivity is modified. Further analysis is required to identify drivers of these changes.
Scanning movements during haptic search: similarity with fixations during visual search
Authors: Achille Pasqualotto
Journal: Behavioral and Brain Sciences (2017)

Abstract Finding relevant objects through vision, or visual search, is a crucial function that has received considerable attention in the literature. After decades of research, data suggest that visual fixations are more crucial to understanding how visual search works than are the attributes of stimuli. This idea receives further support from the field of haptic search.
Why the item will remain the unit of attentional selection in visual search
Authors: Martin Eimer
Journal: Behavioral and Brain Sciences (2017)

Abstract Hulleman &amp; Olivers (H&amp;O) reject item-based serial models of visual search, and they suggest that items are processed equally and globally during each fixation period. However, neuroscientific studies have shown that attentional biases can emerge in parallel but in a spatially selective item-based fashion. Even within a parallel architecture for visual search, the item remains the critical unit of selection.
Combination of active targeting, enzyme-triggered release and fluorescent dye into gold nanoclusters for endomicroscopy-guided photothermal/photodynamic therapy to pancreatic ductal adenocarcinoma
Authors: Hui Li, Ping Wang, Yunxiang Deng, Meiying Zeng, Yan Tang, Wei-Hong Zhu, Yingsheng Cheng
Journal: Biomaterials (2017)
Irritability and aggression in persistent youth concussions
Authors: Y Han Dong (Dan), Hannah L Combs, Lisa Koehl, Fernanda C Camargo, Carl G Mattacola
Journal: British Journal of Sports Medicine (2017)

Objective To assess whether irritability and aggression are viable indicators of persistent post-concussive symptoms in adolescents. Design Group differences between those diagnosed with concussions were analysed using ANOVAs ( p &lt; 0.05). Setting Outpatient clinic. Participants 46 concussed adolescents age 12–17 with persisting concussion symptoms were assessed. Athletes were split into two groups: those endorsing irritability/aggression (AGG, n=24) and a control group of those denying irritability/aggression (CON, n=22). Those with baseline psychiatric history and/or special education were excluded. Assessment of risk factors Post-concussive symptom variable relationships were assessed. Outcome measures group differences were analysed using ANOVAs. Results Adolescents endorsing irritability/aggression reported more fatigue ( p =0.002), disordered sleep ( p =0.001), anxiety (p =0.028), depression ( p =0.003), and mood lability ( p &lt;0.001) during clinical assessment. Adolescents reporting more irritability also had elevated scores on related psychometric scales, including the Beck Youth Inventory-II Anxiety [ t (41)=−2.916, p = 0.006], Depression [ t (41)=−3.551, p = 0.001], and Anger Scales [ t (41)=−2.958, p =0.005]. Conclusions Results indicate that adolescents with self-reported irritability and aggression post-concussion were more likely to display more affective symptoms than those who did not endorse irritability and aggression following concussions. They were also more likely to complain of fatigue and disordered sleep. These findings suggest that change in level of irritability/aggression could potentially serve as an identifiable indicator for parents and coaches to recognise when an adolescent is not recovering well post-concussion. Competing interests None.
Reply: “FULFIL an Unmet Need in Chronic Obstructive Pulmonary Disease” and “Triple Therapy in Chronic Obstructive Pulmonary Disease”
Authors: David A. Lipson, Helen Barnacle, Ruby Birk, Noushin Brealey, Nicholas Locantore, David A. Lomas, Andrea Ludwig-Sengpiel, Rajat Mohindra, Maggie Tabberer, Chang-Qing Zhu, Steven J. Pascoe
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
High Sustained Virologic Response (SVR) Rates in Patients with Chronic HCV GT1, 2 or 3 Infection Following 16 Weeks of MK-3682/Grazoprevir/MK-8408 Plus Ribavirin After Failure of 8 Weeks of Therapy (Part C of C-CREST-1 & 2)
Authors: L. Serfaty, S. Pianko, Z. Ben Ari, A. L. Laursen, Jesper Hansen, E. J. Gane, H. C. Huang, S. Jin, J. Bourque, D. Fernsler, S. Y. Wan, F. Dutko, B. Y. T. Nguyen, J. Wahl, E. Barr, J. R. Butterton
Journal: Hepatology (2016)
Redefining Acute Coronary Syndrome Therapy
Authors: Anita Slomski
Journal: JAMA (2017)

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Malignant germ cell ovarian cancer (MGCOC) in the Cancer Registry of Norway (CRN): A long-term follow-up study of presentation, survival, and second cancers.
Authors: Olesya Solheim, Alv A. Dahl, Jahn M Nesland, Janne Kaern, Claes Trope, Erik Rokkones, Sophie D Fossaa
Journal: Journal of Clinical Oncology (2013)

5533 Background: Significant improvements in the management of MGCOC have been achieved during the past two decades. However, data on long term risk conferred by radiation and chemotherapy is scarce. This is a long-term follow-up study of presentation, survival and second cancers. Methods: 360 female patients with histologically confirmed MGCOC, recorded in the CRN between 1953 and 2009 were identified. Patients, diagnosed before 1980 were separated from those with a diagnosis 1980+, reflecting the introduction of cis-platin based chemotherapy. Data on survival and second cancer incidence were obtained by linkage to the CRN. Cox Hazards Models and Kaplan Meier estimates were used. Results: The annual incidence doubled during the observation time. Malignant teratoma was the most common histological subtype (n = 190 [53%]), followed by dysgerminoma (n = 113 [31%]) and other non - dysgerminoma tumors (n = 57 [16%]). Over two thirds of the patients (median age 34 years [range 2-92]) had localized disease with distant disease in 23%. Before 1980 70% of 159 patients received subdiaphragmatic radiotherapy, this percentage was reduced to 24% after 1980, while chemotherapy increased from 11% to 38%. The 10 years ovarian cancer specific survival (OvCSS) (median follow-up time of 9.8 years [range: 0 - 54]) increased significantly to 93% in women treated in 1980+ compared to 62% to those with an earlier diagnosis (p &lt;0.001) . Significant period-related improvement in OvCSS was observed independently from the extent of the disease and for all histological subtypes. Women aged &gt;50 years had a significantly poorer OvCSS than younger ones, (HR=5.98, 95%CI [3.39 to 10.57]) adjusted for histological type and stage. A second cancer was diagnosed in 27 women, 63% of these cancers were located below the diaphragm within or close to the radiation field. Conclusions: The incidence of MGCOC is rising in Norway. We observed significant improvement of ovarian cancer specific survival after the introduction of cisplatin-based chemotherapy. The development of second cancer after treatment for MGCOC seems to be related to abdominal radiotherapy.
Multiple introductions and onward transmission of HIV-1 subtype B strains in Shanghai, China
Authors: Xiaoshan Li, Kexin Zhu, Yile Xue, Feiran Wei, Rong Gao, Ralf Duerr, Kun Fang, Wei Li, Yue Song, Guoping Du, Wenjuan Yan, Taha Hussein Musa, You Ge, Yu Ji, Ping Zhong, Pingmin Wei
Journal: Journal of Infection (2017)
TRTH-18. COMBINED TOPOTECAN AND CARBOPLATIN THERAPY FOR DIPG SUPPRESSES CELL GROWTH IN VITRO AND IS WELL TOLERATED WHEN DELIVERED BY CONVECTION ENHANCED DELIVERY IN VIVO
Authors: Alison Bienemann, Clare Killick-Cole, William Singleton, Azeem Arshad, Wyatt Marcella, Barua Neil, Gill Steven
Journal: Neuro-Oncology (2017)

Despite clinical advances, diffuse intrinsic pontine glioma (DIPG) remains universally fatal and urgently requires new treatment modalities to improve prognosis. Topotecan and carboplatin have formed treatment regimes for pediatric cancers as single agents with limited success. Both drugs have poor central nervous system penetration which may explain the lack of efficacy in the clinic when delivered systemically, furthermore, as single agents they have been administered to children with DIPG by convection enhanced delivery (CED) in early phase clinical trials and compassionate use programmes. Here, we describe the use of topotecan and carboplatin as combinatorial therapy for the treatment of DIPG in vitro and its tolerance when administered in vivo in a small animal model of intermittent CED. In this study, we assessed the in vitro cytotoxicity of combined topotecan and carboplatin in two ex vivo patient derived DIPG cell lines (SF7761 and SF8628). Combination therapy in vitro showed an additive effect on cell viability when compared to each single agent. Next, we determined the tolerance and toxicity of both drugs administered by CED using an implantable catheter system in juvenile wistar rats by clinical and neuropathological examination of infused brain 21 days after treatment. Results show that topotecan and carboplatin have an enhanced effect on DIPG cell viability in vitro when used in combination. This combination is currently being explored in a wider cohort of DIPG cell lines. In vivo assessment of sequential drug therapy in normal rat brain, shows this combination to be well tolerated and exhibited minimal CNS toxicity. Further work is required to see if this combination is effective in pre-clinical models of DIPG when administered by CED.
miR-196b-5p Regulates Colorectal Cancer Cell Migration and Metastases through Interaction with HOXB7 and GALNT5
Authors: Verena Stiegelbauer, Petra Vychytilova-Faltejskova, Michael Karbiener, Anna-Maria Pehserl, Andreas Reicher, Margit Resel, Ellen Heitzer, Cristina Ivan, Marc Bullock, Hui Ling, Alexander Deutsch, Annika Wulf-Goldenberg, Jan Basri Adiprasito, Herbert Stoeger, Johannes Haybaeck, Marek Svoboda, Michael Stotz, Gerald Hoefler, Ondrej Slaby, George Adrian Calin, Armin Gerger, Martin Pichler
Journal: Clinical Cancer Research (2017)

Purpose: miR-196b-5p has been previously implicated in malignant transformation; however, its role in colorectal cancer has not been fully explored. In this study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in colorectal cancer.Experimental Design: miR-196b-5p expression was quantitated by qRT-PCR in 2 independent cohorts composed of 292 patients with colorectal cancer in total, to explore its biomarker potential. Transient and stable gain- and loss-of-function experiments were conducted in a panel of colorectal cancer cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemosensitivity, migration/invasion, and metastases formation in vitro and in vivo The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in silico target prediction tools, luciferase interaction assays, and phenocopy/rescue gene knockdown experiments.Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in 2 independent colorectal cancer patient cohorts (P < 0.05, log-rank test). miR-196b-5p inhibition led to significantly increased colorectal cancer cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulated colorectal cancer cell migration.Conclusions: The association of low levels of miR-196b-5p and poor prognosis in patients with colorectal cancer can be explained by its influence on cancer cell migration and metastases formation. miR-196b-5p has an impact on colorectal cancer progression pathways through direct interaction with genes involved in cancer cell migration. Clin Cancer Res; 23(17); 5255-66. ©2017 AACR.
CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies
Authors: Diogo Gomes-Silva, Madhuwanti Srinivasan, Sandhya Sharma, Ciaran M. Lee, Dimitrios L. Wagner, Timothy H. Davis, Rayne H. Rouce, Gang Bao, Malcolm K. Brenner, Maksim Mamonkin
Journal: Blood (2017)
Abstract P239: Differential Proteomics of Subsarcolemmal and Intermyofibrillar Mitochondria in Aging Rat Cardiac Muscle
Authors: Cecilia Gelfi, Roberta Leone, Daniele Capitanio, Agnese Viganò, Chiara Fania, Luigi Anastasia, Annarosa Leri
Journal: Circulation Research (2011)

Recent studies revealed a key role of mitochondria in the 'axis of aging'. Mitochondrial dysfunction induces ROS production, leading to genotoxic damage, increasing erosion of telomeres followed by the activation of p53, blocking the mitochondrial biogenesis and generating a vicious cycle which induces the age-related mitochondrial dysfunction. This study, based on proteomic analysis, aims to elucidate the role of different mitochondrial subpopulations in the aging of heart in a rat model. Subsarcolemmal (SS) mitochondria play a major role in the adaptation of cells to physiological stimuli, whereas intermyofibrillar (IMF) mitochondria, are “power plants” for cardiac muscle contraction. The two subpopulations were isolated according to their localization in young (6 months), old adult (22 months) and senescent (30 months) Sprague Dawley rats by differential centrifugation in a density gradient. The differences at proteomic level were monitored by 2D-DIGE coupled with Maldi Tof and ESI MS/MS. While only few significant differences were detected in whole cardiac muscle proteome among young, adult and old rats, we detected many differences in SS mitochondrial proteome, particularly related to cell metabolism, cytoskeletal organization, membrane permeability and chaperon proteins indicating that aging may affect the SS mitochondria to maintain heart tissue homeostasis. Proteome of IMF mitocondria was characterized by a different pattern as compared to SS mitochondria and the number of proteins changed in aging were lower, even though a progression was observed from 22 to 30 months. These preliminary results suggest that protein dysregulation in mitochondrial proteome could significantly contribute to age-dependent impairment of cardiac function. However, these changes are not appreciable when analyzing the heart muscle proteome as a whole, highlighting the relevance of sub-cellular fractionation to detect molecular events involved in the aging process.
DIPG-16. NONINVASIVE ASSESSMENT OF TREATMENT RESPONSE FOR DIFFUSE INTRINSIC PONTINE GLIOMA USING HYPERPOLARIZED 13C METABOLIC IMAGING
Authors: Ilwoo Park, Adam Elkhaled, Xiaodong Yang, Yuying Zhai, Renuka Sriram, Dave Korenchan, John Kurhanewicz, Adam Cunha, I-Chow Hsu, Sarah Nelson, Sabine Mueller
Journal: Neuro-Oncology (2017)

INTRODUCTION: It remains often challenging on conventional MR imaging to distinguish between true versus pseudo-progression in children with diffuse intrinsic pontine glioma (DIPG). Hyperpolarized 13C MR metabolic imaging is a promising new technology that provides a non-invasive imaging approach to monitor changes in functional properties of tumors. We have shown previously that 13C-pyruvate can be used to monitor the rate and magnitude of conversion to 13C-lactate, which is elevated in tumors due to increased activity of the enzyme lactate dehydrogenase (LDH). We hypothesize that levels of hyperpolarized lactate, detected by monitoring hyperpolarized pyruvate metabolism using 13C MR metabolic imaging, will be modulated in response to therapy and might be a suitable noninvasive biomarker of therapy response. METHODS: In vitro imaging studies were performed by treating primary DIPG cells (SF8628) with panobinostat and assessing lactate to pyruvate ratios using 13C MR metabolic imaging. Activity of LDH was assessed using spectrophotometric assays. For in vivo studies, SF8628 cells were injected directly into the pons of rats and hyperpolarized 13C imaging was used to assess lactate/pyruvate ratios after therapy with 8 Gy radiation (n=3) compared to control animals (n=3). RESULTS: Pyruvate to lactate conversion was significantly reduced in the panobinostat-treated DIPG cells compared to control (p=0.03). As expected, the reduced lactate signal was associated with decreased levels of LDHA activity compared to control (p=0.03). Rats treated with radiation showed a decrease in lactate/pyruvate at day 2 and 4 compared to baseline, whereas control rats showed a continuous increase in lactate/pyruvate at day 2 and 4 compared to baseline. CONCLUSION: The results from this study suggest that hyperpolarized 13C metabolic imaging may be a suitable imaging marker to monitor therapy response in DIPG. A phase 1 study trial testing this imaging modality is ongoing.
Abstract 19626: Sudden Cardiac Arrest Risk of Non-Cardiac Depolarization-Blocking Drugs
Authors: Marieke T Blom, Emine Eke, Daniel A van Hoeijen, Patrick C Souverein, Anthonius de Boer, Hanno L Tan
Journal: Circulation (2016)

Introduction: Drugs may increase risk of ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac arrest (SCA) in susceptible individuals by blocking cardiac ion channels. This also applies ...