tbuckley/cabot-search huggingface dataset:
Nutlin-3a sensitizes a p53-null neuroblastoma cell line to doxorubicin: Potential roles for p73 and E2F1
Authors: Susan Peirce, Harry Findley
Journal: Cancer Research (2008)

3002   Neuroblastoma (NB) is a childhood solid tumor of the sympathetic nervous system arising from neural crest progenitor cells, and children with advanced Stage 3 and 4 cancers are particularly at risk for relapse and chemoresistant disease. Alterations in p53 expression from the wild-type phenotype are rare in NB at diagnosis. However, inactivation or elimination of p53 are common in relapsed NB, one likely mechanism of resistance to therapy. Recently, a selective small-molecule antagonist  of Mdm2, Nutlin-3 (N-3), was developed; this binds the p53 pocket  of Mdm2, releasing p53 from negative control. Doxorubicin (dox), a genotoxic agent commonly used in NB therapy, induces pleiotropic effects not well understood, but tumor suppressors are known to be upregulated. In this study, we investigated the ability of N-3 to induce apoptosis in a p53-null and dox-resistant NB cell line, LA155N, a cell line containing a homologue of p53 which occurs in multiple isoforms. The full-length, tumor-suppressive form (TAp73alpha) may functionally substitute for p53. Using WST-1 assays, we demonstrated that N-3 sensitizes LA155N cells to dox treatments in a synergistic manner, although cells were relatively resistant to N-3 as a single agent. Immunoblot analysis of N-3 single treatments indicated increases in TAp73alpha levels as well as the transcription factor E2F1, which also binds to Mdm2 and is known to enhance apoptosis in some systems. Although there were no changes in the levels of Bax or pro-caspase-3 following N-3 treatment, combination treatments resulted in increases in Bax and Puma. By cell cycle analysis, we found that N-3 has no effect on subG1-G1 levels, but induces significant cell cycle blocking in combination with dox treatment. Using IP, we showed that p73 binds to Mdm2, and that N-3 prevents this binding. Thus, we used siRNA to knock down p73 expression to reverse the sensitization to the combination treatment. Using three siRNA primer sets, we achieved an almost complete reduction of TAp73alpha with one set, and incremental decreases with two sets, at both protein and mRNA levels. WST-1 assays indicated a reduction of sensitization corresponding to the siRNA used. Strikingly, we found a significant increase in proliferation with N-3 treatment alone following complete TAp73alpha knockdown, and this corresponded to decreased levels of E2F1 seen on immunoblots. Unlike the interaction of p53 with Mdm2, TAp73alpha is protected from proteosomal degradation by its binding to Mdm2. Thus, we conjecture that TAp73alpha interacts with E2F1 to induce apoptosis, that E2F1 and TAp73alpha are stabilized by their association, and that knockdown of TAp73alpha results in E2F1 instability and loss. siRNA knockdown of E2F1 should help to answer these questions. This study begins to address p53-independent mechanisms of Nutlin-3 action in NB, especially in combination with other chemotherapeutics.
LncRNA MIR31HG targets HIF1A and P21 to facilitate head and neck cancer cell proliferation and tumorigenesis by promoting cell-cycle progression
Authors: Ru Wang, Zhihong Ma, Ling Feng, Yifan Yang, Chen Tan, Qian Shi, Meng Lian, Shizhi He, Hongzhi Ma, Jugao Fang
Journal: Molecular Cancer (2018)

LncRNAs are involved in the initiation and progression of cancer. However, the molecular mechanism and diverse clinical prognosis of MIR31HG in head and neck squamous cell carcinoma (HNSCC) are still unclear. Our previous microarray analysis showed that lncRNA MIR31HG interacted with HIF1A may play an oncogenic role in laryngeal squamous cell cancer (LSCC). To determine whether lncRNA MIR31HG served as a poor prognosis factor and targeted HIF1A to facilitate cell proliferation and tumorigenesis in human HNSCC, we found MIR31HG and HIF1A were overexpressed in LSCC, MIR31HG overexpression or co-expression of HIF1A-positive and p21-negative could serve as a poor prognostic factor for LSCC patients. We further confirmed that MIR31HG promoted cell proliferation, cell cycle progression, and inhibited cell apoptosis in vitro and in vivo. The ingenuity pathway analysis and Western blot indicated that MIR31HG regulated cell cycle progression via HIF1A and p21 in HNSCC. The current results provide evidences for the role of MIR31HG in promoting HNSCC progression and identify MIR31HG as a prognostic biomarker and putative therapeutic target in HNSCC.
Histologic Analysis of Endoscopic Ultrasound-Guided Through the Needle Microforceps Biopsies Accurately Identifies Mucinous Pancreas Cysts
Authors: Dennis Yang, Arvind J. Trindade, Patrick Yachimski, Petros Benias, Jose Nieto, Amar Manvar, Sammy Ho, Ashwini Esnakula, Anthony Gamboa, Amrita Sethi, Anand Gupte, Harshit S. Khara, David L. Diehl, Abdul El Chafic, Janak Shah, Christopher E. Forsmark, Peter V. Draganov
Journal: Clinical Gastroenterology and Hepatology (2018)
Mast cell chymase impairs bronchial epithelium integrity by degrading cell junction molecules of epithelial cells
Authors: Xiaoying Zhou, Tao Wei, Christopher W. Cox, Yuan Jiang, William R. Roche, Andrew F. Walls
Journal: Allergy (2018)

An increased degree of mast cell (MC) degranulation and damage to the epithelial lining are prominent features of bronchial asthma. In asthmatic airways, it seems likely that epithelial cells will be exposed to increased concentrations of proteases from MC, though their actions on the epithelium are still not very clear.Bronchial rings from human lung tissue or 16HBE cell monolayer were incubated with MC chymase in different doses or various inhibitors. The sections of paraffin-embedded tissue were haematoxylin-eosin stained and computerized by image analysis for epithelial damage-scale-evaluation; the cell viability, proliferation, adhesion and lactate dehydrogenase activity release were assayed; the expressions of gelatinases, cell junction molecules and structure proteins of 16HBE were examined.Mast cell chymase was found to provoke profound changes in the morphology of bronchi epithelial layer. Following incubation with chymase, there was 40% reduction in the length of epithelium that was intact, with detachment of columnar epithelial cells and basal cells. Chymase reduced epithelial cell proliferation and induced cell detachment, which were associated with the changes in secretion and activation of matrix metalloproteinase-2/9. In intact epithelial cell layers, immunocytochemistry study revealed that chymase reduced the expressions of occludin, claudin-4, ZO-1, E-cadherin, focal adhesion kinase and cytokeratin. Overall data of this study indicated that MC chymase can influence tissue remodelling, disrupt epithelial cell junctions, inhibit wound healing and impair the barrier function of epithelium, resulting in dysfunction of airway wall and ECM remodelling in pathogenesis of asthma.Mast cell chymase plays a key role in inducing the damage to bronchial epithelium in asthma.
Abstract 12870: Macrophage Toll-like Receptor 9 Signaling Contributes to the Development of Insulin Resistance through the Promotion of Inflammation in Adipose Tissue
Authors: Sachiko Nishimoto, Daiju Fukuda, Michio Shimabukuro, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Yutaka Nakaya, Masataka Sata
Journal: Circulation (2013)

Background: Chronic inflammation closely associates with insulin resistance. Toll-like receptor (TLR)9 recognizes bacterial unmethylated DNA and plays a role in innate defense, although it can also provoke inflammation in response to fragmented DNA from mammalian cells, contributing to the pathogenesis of autoimmune diseases. The role of TLR9 in the development of insulin resistance, however, remains unknown. This study tested the hypothesis that TLR9 signal promotes inflammation in adipose tissue and causes insulin resistance in high-fat fed mice. Methods and Results: We fed TLR9 deficient (TLR9 KO) mice or wild type (WT) mice a high-fat diet (60% fat) for 12 weeks. High-fat feeding increased TLR9 expression in adipose tissue. Results of quantitative PCR demonstrated macrophage fraction in adipose tissue dominantly expressed TLR9. Weight of epididymal fat pad and liver, and plasma lipid levels were similar between two groups, however results of glucose tolerance test and insulin tolerance test at 10 week...
AB1030 Febuxostat versus allopurinol streamlined trial (FAST): baseline characteristics of the randomised patient population
Authors: I. Mackenzie, T. MacDonald, I. Ford, G. Nuki
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The Febuxostat versus Allopurinol Streamlined Trial (FAST) is a prospective, randomised, open-label, blinded endpoint trial comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricaemia.<sup>1</sup> The trial includes patients aged over 60 years who are taking chronic allopurinol therapy at baseline and have at least one additional cardiovascular risk factor. After uptitration on allopurinol to reach EULAR urate targets, patients are randomised to febuxostat or allopurinol then followed up for events. Patient recruitment to the trial completed in late 2017 and follow-up is ongoing. <h3>Objectives</h3> To describe the baseline characteristics of the patients randomised into the FAST study. <h3>Methods</h3> The primary endpoint of the FAST study is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the hazard ratio for the primary outcome of 1.3. <h3>Results</h3> 6142 patients from UK, Denmark and Sweden have been randomised into the FAST study. The mean age at randomisation was 71.0±6.4 (SD) years. 85.3% of participants are male. 57.3% are former smokers and 7.9% current smokers. Mean systolic blood pressure was 138±18 mmHg and mean diastolic blood pressure 75±12 mmHg. Mean body mass index was 31.1±5.2 kg/m<sup>2</sup>. 10.7% of participants had a history of previous myocardial infarction, 5.0% a history of previous cerebrovascular accident and 4.8% a history of peripheral arterial disease. 22.5% had a history of diabetes mellitus and 4.6% a history of heart failure. 78.0% had a history of high blood pressure. 33.3% had a history of any cardiovascular disease (defined as history of myocardial infarction, cerebrovascular accident, transient ischaemic attack, acute coronary syndrome, coronary revascularisation, angina pectoris or heart failure). The mean baseline urate at study entry (screening) was 297±47 umol/L. The mean allopurinol dose being taken at study entry (screening) was 225±106 mg daily. 2206 patients (35.9%) had at least one uptitration of allopurinol dose prior to randomisation. <h3>Conclusions</h3> This ongoing European trial will report on the cardiovascular safety of febuxostat versus allopurinol in patients with symptomatic hyperuricaemia. <h3>Reference</h3> [1] MacDonald TM, Ford I, Nuki G, Mackenzie IS, et al. Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large, prospective, randomised, open, blinded-endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. BMJ Open2014;4:e005354. doi:10.1136/bmjopen-2014-005354 <h3>Acknowledgements</h3> The FAST study is funded by Menarini and sponsored by the University of Dundee. <h3>Disclosure of Interest</h3> None declared
AB0658 Different orbital manifestations of granulomatosis with polyangiitis. comparative study
Authors: D. Ismailova, I. Abramova, P. Novikov
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ophthalmic manifestations are typical for granulomatosis with polyangiitis (GPA), and occur in 28.6%–60% of patients. In 8% of cases they lead to permanent visual loss. According to different studies orbital lesion develops in 5%–30.6% of GPA patients and is considered to be the second most prevalent ophthalmic manifestation after conjunctivitis/episcleritis. <h3>Objectives</h3> to study clinical features of different orbital manifestations of GPA. <h3>Methods</h3> 74 GPA patients with orbital involvement were studied and compared. 3 types of orbital involvement were proposed: orbital mass (45 patients), dacryoadenitis (26 patients) and myositis (3 patients). Patients with orbital mass (group 1) and dacryoadenitis (group 2) were included into further investigation. <h3>Results</h3> Patients in group 1 had systemic disease in 51,1% compared to 7,7% in group 2. Patients with orbital mass presented with more severe clinical manifestations, including significant exophthalmos (82,2%), periorbital oedema (95,5%) and hyperemia (46,7%), strabismus (31,1%), globe movement restriction (71,1%), chemosis (8,9%). Orbital mass was accompanied by necrotizing scleritis in 7 and PUK in 6 patients. Symptoms included orbital pain (88,9%) and binocular diplopia (73,3%). BCVA in this group was 0.67. Clinical outcome was relatively unfavourable: in 24,4% BCVA was less than 0.3, in 5 patients enucleation was performed, in 24,4% strabismus developed and in 73,3% globe movement restriction occurred. Clinical course and outcome were significantly more favourable in patients with dacryoadenitis. Periorbital oedema, exophthalmos and chemosis did not show significant difference in groups, though orbital pain, binocular diplopia, globe movement restriction, strabismus, optic neuropathy, necrotizing scleritis, PUK were observed in group1 significantly more often. Clinical outcome in group 2 was much more favourable with no cases of enucleation and persistent visual loss. They only had moderate exophthalmos 1–3 mm (65,4%), strabismus (7,7%) and mild globe movement restriction (19,2%). <h3>Conclusions</h3> Three types of orbital involvement in GPA were proposed: orbital mass, dacryoadenitis and myositis. Patients with orbital mass are characterised more often with systemic disease, more severe clinical course not uncommon associated with other ocular manifestations (necrotizing scleritis, PUK, orbital walls destruction), relatively unfavourable outcome with high level of morbidity (optic nerve atrophy, anophthalmos, strabismus) and higher rate of recurrences. <h3>Disclosure of Interest</h3> None declared
Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia
Authors: Qiang Wang, Hei Man Wu, Weihua Yue, Hao Yan, Yamin Zhang, Liwen Tan, Wei Deng, Qi Chen, Guigang Yang, Tianlan Lu, Lifang Wang, Fuquan Zhang, Jianli Yang, Keqing Li, Luxian Lv, Qingrong Tan, Hongyan Zhang, Xin Ma, Fude Yang, Lingjiang Li, Chuanyue Wang, Xiaohong Ma, Liansheng Zhao, Hongyan Ren, Hao Yu, Yingcheng Wang, Xun Hu, Dai Zhang, Pak Sham, Tao Li
Journal: JAMA Psychiatry (2018)

The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown.To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy.In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017.Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach.Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs.Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics.Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934.
AB0077 Ciprofloxacin-related acute peripheral neuropathy in a patient with sle
Authors: J Singh, R Brasington
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Ciprofloxacin is a broad-spectrum antibiotic commonly used for skin, respiratory tract and urinary tract infections. It is associated with a very few serious adverse effects.<sup>1,2</sup> In a report of worldwide experience with ciprofloxacin, peripheral neuropathy was reported in one patient only, with no details available.<sup>3</sup> We describe the first case of ciprofloxacin-related peripheral neuropathy in a patient with SLE. <h3>Objectives</h3> <h3>Methods</h3> <h3>Results</h3> The patient, 18-yr-old African-American female, presented with five-day history of an acute onset of progressive tingling, numbness and weakness of both lower extremities. The symptoms began one day after the initiation of ciprofloxacin for treatment of urinary tract infection. At the time of hospital admission, patient was found to have bilateral symmetrical decrease in pain, temperature and light touch perception below knees, with weakness of both plantar- and dorsi-flexion of the ankle and an absence of bilateral ankle reflexes. Nerve conduction studies and EMG were done, which revealed a predominant sensory axonal neuropathy in lower extremities, with relative sparing of the motor component. MRI of the spine didn't reveal any evidence of transverse myelitis. A diagnosis of ciprofloxacin-related peripheral neuropathy was made. Ciprofloxacin was discontinued. During the two day stay in the hospital, she started regaining the sensation in both lower extremities, without any other intervention. Within 10 days of the discontinuation of ciprofloxacin, her symptoms had completely resolved. She had no recurrence of the symptoms and no residual neurological deficit. <h3>Conclusion</h3> Peripheral neuropathy is an uncommon manifestation of SLE. It is more rarely seen as adverse effect of ciprofloxacin. It is possible that the presence of SLE, and the concomitant use of hydroxychloroquine in our patient may have predisposed her to the occurrence of this rare adverse effect of ciprofloxacin. A similar case of possible drug interaction has been reported in a patient receiving therapy with ciprofloxacin, NSAID?s and chloroquine, who experienced neurological adverse effect.<sup>4</sup> <h3>References</h3> Rahm V, Schacht P. Safety of ciprofloxacin. A review. Scand J Infect Dis Suppl. 1989;60:120–8 Schacht P, Arceri G, Hullmann R. Safety of oral ciprofloxacin. An update based on clinical trial results. Am J Med. 1989;<b>87</b>(5A):98S–102S Reiter C, Pfeiffer M, Hullman RN. Safety of ciprofloxacin based on Phase IV studies in the Federal Republic of Germany. Am J Med. 1989;<b>87</b>(5A):103S–108S Rollof J, Vinge E. Neurologic adverse effects during concomitant therapy with ciprofloxacin, NSAID?s and chloroquine: possible drug interaction. Ann Pharmacother. 1993;27(9):1058–9
Immunotherapy for Glioblastoma: Adoptive T-cell Strategies
Authors: Bryan D. Choi, Marcela V. Maus, Carl H. June, John H. Sampson
Journal: Clinical Cancer Research (2018)

Abstract Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immunotherapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors (CAR), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anticancer therapy will ultimately work for brain tumors, and whether the primary immunologic challenges in this disease, which include antigenic heterogeneity, immune suppression, and T-cell exhaustion, can be adequately addressed. Here, we contextualize these concepts by reviewing recent developments in ACT for GBM, with a special focus on pioneering clinical trials of CAR T-cell therapy.
Fluorescent Lymphography–Guided Lymphadenectomy During Robotic Radical Gastrectomy for Gastric Cancer
Authors: In Gyu Kwon, Taeil Son, Hyoung-Il Kim, Woo Jin Hyung
Journal: JAMA Surgery (2018)

<h3>Importance</h3> Fluorescent imaging with indocyanine green can be used to visualize lymphatics. Peritumoral injection of indocyanine green may allow for visualization of every draining lymph node from a primary lesion on near-infrared imaging. <h3>Objectives</h3> To evaluate the role of fluorescent lymphography using near-infrared imaging as an intraoperative tool for achieving complete lymph node dissection and compare the number of lymph nodes retrieved with the use of near-infrared imaging and the number of lymph nodes retrieved without the use of near-infrared imaging. <h3>Design, Setting, and Participants</h3> This prospective single-arm study was conducted among 40 patients who underwent robotic gastrectomy between August 30, 2013, and July 21, 2014, at a single-center, tertiary referral teaching hospital. After propensity score matching, the results of these 40 patients were compared with the results of 40 historical control patients who underwent robotic gastrectomy without indocyanine green injection between January 1, 2012, and August 31, 2013. Statistical analysis was performed from January 1, 2015, to July 31, 2016. <h3>Interventions</h3> Robotic gastrectomy with systemic lymphadenectomy and retrieval of lymph nodes under near-infrared imaging after peritumoral injection of indocyanine green to the submucosal layer 1 day before surgery. <h3>Main Outcomes and Measures</h3> The primary outcome was the number of retrieved lymph nodes in each nodal station. <h3>Results</h3> Among the 40 patients in the study (19 women and 21 men; mean [SD] age, 52.2 [11.7] years), no complications related to indocyanine green injection or near-infrared imaging were observed. On completion of the lymphadenectomy, the absence of fluorescent lymph nodes in the dissected area was confirmed. A mean (SD) total of 23.9 (9.0) fluorescent lymph nodes were recorded among a mean (SD) total of 48.9 (14.6) overall lymph nodes retrieved. The mean number of overall lymph nodes retrieved was larger in the near-infrared group than in the historical controls (48.9 vs 35.2;<i>P</i> &lt; .001), with a significantly greater number of lymph nodes retrieved at stations 2, 6, 7, 8, and 9. In the near-infrared group, 5 patients exhibited lymph node metastases, and all metastatic lymph nodes were fluorescent. <h3>Conclusions and Relevance</h3> This study’s findings suggest that fluorescent lymphography may be useful intraoperatively for identifying and retrieving all necessary lymph nodes for a complete and thorough lymphadenectomy.
Significance of PARP1 expression levels in patients with acute myeloid leukemia
Authors: H. Pashaiefar, M. Yaghmaie, J. Tavakkoly-Bazzaz, S.H. Ghaffari, K. Alimoghaddam, M. Momeny, M. Izadifard, A. Kasaeian, A. Ghavamzadeh
Journal: Annals of Oncology (2018)