tbuckley/cabot-search huggingface dataset:
Abstract 2431: Inhibition of metastasis through therapeutic targeting of focal adhesion kinase (FAK) in pancreatic cancer
Authors: Neesha C. Dhani, Joerg Schwock, Ping-Jiang M. Cao, Ming-Sound Tsao, David W. Hedley
Journal: Cancer Research (2011)

Abstract BACKGROUND: Cancer mortality is primarily caused by metastatic disease; it has therefore been suggested that the preclinical evaluation of novel therapies should include testing in metastatic models of disease. This is especially relevant in light of recent reports of both conventional and targeted therapies being associated with accelerated metastases despite maintenance of primary tumor control. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which also acts as molecular scaffold, and localizes to focal adhesions, contact points between the cell and the extra-cellular matrix. Downstream of integrins and transmembrane receptors, FAK acts as a signaling hub, participating in processes integral to tumor progression including cell survival, proliferation, angiogenesis, migration and invasion. In this ongoing study, we explore the efficacy of selective genetic and pharmacologic FAK inhibition in preclinical models of human pancreatic cancer, including spontaneously metastasizing, cell-line derived and primary xenografts. METHODS &amp; RESULTS: We constructed modified pancreatic cancer cell lines using retroviral over-expression of the dominant negative FRNK (FAK related non-kinase). Pharmacologic inhibition of FAK was performed with PF-562271 (Pfizer), a selective FAK/Pyk2 inhibitor which recently completed Phase I testing. Adhesion, invasion and migration in vitro assays were conducted using the xCELLigence RTCA system. In vivo efficacy of FAK inhibition was evaluated in orthotopic xenograft models. In vitro studies demonstrated that both modalities of FAK inhibition resulted in impaired adhesion, invasion and migration and 3D colony formation, without comparable effects on viability, proliferation or colony formation in 2D. Expression of dominant-negative FRNK resulted in 49% smaller xenograft tumors (p=0.003), a 78% reduction in metastatic disease (p&amp;lt; 0.001) and longer overall survival (p &amp;lt; 0.001). There was a similar, 46% trend to reduction of metastatic burden (p=0.089) in orthotopic cell line xenograft models treated with PF-562271, despite a lack of significant primary tumor growth delay. CONCLUSIONS: Our data suggest a potential utility of selective FAK inhibition in delaying metastatic progression of pancreatic cancer. This is particularly relevant clinically since patients frequently present with locally advanced, unresectable disease and subsequently develop metastases. Pharmacologic FAK inhibition (in combination with conventional therapies) is currently being evaluated in neo/adjuvant models of this disease. 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 2431. doi:10.1158/1538-7445.AM2011-2431
AB1019 The Detection of Microcirculation Disturbances in Both Hands of Patients with Systemic Sclerosis Using Fluorescence Optical Imaging
Authors: S. Friedrich, S. Riemekasten, S. Werner, G. Schmittat, G.-R. Burmester, G. Riemekasten, S. Ohrndorf, M. Backhaus
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Indocyanine green-enhanced (ICG) fluorescence optical imaging (FOI) is a novel imaging method for the detection of inflammation in both hands of patients with arthritis [1,2]. Patients with systemic sclerosis (SSC) suffer from an impaired microcirculation (Raynaud phenomenon) with the risk of digital ulcers. <h3>Objectives</h3> To present microcirculatory disturbances identified by FOI. To this end, distribution patterns of ICG in patients with SSC in comparison to healthy subjects were analyzed. <h3>Methods</h3> N=79 subjects (n=53 patients with SSC and n=26 healthy subjects) were included. All participants received FOI examination following the Xiralite-System guidelines (ICG 0.1mg/kg BW i.v.; 6 minute duration). The PrimaVistaMode and the 360s long clip mode (one frame per second) were analyzed. <h3>Results</h3> FOI detects the distribution of ICG in the tissue of both hands. After a first strong signal enhancement in the fingertips, the coloring agent usually spreads to the proximal parts of the fingers and hands. Some typical changes in the distribution patterns in SSC were defined as demarcated areas of high ICG-signals ("islands") in the early phase. We detected those "islands" in 58% of patients with SSC and in 23% of healthy subjects (p=0.0004). To find evidence for a reduced acral perfusion, we examined whether the first strong signal enhancement reached the tip of each finger or not. This was apparent in 73% of the healthy subjects and in 33% of the patients with SSC (p=0.0016). A complete disruption of digital microcirculation was defined as lack of an appropriate signal in the distal part of the finger during the whole time of the examination. This was found in 19% of patients with SSC, but in none of the healthy subjects (p=0.026). <h3>Conclusions</h3> The FOI-findings show a distinctive scleroderma-pattern: circumscribed ICG-accumulations ("islands") in different regions of the hands early in the examination and initial digital ICG-enhancement proximal of the fingertips. This could be a result of microvascular damage due to SSC as it was significantly more often detected in SSC patients compared to healthy subjects. <h3>References</h3> Werner SG et al. Ann Rheum Dis. 2012;71:504-10. Werner SG et al. Arthritis Rheum. 2013;65:3036-44 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3349
Abstract LB-292: Role of TLR engagement in TIL-B and clinical implications for ovarian cancer
Authors: Selene G. Nunez-Cruz, Matthew Guerra, Denise Connolly, Phyllis Gimotty, Nathalie Scholler
Journal: Cancer Research (2011)

Abstract Ovarian cancer is the eighth most common cancer in women and represents the most lethal gynecological cancer, where less than a third of the women survive longer than five years after diagnosis. The identification of novel therapeutic strategies is urgently needed to improve patient prognosis. Solid and hematologic malignant cells express a broad range of Toll-like receptors (TLR). Activation of TLR signaling through recognition of pathogen-associated molecular patterns leads to the transcriptional activation of genes encoding for pro-inflammatory cytokines, chemokines and co-stimulatory molecules. Solid tumor development has been associated with TLR engagement through both growth acceleration and immune escape, and epidemiological studies reported a link between TLR expression by ovarian tumor cells and chemoresistance. We previously observed a large proportion of B cells in the immune infiltrate of mouse ovarian tumors and in human ascites from ovarian cancer patients, but the role of TLR stimulation in ovarian tumor-infiltrating lymphocyte B (TIL-B) remains unclear. The objective of this study is to investigate the functional consequences of TLR expression and engagement on TIL-B in ovarian cancer. Our work has been carried in a transgenic mouse model (TgMISIIR-Tag) that spontaneously develops tumors through the expression of SV40 T antigen under the Mullerian Inhibitor Receptor type II (MISIIR) promoter. TgMISIIR-Tag tumors resemble human serous ovarian cancer, the most common type of ovarian cancer. Microarrays and flow cytometry analyzes were used to characterize the phenotype of TIL-B after CD19 magnetic sorting ex vivo or after in vitro culture. We first found that TIL-B significantly over-expressed transcripts encoding for inflammatory cytokines, growth factors, adhesion molecules and chemokines, compared to B cells from spleens and lymph nodes of healthy or tumor bearing mice. We also showed that B cells from TgMISIIR-TAg tumors and from ascites of ovarian cancer patients over-expressed TLR2, TLR4 and/or TLR9, to compare with mouse splenic or human peripheral B cells, respectively. In addition, five days co-culture of TIL-B with ovarian tumor cells and TLR4 and TLR 9 agonists further increased TLR4 and TLR9 expression, as well as the expression of CD5 and CD1d costimulatory molecules and IL10 production. Concomitant treatment with TLR antagonists reduced TLR expression and IL-10 production of TIL-B. In vivo studies aiming to interrogate the role of TLR engagement on TIL-B in ovarian cancer are ongoing. 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 LB-292. doi:10.1158/1538-7445.AM2011-LB-292
524p75NTR-dependent activation of NF-kB is required for the trafficking and transcriptional regulation of microRNA-503 in microvascular complications of diabetes
Authors: A Caporali, M Meloni, T Mitic, A Nailor, C Emanueli
Journal: Cardiovascular Research (2014)

Purpose: Uncontrolled hyperglycemia is responsible for vascular complications in diabetes. Together with pericytes, endothelial cells (ECs) establish direct cell-to-cell communication in the blood vessel that is fundamental for the regulation of microvascular formation, stabilisation and function. Notably, circulating microparicles (MPs) can serve as signalling molecules and mediators of inter-cellular communication. Recently, we also demonstrated that in ECs microRNA-503 (miR-503) and neurotrophin receptor p75 (p75NTR) individually facilitate diabetes-induced impairment of EC function. This study investigated how expression of miR-503 and its release are regulated by p75NTR in diabetes, and what role do miR-503-carrying microparticles (MPs-miR-503) play in communication between EC and vascular pericytes. Methods: Type 1 diabetes was induced in mice by injection of streptozotocin. Mice underwent unilateral limb ischemia followed by gene transfer using adenoviral vectors. Blood flow recovery was monitored by laser Doppler and post-ischemic angiogenesis was assessed by immunostaining. ECs were cultured in high glucose and reduced of growth factors to mimic diabetes and ischemia. Binding of NF-kB to miR-503 promoter was verified by chromatin immunoprecipitation. MPs were prepared by centrifugation and validated by flow cytometric analysis as events with 0.1-1mm diameter expressing Annexin V. To study the trafficking between ECs and pericytes, an in vitro co-culture system was used, along with an ex-vivo model from diabetic limb muscles. Results: Our findings show that expression of miR-503 and p75NTR increase in ECs in vitro, due to high glucose, as well as in diabetes with ischemia in vivo. Modulation of p75NTR expression regulates transcription of miR-503 and consequently EC function and post-ischemic angiogenesis. We provide evidence that p75NTR promotes activation of NF-kB in ECs, which binds the promoter of miR-503 thus upregulating its expression. NF-kB further induces the shedding of MPs-miR-503 from the ECs, through activation of Rho kinase (ROCK). Circulating MPs-miR-503 are engulfed by vascular pericytes in a RAGE (receptor for advance glycation end product)-dependent manner. This reduces the expression of miR-503 targets like ephrinB2 (EFNB2) and vascular endothelial growth factor-A (VEGFA), and causes functional impairments in pericytes. Conclusion: Here we describe a newly-established mechanism for regulation and release of miRNA-503 into MPs during diabetes-induced vascular diseases.
Abstract 5288: Tumor-endothelial 3D spheroids for dynamic imaging of cancer progression
Authors: Meenakshi Upreti
Journal: Cancer Research (2011)

Abstract The increasing use of anti-angiogenic drugs for the treatment of cancer has emerged from the explosion of knowledge about the process of tumor angiogenesis. However, the clinical results of using such drugs have been relatively modest and new agents are likely needed. A robust pre-clinical model of cellular mechanisms governing tumor angiogenesis may improve our ability to develop strategies for tumor specific drug delivery with superior pharmacokinetics, controlled biodistribution, efficacy, and safety profiles. We have developed a system to grow 3D-cultures of tumor and endothelial cells in hanging drops of medium. Subsequently, we transplant these spheroidal cultures into the dorsal skin fold window chamber of mice for intravital multiphoton imaging of neovasculature and disease progression. Our initial observation was that there was a marked difference in neovascularization from the GFP-tumor-endothelial spheroids in comparison to GFP-tumor spheroids in the window chamber mouse model. Molecular analysis using an antibody array showed a pronounced upregulation of angiogenic factors in the tumor tissue derived from the tumor-endothelial spheroid compared to the spheroid grown with tumor cells alone. Interleukin-1α, FGF-1α, CCN3/NOV, PIGF-2, MMP-3, MMP-8 and MMP-9 were seven identified proteins that showed distinct differences in expression between the two spheroid types. Further, the relative increase in tumor growth of tumor-endothelial spheroids implanted on the rear hind limb was much faster than the tumor cell alone spheroid and resulted in evidence of greater metastasis to the lung. We thus strongly believe that the 3D tumor-endothelial spheroid implanted in the dorsal fold window chamber of mice is a more realistic and informative model for dynamic imaging of critical aspects of tumor angiogenesis and the study of metastasis. Efforts are underway to monitor molecular and cellular events related to radiation exposure combined with anti-angiogenic agents of varying mechanisms of action to determine prudent new avenues for therapeutic success. 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 5288. doi:10.1158/1538-7445.AM2011-5288
PTH-100 Utility Of Eus-guided Fine Needle Aspiration Of Pancreatic Cystic Lesions: Abstract PTH-100 Table 1
Authors: MC Donnelly, P Cheng, JS Leeds
Journal: Gut (2014)

<h3>Introduction</h3> At least 1% of hospitalised patients will have a pancreatic cystic lesion on cross sectional imaging <sup>1</sup>. Differentiation of benign and potentially malignant/malignant pancreatic cystic lesions using conventional radiology and prior to surgery is difficult. Endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) is considered safe, yet there is relatively limited data on the clinical utility of EUS in this setting or its complication rate. <h3>Methods</h3> Retrospectively, 43 consecutive patients (F = 26, M = 17, mean age 63) undergoing EUS-FNA of a pancreatic cystic lesion (no. procedures = 46) following abnormal imaging were identified from an institutionally approved database. Data collected included pre-EUS imaging, EUS findings, number of passes, cyst fluid CEA, amylase and cytology, sedation requirements, complication rate and six month follow up where available. <h3>Results</h3> 44 procedures provided sufficient information for further analysis. At EUS, 23 cystic lesions appeared benign and 21 premalignant/malignant. Median CEA (ug/L) in the benign group was 6 vs. 2234 in the malignant group; p &lt; 0.001. Median amylase (U/L) in the benign group was 2989, versus 2795 in the malignant group; p = 1.0. In the malignant group, 4/21(19%) had positive cytology. In the benign group, 16/23 (69.5%) had no malignant cells. Cytology was insufficient for analysis in 4/23 of benign appearing lesions, and 3/21 in malignant appearing lesions. Average midazolam dose was 3.3 mg, and average pethidine dose 27.9 mg. Complication rate was 4% (n = 2), with one patient experiencing severe abdominal pain (serum amylase normal) and another having a documented bile leak. Availability of follow up data was limited by patients returning to their secondary care referral centres. 4 patients proceeded to surgery and had resection pathology available. Of these, 3 patients had confirmed malignant IPMN (one patient had no cyst fluid for analysis, one had raised CEA and no available cytology, and one had suggestive cytology but no CEA analysis). The fourth patient had a mucinous cystadenoma, with mucin aspirated at FNA but no CEA analysed. <h3>Conclusion</h3> EUS provides useful information with regards to the macroscopic appearances of pancreatic cystic lesions. FNA is safe and allows the addition of fluid CEA as a useful marker for malignancy. Negative cytology does not exclude malignancy but false positives are rare. Difficulty in aspirating fluid should be considered suspicious. <h3>Reference</h3> 1 Khalid A, Brugge W. ACG Practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. <i>Am Journ Gastroenterol </i>(2007);102:2339-2349 <h3>Disclosure of Interest</h3> None Declared.
Abstract 1098: Mechano-molecular imaging of the role of COX-2 in cell traction force.
Authors: A Rum Yoon, Ioannis Stasinopoulos, Steven An, Zaver M. Bhujwalla
Journal: Cancer Research (2013)

Abstract The cytoplasmic enzyme cyclooxygenase (COX)-2 and its secondary lipid byproducts are critical determinants of cancer cell invasion and metastasis. Poorly differentiated MDA-MB-231 human breast cancer cells stably expressing COX-2 shRNA exhibit marked attenuation in their ability to secrete secondary lipid mediator products of the COX reaction, as well as invade and degrade reconstituted extracellular matrix in vitro. COX-2-silenced cells inoculated in vivo show significant reduction of tumor growth and extrapulmonary colonization than their parental counterpart. Based on compelling evidence for the positive correlation between cancer invasion and cell traction force, here we interrogated the mechanistic role for COX-2 in mediating this physical force and imaged the spatiotemporal distribution of contractile stress arising at the interface between each adherent cell and its substrate. Over a physiological range of substrate stiffness, COX-2-silenced MDA-MB-231 cells exhibited a smaller spreading area and a lower cell traction force than their highly metastatic, parental counterpart. Strikingly, unlike COX-2-silenced cells, COX-2-high parental MDA-MB-231 cells showed progressive increases in cell spreading area and traction force with increasing substrate rigidity. Cell spreading and traction force in COX-2-silenced cells were restored with an exogenous addition of COX-2-derived PGE2, however. COX-2-high MDA-MB-231 cells also showed increases in the expression of mechanosensitive integrin β1, and not β3, with increasing substrate rigidity. Consistent with these physical attributes, COX-2-silenced cells expressed a 4.6-fold reduction of the transcript coding for RhoJ, a member of the family of Rho GTPases, and displayed a slower remodeling dynamics of the cytoskeleton (CSK). To our knowledge this is the first report linking the expression of COX-2 with increased cell traction force and CSK remodeling in a highly metastatic human breast cancer. Citation Format: A Rum Yoon, Ioannis Stasinopoulos, Steven An, Zaver M. Bhujwalla. Mechano-molecular imaging of the role of COX-2 in cell traction force. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2013-1098
Racial Differences in the Cause-Specific Prevalence of Blindness in East Baltimore
Authors: Alfred Sommer, James M. Tielsch, Joanne Katz, Harry A. Quigley, John D. Gottsch, Jonathan C. Javitt, James F. Martone, Richard M. Royall, Kathe A. Witt, Sandi Ezrine
Journal: New England Journal of Medicine (1991)

Bilateral blindness unrelated to simple refractive error is twice as prevalent among blacks as among whites, although the difference narrows among the elderly. The reasons for this race- and age-related pattern are uncertain.
Sex-Based Differences in Early Mortality after Myocardial Infarction
Authors: Viola Vaccarino, Lori Parsons, Nathan R. Every, Hal V. Barron, Harlan M. Krumholz
Journal: New England Journal of Medicine (1999)

There is conflicting information about whether short-term mortality after myocardial infarction is higher among women than among men after adjustment for age and other prognostic factors. We hypothesized that younger, but not older, women have higher mortality rates during hospitalization than their male peers.We analyzed data on 384,878 patients (155,565 women and 229,313 men) who were 30 to 89 years of age and who had been enrolled in the National Registry of Myocardial Infarction 2 between June 1994 and January 1998. Patients who had been transferred from or to other hospitals were excluded.The overall mortality rate during hospitalization was 16.7 percent among the women and 11.5 percent among the men. Sex-based differences in the rates varied according to age. Among patients less than 50 years of age, the mortality rate for the women was more than twice that for the men. The difference in the rates decreased with increasing age and was no longer significant after the age of 74 (P< 0.001 for the interaction between sex and age). Logistic-regression analysis showed that the odds of death were 11.1 percent greater for women than for men with every five-year decrease in age (95 percent confidence interval, 10.1 to 12.1 percent). Differences in medical history, the clinical severity of the infarction, and early management accounted for only about one third of the difference in the risk. After adjustment for these factors, women still had a higher risk of death for every five years of decreasing age (increase in the odds of death, 7.0 percent; 95 percent confidence interval, 5.9 to 8.1 percent).After myocardial infarction, younger women, but not older women, have higher rates of death during hospitalization than men of the same age. The younger the age of the patients, the higher the risk of death among women relative to men. Younger women with myocardial infarction represent a high-risk group deserving of special study.
A Cluster of Rhodococcus (Gordona) Bronchialis Sternal-Wound Infections after Coronary-Artery Bypass Surgery
Authors: Herve M. Richet, Philip C. Craven, June M. Brown, Brent A. Lasker, Candice D. Cox, Michael M. McNeil, Alan D. Tice, William R. Jarvis, Ofelia C. Tablan
Journal: New England Journal of Medicine (1991)

RHODOCOCCUS species are gram-positive bacillary aerobic actinomycetes found in soil, sewage, fresh water, and feces of horses, sheep, and cattle.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Only one report of Rhodococcus (Gordona) bronchialis infection in humans has been published; the organism was isolated from the sputum of patients with cavitary pulmonary tuberculosis or bronchiectasis.24 We describe a hospital outbreak of surgical-wound infections caused by a single genetically distinct strain of R. bronchialis that was traced to an operating-room nurse. Methods Definition and Ascertainment of Cases A case was defined as a sternal-wound infection that was culture-positive for R. bronchialis in a patient who had undergone open-heart . . .
Successful Suture of Ruptured Myocardium after Nonpenetrating Injury
Authors: Gerard Desforges, William P. Ridder, Ralph J. Lenoci
Journal: New England Journal of Medicine (1955)

PENETRATING injuries of the heart secondary to bullet or stab wounds are not uncommon. Their diagnosis is not difficult, and management of such cases by conservative and surgical measures has surprisingly good results.1 2 3 4 Not so well appreciated, however, is another type of cardiac trauma produced by concussive or contusive forces. Such injuries may also lead to disruption of cardiac musculature, serious hemorrhage and an ultimately fatal issue if not discovered and treated promptly.5 , 6 Bright and Beck,5 in an extensive review of 168 fatal cases, revealed that, of these, 30 patients who lived longer than an hour might have been helped . . .