tbuckley/cabot-search huggingface dataset:
Abstract 5084: Functional genomic classification of breast cancer using pooled lentivirus shRNA screens
Authors: Richard Marcotte, Kevin Brown, Azin Sayad, Maliha Haider, Troy Ketela, Jason Moffat, Benjamin G. Neel
Journal: Cancer Research (2012)

Abstract Targeted therapies for most breast cancers are lacking because our knowledge of essential genes driving tumor proliferation is still primitive for each subtype. Although ongoing intensive efforts to genetically characterize large numbers of breast tumors are providing a plethora of new data on genomic abnormalities (e.g., amplifications, deletions, somatic mutations), it can be difficult to access which of these actively drive pathogenesis. Even if an oncogene or tumor suppressor is identified, these often are not amenable to targeted therapy (eg. KRAS, c-MYC, p53, etc). However, unanticipated gene/pathway dependencies can arise as a consequence of these genetic abnormalities in cancer cells (“synthetic lethality”). The recent development of lentiviral-based shRNA libraries enables genome-wide screening of cultured cancer cells in a pooled format, facilitating the identification of genes necessary for cancer cell proliferation and survival in cell culture as well as potential synthetic lethal interactions. The overall objective of this project was to identify subtype-specific targets for human breast cancer using a genome-wide shRNA screen, as well as to compare “functional genomic” and genomic classification schemes. We screened a panel of 53 breast cancer lines using an 80,000 lentiviral shRNA library targeting 16,000 genes in a pooled format. We identified several classes of gene “dropouts,” including general essential genes, which are required for survival or growth in more than 70% of all cell lines, irrespective of subtype. Most of these were enriched in housekeeping functions, although several genes involved in cellular signal transduction also were identified, including mTORC1, RAPTOR, TGFBR2, DDR1 and DDR2. In addition, we observed several “subtype-specific” genes, whose essentiality is restricted to a defined subtype. Furthermore, unsupervised and supervised clustering of our functional screening results identified potential “drivers” unique to each subtype. These include amplified/overexpressed genes such as ERBB2, ERBB3, FOXA1, SPDEF, TFAP2C, and CCDN1 known to be specific to the luminal and HER2 subtypes, respectively. Finally, integration of gene expression, copy number variation, and functional screening results identified potential synthetic lethal interactions with common genetic changes. Our study represents an extensive functional genetic survey of three major breast cancer subtypes, reveals complexities between genomic and functional genomic results, and uncovers several unexpected gene dependencies and potential novel therapeutic target for each subtype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5084. doi:1538-7445.AM2012-5084
Human Brain — Morphologic Differences in the Hemispheres Demonstrable by Carotid Arteriography
Authors: Marjorie LeMay, Antonio Culebras
Journal: New England Journal of Medicine (1972)

Functional differences of the cerebral hemispheres are great, but few consistent morphologic differences have been noted. On carotid arteriograms and on coronal sections of brains through the posterior ends of the sylvian fissures, we found the parietal operculum to be more highly developed on the left than on the right in 38 of 44 persons. However, arteriograms suggested that in 15 of 18 left-handed persons right parietal opercularization is as great as on the left. The study showed definite morphologic differences between the right and left hemispheres in a region of major importance for language. Endocranial casts of a fossil skull suggest that these differences were present in Neanderthal man. Arteriography offers a method of studying anatomic hemispheric differences.
PTH-051 Safety and Efficacy of Colonic Stents (SEMS) for Large Bowel Obstruction from Proximal Colorectal Cancer
Authors: S Mahmood, P O’Toole, J Geraghty, S Sarkar
Journal: Gut (2013)

<h3>Introduction</h3> Colonic stenting of proximal Colorectal Cancers (CRC) (lesions at splenic flexure or beyond) is technically challenging and currently out-favour as surgical techniques allow safe primary anastomosis on unprepared dilated colon. Consequently, randomised trials (RCTs) have only compared colonic self-expandable metal stent (SEMS) with emergency surgery for acute left sided obstruction. However, emergency surgery is associated with substantial morbidity and mortality. <h3>Aim:</h3> To assess the safety and effectiveness of colonic SEMS for obstruction caused by proximal CRC. <h3>Methods</h3> Retrospective case series by 2 Consultant Gastroenterologists between 2005 to 2012 was audited. All procedures were performed using Through the Scope (TTS) technique and fluoroscopic guidance. End-points were technical success (correct SEMS placement confirmed radiologically at time of procedure), clinical success (resolution of patient symptoms within 48 hrs), re-intervention, patient discharge and mortality. <h3>Results Demographics</h3> 31 patients (Male: Female ratio 2.1:1); median age 85.5 years (range 40–92), mean ASA score 2.5.<b> Indications:</b> 84% (n = 26) were palliative and 16% (n = 5) were bridge to surgery. 48% patients had subacute obstruction, 10% had total obstruction, and extent of obstruction was unknown in 42%. Lesions were located at Splenic flexure (n = 15), Distal Transverse (n = 7), Proximal Transverse (n = 3), Hepatic flexure (n = 4), Ascending (n = 1) &amp; caecum (n = 1). <h3>Procedural Success</h3> Technical success was 100%. Clinical Success was 81% (n = 25) with these patients being successfully discharged without requiring any further procedures during their hospital stay. Re-intervention was required in 5 patients (16%) due to SEMS dysfunction; managed by re-stenting in 1 and colostomy in 3 patients (Bridge group). The remaining was a colostomy for the only perforation in series (3%). Further surgery was only required in the 2 patients within the bridge group who went onto have uncomplicated elective surgery with primary anastomosis. <h3>Mortality</h3> There was no procedure related mortality (0%). All cause 30 &amp; 90 day mortality was 13% &amp; 38% respectively, all of which were in palliative group. Over a third were alive at 1 year (1 year survival of 35%) and a further 2 patients are alive but yet to reach the 1 year end point. <h3>Conclusion</h3> Colonic stenting by experienced operators for proximal CRC using TTS can be performed successfully and safely. It negated the need for emergency surgery with successful discharge of 81% of patients. These results are important when interpreting the RCT, when considering palliation and the developments of neo-adjuvant chemotherapy strategies in Bridge group. <h3>Disclosure of Interest</h3> None Declared.
Abstract P1-01-12: The Performance of the One Step Nucleic acid Amplification (OSNA) Assay in Breast Cancer Patients with Receiving Preoperative Systemic Therapy
Authors: H Yagata, H Yamauchi, R Horii, T Osako, T Iwase, F Akiyama, T Kinoshita, H Tsuda, K Tsugawa, S Nakamura
Journal: Cancer Research (2012)

Abstract Background: The OSNA (One Step Nucleic acid Amplification) assay is a semi-automated lymph node examination method using molecular biological technique. The OSNA assay has been validated for breast cancer patients without receiving preoperative systemic therapy (PST) by several clinical studies and has currently become more popular as sentinel lymph node (SLN) examination method with the following two main advantages; 1) to allow examination of the whole portion of a node, 2) to allow intraoperative judgment of metastasis positive or negative. However, the feasibility of the OSNA assay in breast cancer patients treated by PST has never been confirmed. In this multi-central clinical study, we compared the judgments of the OSNA assay and of pathological examination on lymph nodes dissected after receiving PST to evaluate the performance of the OSNA assay. Material &amp; Methods: Three hundred two nodes dissected from the 80 breast cancer patients who received PST were examined. Each lymph node was divided at 2mm intervals and the slices were alternately applied to the OSNA assay and pathological examination with H&amp;E staining and CK19 immunohistochemical staining of permanent-section. In pathological examination, judgments of metastasis positive or negative were determined by one central-review pathologist according to the criteria of AJCC 7th edition (“positive” if &amp;gt;0.2mm metastases were detected). Result: The overall concordance rate between the OSNA assay and pathological examination was 91.1% (275/302) with sensitivity of 88.3% (53/60) and specificity of 91.7% (222/242) (Table). These results are very similar to those of the Japanese clinical validation study in breast cancer patients without receiving PST which was conducted by the almost same protocol (Tamaki Y, et al. Clin Cancer Res, 2009, 15: 2879–2884). Conclusion &amp; Discussion: These results indicate the OSNA assay can be applicable for breast cancer patients after receiving PST as well as breast cancer patients without receiving PST. The OSNA assay will enable to examine the whole portion of nodes, leading to more detection of metastases (especially micrometastases) and more exact nodal staging for breast cancer patients treated by PST. Also, for the patients who receive sentinel lymph node biopsy after PST, the OSNA assay will be useful as intraoperative examination method of SLNs because it is expected to provide more correct judgments than current intraoperative methods such as frozen-section or touch-print cytology. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-12.
Kanehiro Takaki and the control of beriberi in the Japanese Navy
Authors: Yoshifumi Sugiyama, Akihiro Seita
Journal: Journal of the Royal Society of Medicine (2013)

Kanehiro Takaki (1849–1920) was a Japanese naval medical officer at the end of the 19th and the beginning of the 20th centuries. At that time, beriberi – a feared and often fatal disease – was prevalent throughout Japan and in many Southeast Asian countries.1,2 Takaki used an epidemiological approach – which was then unfamiliar in Japan – to study the disease. He showed that it was caused by a nutritional deficiency and demonstrated how it could be prevented and treated. Takaki’s research led to the eradication of the disease in the Japanese Navy more than 30 years before the specific cause of beriberi was shown to be a deficiency of vitamin B1.

Apart from his epidemiological research, Takaki worked hard to promote what we would today call ‘patient-centred’ medicine. In 1881, he founded the Sei-I-Kwai Koshujo (the Sei-I-Kwai Medical Training School), not only to impart medical knowledge and skills but also to teach students to empathize with patients, an approach continued to this day in the Jikei University School of Medicine. The following year Takaki founded a charitable hospital – the Yushi Kyoritsu Tokyo Byoin – to serve the poor, and this was the predecessor of today’s Jikei University Hospital. Recognizing the key role played by nurses in good healthcare, Takaki also founded the first nursing school in Japan – the Kangofu Kyoiku-jo (now the Jikei Training School for Nurses).
Abstract LB-72: A20 ubiquitin ligase-mediated RIP1 polyubiquitin chains inhibits TRAIL-induced apoptosis in glioblastoma
Authors: Anita C. Bellail, Jeffrey J. Olson, Xiaolu Yang, Zhijian J. Chen, Chunhai Hao
Journal: Cancer Research (2012)

Abstract The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway has emerged as a cancer therapeutic target; however, clinical trials have proven that the vast majority of human cancers are resistant to TRAIL apoptotic pathway-targeted therapies. We show here that A20-mediated ubiquitination inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma through two signaling complexes. A20 is highly expressed in glioblastomas and, together with the death receptor 5 (DR5) and receptor-interacting protein 1 (RIP1), forms a DR5-associated plasma membrane bound signaling complex that we named the preligand assembly complex (PLAC) under physiologic conditions. TRAIL treatment leads to the recruitment of caspase-8 to the PLAC for the assembly of a death-inducing signaling complex (DISC). In the DISC, the C-terminal Zinc finger domain of the A20 ubiquitin ligase mediates RIP1 ubiquitination through lysine (K)-63-linked polyubiquitin chains, which bind to the protease domain of caspase-8 and inhibits its dimerization, cleavage and the initiation of TRAIL-induced apoptosis in glioblastoma-derived cell lines and tumor-initiating cells. These results identify A20 ubiquitin ligase as a therapeutic target whose inhibition can overcome TRAIL resistance in glioblastoma and thus have an impact on ongoing clinical trials of TRAIL apoptotic pathway-targeted combination cancer therapies (the manuscript was published online first in Cancer Discovery). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-72. doi:1538-7445.AM2012-LB-72
P212 Parasternal Intercostal Electromyography To Assess Neural Respiratory Drive In Healthy Adult Subjects
Authors: V. MacBean, C. Hughes, G. Nicol, C. Reilly, G. Rafferty
Journal: Thorax (2014)

<h3></h3> Neural respiratory drive (NRD), measured using the parasternal intercostal muscle electromyogram (EMGpara), relates to lung disease severity as quantified by conventional methods in a range of diseases. Reference data from healthy populations are required for the technique to be used as an independent measure of lung disease severity. EMGpara has previously been expressed as a percentage of that obtained during a maximal inspiratory effort (EMGpara%max), restricting the use of the technique to subjects able to reliably perform such manoeuvres. The aim of this study was to investigate variability of both raw EMGpara (rEMGpara) and EMGpara%max in healthy adults. EMGpara was measured during tidal breathing in 43 healthy adult non-smokers (25 females, median (range) age 32 (19–79)years, mean (SD) BMI 23.4 (3.5) kg/m<sup>2</sup>), using surface electrodes positioned bilaterally over the second interchondral space. Measurements were made with and without a mouthpiece/pneumotachograph <i>in situ</i> in 20 participants. Repeated measures were obtained within the same testing session in 27 subjects, and at least seven days later in 13 individuals. Spirometry, height, weight, BMI, fat free mass (FFM) via bioelectrical impedance and measures of regional fat distribution (waist/hip ratio and neck circumference) were also recorded. Mean (SD) EMGpara%max and rEMGpara were 5.88 (3.63)% and 5.06 (2.26)µV respectively. Significant relationships were observed between anthropometric measures and rEMGpara and EMGpara%max (Table 1). rEMGpara and EMGpara%max were unrelated to spirometry variables. Median (range) rEMGpara and EMGpara%max increased significantly with the pneumotachograph in place (4.86 (2.11–8.19)µV <i>versus</i> 5.62 (2.47–10.98) µV and 4.77(1.68–17.00)% <i>versus</i> 6.78 (2.35–20.94)%, both p &lt; 0.0001). Analysis of variance by subject was used to assess within-subject variability. Measurement error was higher for EMGpara%max than rEMGpara (upper 95% confidence limit of difference between repeat measures of EMGpara%max 3.14%, <i>versus</i> 2.35 µV for rEMGpara; within-subject coefficient of variation EMGpara%max 30.8% <i>versus</i> rEMGpara 24.5%). rEMGpara appears to be a reproducible marker of NRD. Both rEMGpara and EMGpara%max are influenced by subjects’ anthropometry. Further investigation is required to determine whether these influences are technical or physiological and must be considered when the technique is applied clinically or for research, or when developing reference values.
Abstract 3956: Differential miR-141 expression in primary cultured human breast cancer epithelium (PCHBCEs) and normal adjacent part epithelium (PCHBNEs) correlates with tumor suppressor protein tyrosine phosphataseγ (PTPγ)
Authors: Shu-Hong Lin, Jinmai Jiang, Chieh-Ti Kuo, Weiping Ye, Pingping Xu, Hong Li, Jie-Yu Liu, Saiyi Zhong, Thomas D. Schmittgen, Young C. Lin
Journal: Cancer Research (2011)

Abstract MicroRNAs (miR) have been shown to be extensively involved in tumorigenesis by post-transcriptional inhibition of oncogenes and/or tumor-suppressor genes. The purpose of our study is to investigate the difference in miRNA expression between cancer epithelium and epithelium from normal breast adjacent tissues. The clinical samples were procured from the Tissue Procurement Program at the Ohio State University Comprehensive Cancer Hospital from breast cancer patients who underwent partial or complete mastectomy. The miRNA profiling for one pair of PCHBCEC and PCHBNEC from the same patient was carried out, and the difference of miRNA expression and potential target genes were further verified by realtime qPCR in 7 pairs of clinical samples. The miRNA profiling showed that 24 miRNAs (let-7a, let-7c, let-7f, let-7g, miR-24, miR-28, miR-29a, miR-29c, miR-30a-5p, miR-30d, miR-92, miR-125a, miR-126*, miR-132, miR-135a, miR-135b, miR-137, miR-141, miR-182, miR-200c, miR-339, miR-365, miR-425-5p, miR-391, p&amp;lt;0.05) are statistically up-regulated in cancer while only 1 miRNA (miR-221) is down-regulated. Based on the magnitude of change and predicted target, we selected miR-141 for further validation. Compared with its normal adjacent counterpart, 4 PCHBCECs had lower miR-141 while 2 were up-regulated and 1 unaltered. Further validation on gene expression of the samples confirmed the negative correlation of miR-141 with its putative target PTPγ. Our comparison of PCHBCECs and PCHBNECs under the same genetic background demonstrated a distinct expression of miRNAs. The dysregulation of miR-141 was shown to result in modulation of the potential tumor-suppressor gene PTPγ which might have an impact on the etiological process of tumor lesion and discriminate cancer epithelial cells from their surrounding normal breast epithelial compartments. Our results implicate that miR-141 might serve as molecular biomarker for therapy of human breast cancer patients. (Supported by NIH R01 Grant ES 015212). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3956. doi:10.1158/1538-7445.AM2011-3956
AB0664 Efficacy and Safety of Methylprednisolone Administered Intravenously for the Treatment of Patients with Active Ankylosing Spondylitis: Results of A 12-Week, Prospective, Open-Label Study (METALL): Table 1.
Authors: I. Gaydukova, A. Rebrov, D. Poddubnyy
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Treatment options for patients with ankylosing spondylitis (AS) are limited to non-steroidal anti-inflammatory drugs (NSAIDs) and to tumour necrosis factor (TNF) α blockers. Treatment of the patients with contraindications/intolerance/absence of response to NSAIDs and/or anti-TNF α requires the development of new approaches of therapy. <h3>Objectives</h3> The aim of the present study was to evaluate the short-term efficacy and safety of methylprednisolone (MP) 500 mg administered intravenously in patients with active AS. <h3>Methods</h3> A total of 20 AS patients fulfilling the modified New York criteria with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 who have had an inadequate response to ≥2 NSAIDs or NSAIDs contraindications/intolerance were included (mean age 35.35±8.19 years, disease duration 10.2±9.2 years). MP in a dose of 500 mg was given as a single intravenous infusion at baseline. The primary study endpoint was the percentage of patients who met ASAS40 (Assessment of Spondyloarthritis International Society 40) response criteria at week 2. Secondary endpoints included rates of a 50% BASDAI improvement (BASDAI50), ASAS20, ASAS partial remission, the AS disease activity score (ASDAS), clinically important and major improvements, ASDAS inactive disease, changes in the levels of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) up to week 12. <h3>Results</h3> At week 2, ASAS40 response was reached by 9 (45%) patients. ASAS20 response, ASAS partial remission and BASDAI50 responses were achieved by 11 (55%), 15 (15%) and 7 (35%) patients, respectively. ASDAS clinically important improvement improvement at week 2 was observed in 11 (55%) patients, respectively, while ASDAS inactive disease state was achieved by 5 (25%) patients. At week 12, ASAS40 response was observed in 12 (60%) patients, ASAS20 response, ASAS partial remission and BASDAI50 response in 13 (65%), 5 (25%) and 8 (40%) patients, respectively. ASDAS clinically important improvement, ASDAS major improvements and ASDAS inactive disease state at week 12 were noted in 11 (55%), 6 (30%) and 3 (15%) patients, respectively. A significant reduction of BASDAI, ASDAS, CRP and ESR was observed at week 2 and sustained up to week 12 - table. Totally, 13 adverse events (AE) occurred during the study, no serious AE were observed. <h3>Conclusions</h3> Intravenous administration of 500 mg of MP could be effective and safe in a short-term treatment of active AS. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3955