tbuckley/cabot-search huggingface dataset:
Abstract 1759: MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective non-small cell lung cancer (NSCLC) cells
Authors: Kathleen Bridges, Hiroshi Hirai, Carolyn Buser, Raymond E. Meyn
Journal: Cancer Research (2010)

Abstract Wee1 is a tyrosine kinase involved in the S&amp;gt;G2 and G2&amp;gt;M cell cycle transitions. Following DNA damage, Wee1 is phosphorylated by upstream kinases and stabilized. Stabilized Wee1, in turn, phosphorylates and inhibits CDC2, preventing the cells from entering mitosis before repairing their damaged DNA. Abrogation of Wee1 activity, either by decreasing expression using siRNA, or by inhibiting protein activity with selective small molecule inhibitors, sensitizes tumor cells to DNA-damaging agents. This sensitization preferentially takes place in a p53 null or mutant context. We have investigated the ability of a novel, small molecule inhibitor of Wee1, MK-1775, to radiosensitize NSCLC cells treated in vitro. Four NSCLC cell lines were used in the study: A549 and H460 with wild-type p53 status and H1299 and Calu6 with null or mutant p53 status, respectively. A 24 hr pre-irradiation treatment with 200 nM MK-1775 suppressed phosphorylation of CDC2 in both A549 and H1299 cells, however, this treatment did not produce a radiosensitizing effect in either line. An 18 hr post-irradiation treatment slightly radiosensitized the H1299 line but not the A549 line. The optimal treatment of a 1 hr pre-irradiation followed by an 18 hr post-irradiation treatment substantially radiosensitized the H1299 and Calu6 lines, yielding dose-enhancement factors (DEFs) at 10% survival of 1.39 and 1.47 respectively, but did not sensitize the A549 or H460 cells, DEFs of 1.0. To determine the mechanism responsible for the radiosensitizing effect of MK-1775, cells were treated with nocodazole following a dose of 4 Gy and analyzed for phospho-histone H3 as an indication of mitotic index after 4 hrs. Unirradiated cells accumulated in mitosis during the 4 hrs in nocodazole and this accumulation was substantially enhanced by MK-1775 in both p53 wild type A549 and p53 null H1299 cells suggesting that Wee1 inhibition accelerates unirradiated cells into mitosis prematurely. Neither A549 nor H1299 cells, irradiated with 4 Gy, accumulated in mitosis during the 4 hr nocodazole treatment in the absence of MK-1775 indicating a robust G2 block for both lines. However, H1299 cells irradiated with 4 Gy and treated with MK-1775 accumulated in mitosis to a level higher than the unirradiated cells treated with MK-1775 alone. This enhanced entry of irradiated cells into mitosis was not evident to nearly the same degree in the A549 cells. Thus, we conclude that the Wee1 inhibitor, MK-1775, accelerates cells harboring DNA-damage prematurely into mitosis in a p53-dependent manner correlating with its radiosensitizing effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1759.
Constitution of ALK fusion variants in East Asian lung adenocarcinoma
Authors: Ju Cheng, Yoon-La Choi, Fan Yang, Weijie Zhao, Lili Jiang, Qing Xu, Feng Zhang, Qingyang Gu, Jhingook Kim, Caicun Zhou, Mao Mao
Journal: Journal of Thoracic Oncology (2016)
AB0475 Increased Plasma Lactoferrin Levels in Leukocytapheresis Therapy in Patients with Rheumatoid Arthritis
Authors: S. Miyauchi, K. Umekita, T. Kawaguchi, S. Sakaguchi, Y. Kariya, Y. Hashiba, M. Matsuda, K. Kubo, T. Hidaka, K. Umeki, Y. Aratake, N. Takahashi, A. Sawaguchi, A. Nakatake, I. Morinaga, K. Morishita, A. Okayama
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To clarify the mechanism of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Protein profiles of blood samples from 2 patients with RA obtained via LCAP column inlet and outlet lines were analyzed by two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. Then, the lactoferrin (LTF) levels of peripheral and circulating blood samples from 7 patients obtained via the LCAP column blood circuit were determined by enzyme-linked immune sorbent assay. Peripheral blood samples from 14 patients with RA were exposed to unwoven polyester fiber filter (filter) and LTF level was determined. In addition, morphological change of neutrophils after exposure to filter was examined by optical microscopy, electronic microscopy and LTF immunostaining. <h3>Results</h3> LTF levels were increased both in the samples from the LCAP column outlet and in peripheral blood at the end of LCAP treatment. Furthermore, peripheral blood samples exposed to filter revealed a decreased number of neutrophils and increased level of LTF. Morphological analysis of the exposed neutrophils showed vacuolization of the cytoplasm and degranulation of LTF positive granules. These data suggested that LTF stored in the granules of neutrophils was released from the neutrophils caught in the LCAP column. <h3>Conclusions</h3> Because LTF has been reported to have multiple anti-inflammatory properties, increased levels of LTF may contribute to the clinical effect of LCAP in patients with RA. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2179
Paraganglioma of the Middle Ear
Authors: E L Applebaum
Journal: New England Journal of Medicine (1995)

Figure 1. A 40-year-old woman presented with pulsatile tinnitus in her right ear. In this photograph, a red glomus tumor (T), or paraganglioma, is apparent in the right tympanic membrane. The malleus (M) and annulus tympanicus (A) are labeled. The tumor was removed through the external auditory canal, and the patient has been free of symptoms and of the tumor for more than five years.
Transmission of Tuberculosis in New York City -- An Analysis by DNA Fingerprinting and Conventional Epidemiologic Methods
Authors: David Alland, Gary E. Kalkut, Andrew R. Moss, Ruth A. McAdam, Judith A. Hahn, William Bosworth, Ernest Drucker, Barry R. Bloom
Journal: New England Journal of Medicine (1994)

The incidence of tuberculosis and drug resistance is increasing in the United States, but it is not clear how much of the increase is due to reactivation of latent infection and how much to recent transmission.
THU0172 The role of T regulatory lymphocytes in lupus nephritis
Authors: D.P.E. Margiotta, K. Giannakakis, M. Vadacca, A. Gigante, R. Cianci, A. Onetti Muda, A. Afeltra
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Regulatory T cells (Tregs) play a key role in the maintenance of immune tolerance and in the development of autoimmune diseases. Expression of Foxp3, a member of forkheadbox family of transcription factors, is specific for Treg cells and can be used for the identification of these cells. Systemic Lupus Erythematosus (SLE) is a prototype autoimmune disease characterized by dysregulated activation of T and B lymphocytes, causing multiple organ damage. There is a high incidence of renal involvement during the course of the disease with varied pathologic and clinical features. Several studies describe a quantitative and/or qualitative abnormalities of peripheral Tregs in SLE. However, the role of Tregs in lupus nephritis (LN) is still unclear. <h3>Objectives</h3> Aim of the study:The study aims to investigate the variations of Tregs Foxp3+ in the kidney biopsies inflammatory infiltrate of different LN classes (according to ISN/RPS 2003 criteria) compared to that of ANCA associated crescentic glomerulonephritis (ANCA- CrGN), acute tubulointerstitial nephritis (ATIN) and nephroangiosclerosis (NAS). <h3>Methods</h3> Investigation was carried out on renal biopsy samples of 27 patients with histologically proven LN classified according to the ISN/RPS 2003 criteria (class III: 3 patients, class IV: 17 patients, class V: 7 patients), 3 patients with ANCA-CrGN, 6 patients with ATIN, and 2 patients with NAS. Sections of paraffin embedded tissue have been stained by immunohistochemistry with anti-CD3 and anti-FoxP3 antibodies, performed separately on consecutive sections. The number of FoxP3 positive cells and CD3 positive per mm<sup>2</sup> was counted after digitalization of slides and application of a dedicated image analysis software. <h3>Results</h3> Amount of CD3+ cells was higher in ATIN (5713/mm<sup>2</sup>) and in ANCA-CrGN (5121/mm<sup>2</sup>) than in LN-IV (3558/mm<sup>2</sup>), LN-III (2491/mm<sup>2</sup>), NAS (2379/mm<sup>2</sup>) and LN-V (2220/mm<sup>2</sup>). Instead, we found that the ratio of FoxP3+/CD3+ cells was significantly lower in patients with LN-IV (1,6) and, although less significantly, in patients with CrGN (3) than in course of NAS (3,9), ATN (4), and LN-V (4,5). <h3>Conclusions</h3> The data presented herein, demostrate a decrease of Foxp3+ Treg cells in the inflammatory infiltrate of lupus nephritis. These results, although preliminary, suggest an important role of Tregs in the pathogenesis of autoimmune diseases, particularly during the most active phases of LN, as observed in LN-IV class. <h3>Disclosure of Interest</h3> None Declared
Cytotoxic T-Cell Response and In Vivo Protection Against Tumor Cells Harboring Activated ras Proto-oncogenes
Authors: R. G. Fenton, D. D. Taub, L. W. Kwak, M. R. Smith, D. L. Longo
Journal: JNCI Journal of the National Cancer Institute (1993)

Activated forms of the ras proto-oncogene have been found in approximately 30% of human malignancies, including pancreatic, colon, and lung adenocarcinomas. Ras oncoproteins arise by somatic mutation and contain amino acid changes at residues 12, 13, or 61, thus generating unique tumor-specific proteins that are attractive targets for cancer therapy.The goal of this study was to determine whether vaccination with mutant Ras protein could lead to the generation of cytotoxic T lymphocytes (CTLs) specific for the mutant epitope and to protection against challenge with tumor cells expressing the mutant oncoprotein.To determine a methodology for generating CTL responses following immunization with soluble protein, ovalbumin was used as a model tumor antigen. C57BL/6 mice were immunized with soluble ovalbumin administered intraperitoneally at 2-week intervals or with intravenous injection of ovalbumin or osmotically loaded splenocytes. Immunized mice were challenged with E.G7 cells (which express a transfected ovalbumin gene), and tumor growth was monitored. Generation of ovalbumin-specific CTLs was determined by 51Cr release assays. Purified wild-type or mutant H-Ras proteins (containing single amino acid substitutions at position 12 converting Gly to Arg or Val) were used to immunize BALB/c mice intraperitoneally. Ras-immunized mice were challenged with tumor cells containing Arg 12 or Val 12 mutations or not harboring mutant forms of Ras. Cytolytic and proliferative responses to mutant forms of Ras were studied, and the effects of in vivo depletion of CD4+ or CD8+ T lymphocytes were determined.In vivo challenge with E.G7 showed that intraperitoneal immunization with soluble ovalbumin was as effective as osmotic loading, resulting in long-term disease-free survival of some mice and the development of ovalbumin-specific CTLs. Immunization with Arg 12 Ras led to disease-free survival in nine of 10 animals challenged with tumor cells containing an Arg 12 mutation, while no protection was afforded against tumors expressing other forms of Ras or other oncogenes. Splenocytes from BALB/c mice immunized with Arg 12 Ras demonstrated cytolytic activity specific against tumor cells expressing Arg 12 Ras, with most of this activity residing in the CD8+ subset. Mutation-specific proliferation to Arg 12 Ras peptides was also observed. Immunization with Val 12 Ras did not elicit detectable Val 12-specific immunity.Antigen-specific CTLs can be induced following intraperitoneal immunization of mice with purified, soluble proteins. For both ovalbumin and Arg 12 Ras, specific in vivo protection against tumor cell challenge was observed.
Racecadotril in the Treatment of Acute Watery Diarrhea in Children
Authors: Eduardo Salazar-Lindo, Javier Santisteban-Ponce, Elsa Chea-Woo, Manuel Gutierrez
Journal: New England Journal of Medicine (2000)

Racecadotril (acetorphan), an enkephalinase inhibitor with antisecretory and antidiarrheal actions, is an effective and safe treatment for acute diarrhea in adults and children. Whether treatment with racecadotril and oral rehydration therapy is more effective than treatment with oral rehydration alone in hospitalized children with acute watery diarrhea is not known.
Failure of Ristocetin Therapy in Three Cases of Staphylococcal Sepsis with Bacteremia
Authors: Lowell A. Rantz, Ernest Jawetz
Journal: New England Journal of Medicine (1958)

RISTOCETIN is a new antimicrobial agent1 2 3 produced by No cardia lurida, of large molecular size and active against gram-positive bacteria. It has been stated to be effective in the treatment of enterococcal and staphylococcal endocarditis.4 Its bactericidal properties have been emphasized by the manufacturers, but a recent report indicates that this agent is primarily bacteriostatic for staphylococci.5 Recently, 3 patients with staphylococcal sepsis with bacteremia were treated with this agent. Certain problems were encountered that form the basis for this report.Laboratory StudyAttempts to determine the inhibitory and bactericidal concentrations of ristocetin§ in vitro for the organisms isolated from . . .
AB0269 Importance of steady-state trough concentrations after intravenous golimumab with concomitant methotrexate in patients with active rheumatoid arthritis
Authors: J. H. Leu, Z. Xu, C. Hu, A. Mendelsohn, J. Ford, H. M. Davis, H. Zhou
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To determine an optimized dosing regimen for IV golimumab in patients with active RA using population pharmacokinetic (PK) modeling and simulation. <h3>Methods</h3> Two Phase 3 trials were performed for IV golimumab. In the first trial, IV infusions of 2 mg/kg golimumab every 12 weeks (Q12W) or 4 mg/kg Q12W with concomitant methotrexate (MTX) were investigated in RA patients. Population PK modeling was conducted using data from this first trial. Simulations were performed to identify an optimized IV regimen that would result in steady-state trough golimumab concentrations similar to the approved subcutaneous (SC) dosing regimen of 50 mg Q4W. Absolute bioavailability of 50% and Ka of 0.658 day<sup>-1</sup> were used for simulating the SC golimumab profile. The dosing regimen for the second trial was then modified to shorten the dosing interval to Q8W. <h3>Results</h3> In the first trial, although there were strong trends towards clinical benefit, the primary endpoint (ACR 50) was marginally missed. It was found that Q12W dosing was inadequate to maintain adequate trough golimumab concentrations at the later part of the dosing interval. Using population PK analysis, a two-compartmental IV infusion model with first-order elimination was developed. Parameter estimates for the model were: CL: 0.654 L/day; V1: 4.33 L; V2: 2.82 L and Q: 0.215 L/day. Simulations showed that IV golimumab 2 mg/kg Q8W + MTX and currently approved SC golimumab 50 mg Q4W + MTX resulted in similar steady-state trough golimumab concentrations. When the IV regimen of 2 mg/kg golimumab at Weeks 0, 4 followed by Q8W was studied in the second trial, the primary efficacy endpoint (ACR 20) was achieved. <h3>Conclusions</h3> Population PK modeling and simulation aided in the determination of an optimized dosing regimen for IV golimumab in patients with active RA. Both observed data and population PK modeling and simulation corroborate the importance of maintaining adequate steady-state trough concentrations of golimumab for robust clinical efficacy. <h3>Disclosure of Interest</h3> J. H. Leu Employee of: Janssen R &amp; D, LLC, Z. Xu Employee of: Janssen R &amp; D, LLC, C. Hu Employee of: Janssen R &amp; D, LLC, A. Mendelsohn Employee of: Janssen R &amp; D, LLC, J. Ford Employee of: Janssen R &amp; D, LLC, H. M. Davis Employee of: Janssen R &amp; D, LLC, H. Zhou Employee of: Janssen R &amp; D, LLC
Cerebral Syphilitic Gumma in an HIV-Negative Patient Presenting as Prolonged Focal Motor Status Epilepticus
Authors: Jose I. Suarez, Diane Mlakar, Susan M. Snodgrass
Journal: New England Journal of Medicine (1996)

To the Editor: The incidence of seizures in neurosyphilis ranges from 14 to 60 percent,1 with no reports of focal status epilepticus as a presenting complaint. We describe a patient in whom cerebral syphilitic gumma was the underlying cause of focal motor seizures. A 47-year-old previously healthy right-handed man experienced a generalized seizure followed by continuous clonic movement of his right foot 24 hours before admission. His general physical examination was unremarkable. Neurologic evaluation revealed a normal Mini–Mental State Examination, no cranial-nerve deficits, normal strength, and continuous clonic movements of the right foot. There was no reflex asymmetry, and sensory . . .
Role of Amniocentesis in the Intrauterine Detection of Genetic Disorders
Authors: Henry L. Nadler, Albert B. Gerbie
Journal: New England Journal of Medicine (1970)

One hundred and sixty-two transabdominal amniocenteses were performed between the thirteenth and eighteenth weeks of fetal gestation as part of the management of 155 "high-risk" pregnancies. Successful cultivation of amniotic-fluid cells led to the intrauterine detection of Down's syndrome (10 cases), Pompe's disease (one case), lysosomal acid phosphatase deficiency (one case) and metachromatic leukodystrophy (one case). The risk of this procedure is low since neither fetal nor maternal complications were demonstrated in this series of patients. Cultivation of amniotic-fluid cells obtained by transabdominal amniocentesis early in the second trimester of pregnancy provides a method that enables parents at "high risk" for having offspring with certain serious genetic disorders to have children without risk of such a defect.
Gated Tl-201 Myocardial Perfusion SPECT
Authors: SURJIT S. WADHWA, ROBERT MANSBERG, DAVID WILKINSON, DONNA ABBATI
Journal: Clinical Nuclear Medicine (1999)

Purpose: Tl-201 scintigraphy is plagued with poor image quality because of the low-energy photons of Tl-201 decay. Traditionally, a narrow 20% window centered on 71-72 keV has been used to improve sensitivity. Recent studies indicate that better imaging may be possible by optimizing the energy window to 34% centered on 77 keV. In this study, energy window optimization (EWO) was applied to gated Tl-201 myocardial perfusion SPECT, and myocardial functional parameters were compared for gated Tl-201 SPECT and gated Tc-99m sestamibi (Tc-99m MIBI) SPECT. Methods: Count statistics for standard and optimal Tl-201 myocardial scintigraphy were noted in 25 patients by assessing the total counts in a mid-ventricular slice of a rest-gated Tl-201 myocardial SPECT study. The feasibility of performing functional studies with the application of EWO to Tl-201 was assessed using the count statistics of a mid-ventricular slice of an optimized gated Tl-201 SPECT study and a gated Tc-99m MIBI SPECT study. The functional parameters (ejection fraction, wall motion, and thickening) of Tl-201 with EWO and Tc-99m MIBI were compared in 60 patients who underwent rest-gated Tl-201 SPECT followed by poststress gated Tc-99m MIBI SPECT. The left ventricular ejection fraction was calculated using commercially available software, whereas wall thickness and motion were assessed by the consensus of two readers. Results: The application of EWO increased available counts by more than 25%. It also resulted in sufficient counts being available to perform gated Tl-201 SPECT without increasing acquisition times or the dose of Tl-201. The average ejection fraction was 60.4% for gated Tl-201 SPECT and 59.6% for gated Tc-99m MIBI SPECT (not significantly different). Overall, the image quality was rated excellent in 12% for Tl-201 and Tc-99m MIBI and good in 50% and 62%, respectively, and poor in 38% and 26%, respectively. Conclusion: The application of EWO to Tl-201 SPECT allows myocardial functional parameters to be assessed without having to increase the acquisition times or the administered dose of Tl-201.
Abstract 4303: A high-throughput cell invasion assay combined with reverse phase protein microarrays for rational development of drug combination strategies targeting tumor invasion
Authors: John C. Dawson, Neil O. Carragher, Jennifer Fronczak, Keren Hulkower
Journal: Cancer Research (2012)

Abstract Tumor invasion and metastasis is responsible for 90% of all deaths in cancer patients that are non-responsive to surgical procedures or initial therapeutic treatments. Clinical studies of inhibitors targeted against specific signalling pathways associated with tumor invasion frequently fail due to alternate signalling pathways that support persistent invasion through compensatory mechanisms. The aim of this study was to apply an image-based multi-well 3-dimensional (3D) invasion assay platform (OrisTM Pro Cell Invasion Assay, Platypus Technologies LLC) incorporating distinct cancer cell types and extra cellular matrix (ECM) substrates in parallel with an ultra-sensitive and high-throughput reverse phase protein microarray (RPPMA) platform (Zeptosens) to identify and validate drugs and their combinations targeting distinct modes of tumor invasion. At sub-micromolar concentrations the results show that a matrix metalloproteinase inhibitor (GM6001) and panel of tyrosine kinase inhibitors suppress the 3D invasion of two breast cancer cell lines (MDA-MB-231 and HCC1569) into a basement membrane matrix. The image based invasion assays further revealed an altered invasive morphology in response to distinct compound treatments, with cells losing their typical elongated mesenchymal phenotype and adopting a more ameoboid shape. These results suggest that inhibitor treatment initiates alternative invasive mechanisms. An RPPMA platform has been used to identify post-translational signalling pathways that drive adaptive responses to monotherapy and to guide selection of drug combination partners. Further testing of drug combinations in the OrisTM 3D invasion assay format shall enable quantification of additive and synergistic drug combination responses upon tumor invasion in parallel with cell viability endpoints. These studies provide a robust model by which to evaluate different combinations of drugs targeting tumor invasion that will help prioritize clinical development strategies. ACKNOWLEDGEMENT: This work was partially supported by NIH Grant 2R44GM090386 to Platypus Technologies. 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 4303. doi:1538-7445.AM2012-4303
Pancreatic metastasis of a meningeal hemangiopericytoma: a rare cause of obstructive jaundice
Authors: Lídia Ramos, Pedro Marques, Rui Loureiro, Maria Brito, João de Freitas
Journal: Endoscopy (2014)

A 52-year-old man presented to the emergency department with jaundice, pale stools, and dark urine for 1 week, having lost 15 % of his body weight during the previous month. He was a heavy smoker and drinker. He had been diagnosed 4 months previously with a meningeal hemangiopericytoma that had been surgically resected then treated with cranial external radiotherapy. Laboratory evaluation was remarkable for hyperbilirubinemia (9 mg/dL) and cholestasis (alkaline phosphatase [ALP] 1300 IU/L). Magnetic resonance imaging (MRI) revealed a 25-mm pancreatic head mass and upstream dilatation of the bile ducts but a normal main pancreatic duct ([Fig. 1]). A second 15-mm mass in the uncinate process was also noted.