tbuckley/cabot-search huggingface dataset:
Abstract 3579: Mechanistic roles of cytochrome P4501A1 and 1A2 in lung carcinogenesis mediated by polycyclyc aromatic hydrocarbons: Implications for lung cancer in humans .
Authors: Bhagavatula Moorthy, Guodong Zhou, Lihua Wang, Weiwu Jiang
Journal: Cancer Research (2013)

Abstract Humans are frequently exposed to polycyclic aromatic hydrocarbons (PAHs). Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to DNA-binding metabolites, which in turn mediate carcinogenesis in target organs such as lung, breast, and skin. In this study, we tested the hypothesis that CYP1A1 and 1A2 play mechanistic roles in PAH-mediated carcinogenesis and tumorigenesis. Eight week-old female wild type (WT) (A/J) mice or mice lacking the gene for CYP1A1 or CYP1A2 on the A/J background were treated with a single dose of MC (40 μmol/kg), benzo[a]pyrene (BP), or vehicle (corn oil), and liver and lung tumors were studied after 28 weeks. While 100% of WT or Cyp1a2-null mice exposed to MC showed lung tumors after 28 weeks, about 80% of the Cyp1a1-null mice showed lung tumors. However, there were striking differences in the Cyp1a1-null and Cyp1a2-null mice in regard to lung tumor multiplicities. The WT mice treated with MC had about 15 lung tumors/animal. On the other hand, the Cyp1a2-null mice displayed about 40 lung tumors/animal, while the Cyp1a1-null mice showed about 2-3 tumors/mouse. Although BP was less potent in inducing lung tumors in the WT mice compared to MC, it was similar to MC In that tumors were suppressed in the Cyp1a1-null mice and augmented in the Cyp1a2-null mice. DNA adduct studies at early time points showed increased MC or BP adducts in lungs of Cyp1a2-null mice compared to WT mice, and decreased adduct formation in the Cyp1a1-null mice, supporting the hypothesis that DNA adducts are early biomarkers of PAH-mediated carcinogenesis. Immunohistochemical studies showed that CYP1A1 was overexpressed in the tumorous portions of the lung in the Cyp1a2-null or WT mice, compared to non-tumorous regions. These results suggest that CYP1A1 contributes to the formation of tumorigenesis by PAHs, while CYP1A2 protects against carcinogenesis mediated by PAHs, presumably through it role in PAH detoxification. In conclusion, our results strongly suggest that CYP1A1 and 1A2 could be novel candidates for cancer prevention and therapy though either inhibition of CYP1A1 or induction of CYP1A2. (Supported by NIH grant ES009132.) Citation Format: Bhagavatula Moorthy, Guodong Zhou, Lihua Wang, Weiwu Jiang. Mechanistic roles of cytochrome P4501A1 and 1A2 in lung carcinogenesis mediated by polycyclyc aromatic hydrocarbons: Implications for lung cancer in humans . [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 3579. doi:10.1158/1538-7445.AM2013-3579
Abstract 4271: Combination of VEGF Trap (Aflibercept) with docetaxel, but not with gemcitabine, is efficacious in tumors resistant to anti-VEGF therapy
Authors: Cristina L. Abrahams, Baosheng Li, Asma Parveen, Gavin Thurston
Journal: Cancer Research (2011)

Abstract Increased anti-tumor efficacy is often observed when VEGF blockade is combined with certain chemotherapy agents. However, the mechanism by which combination treatment with certain agents, but not others, results in enhanced anti-tumor effects is poorly understood. In this study, we compared the anti-tumor effects of VEGF Trap in combination with either docetaxel or gemcitabine on HT1080, a human fibrosarcoma tumor line that is resistant to anti-VEGF treatment. Immunodeficient SCID mice bearing subcutaneous HT1080 tumors (size ∼150 mm3) were treated with either control protein plus vehicle, VEGF Trap, chemotherapy agent (docetaxel or gemcitabine), or the combination. Following three treatments administered every 3-4 days, tumors were harvested either one day after the final dose or allowed to grow and harvested when the average size of the treatment group reached ∼500mm3. We found that combination treatment with VEGF Trap plus docetaxel was significantly more effective compared to single agents, while there was no added benefit of combining VEGF Trap with gemcitabine. Although treatment with chemotherapy agents alone and in combination with VEGF Trap both initially regressed tumor size, only the combination with docetaxel was effective at delaying long-term tumor re-growth. Immunohistochemical analysis of tumors showed that both combination regimens produced a dramatic decrease in the number of proliferating tumor cells. However, only VEGF Trap and docetaxel combination treatment resulted in pruned tumor vessels with less branching, whereas VEGF Trap plus gemcitabine had minimal effect on tumor vessel morphology. Furthermore, VEGF trap plus docetaxel produced an increase in TUNEL-positive cells associated with the tumor vasculature and a marked decrease in tumor pericytes. These results suggest that in tumors resistant to VEGF blockade, taxanes (docetaxel) can sensitize the vasculature to anti-VEGF treatment (aflibercept), thus resulting in enhanced effects on the tumor vessels and improved anti-tumor efficacy. Further understanding of the mechanistic basis of different combination regimens may allow improvement of current strategies to treat tumors resistant to antiangiogenic therapy. 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 4271. doi:10.1158/1538-7445.AM2011-4271
THU0285 Deadly Chik: A Report of Two Atypical and Fatal Cases of Chikungunya Fever Complicated by Severe Vasculitis and Renal Failure
Authors: G.M. Garcia, N. Trinidad, R. Destura
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Chikungunya fever (CHIK) is caused by an alphavirus, Chikungunya virus (CHIKV) of the family <i>Togaviridae</i>, is native to tropical Africa and Asia. Symptoms of chikungunya include sudden onset of fever, severe arthralgia, and maculopapular rash. Chikungunya is generally considered self-limiting and has been reported as non-fatal in the past. However, after the March 2005 outbreak in La Réunion Island, there have been several reports of unusually severe complications and deaths. To date, there have been no published reports of severe atypical and fatal cases of Chikungunya fever in the Philippines. We thereby present two cases that initially presented with the usual fever, arthropathy and rash of CHIK, but during the course of their hospital stay, their rash worsened into violaceous, vesiculobullous, and vasculitic lesions over the extremities accompanied by edema and oliguria. Rheumatologic workup and bacterial cultures were negative. Treatment was mainly supportive on admission (NSAIDs, antipyretics). Hydrocortisone was started for arthritis refractory to NSAIDs. Pulse therapy with methylprednisolone was started in the first case once with the appearance of vasculitic lesions, eventually given IVIG infusion as a last resort. They both worsened with the development of acute renal failure and cardiopulmonary collapse necessitating continuous renal replacement therapy, vasopressor and ventilatory support. Despite intensive care, they both succumbed to sudden wide QRS bradyarrhythmias and subsequently died. At post-mortem, RT-PCR was positive for CHIKV Asean genotype 1 for both patients. <h3>Conclusions</h3> Although it is generally self-limiting, this report illustrates that CHIK can be a rare cause of vasculitis and acute renal failure. Early identification of features of severe disease with timely aggressive therapy may be prudent especially in the elderly population. Mortality with CHIK may be underreported but it should be noted that the risk of complications increases with age. Since there is no specific treatment for CHIK, prevention through vector control and public health education is key. <h3>References</h3> Sourisseau M, Schilte C, Casartelli N, Trouillet C, Guivel-Benhassine F,Rudnicka D, et al. Characterization of reemerging chikungunya virus.PLoS Pathog. 2007;3:e89. Bonn, D. How did Chikungunya reach the Indian Ocean. Lancet, September 2006; 6(9): 543. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5328
Abstract 2433: Hepatitis B virus X protein induces metastasis-associated protein 1 gene expression through promoter methylation
Authors: Min-Ho Lee, Hyelin Na, Mi-Ock Lee
Journal: Cancer Research (2011)

Abstract Expression of metastasis-associated protein 1 (mta1) gene is well correlated with the degree of invasion and lymphatic metastasis in colorectal, hepatocellular and breast carcinomas. Expression of MTA1 was induced by hepatitis B virus X protein (HBx), however, little is known about transcriptional regulation of mta1 gene expression. Here, we reported that 5′-flanking region of MTA1 promoter contains two CpG islands. CpG island 1 and CpG island 2. The CpG island 1 was highly methylated (32.5%) but CpG island 2 (&amp;lt;1%) was not. Using bisulfite-modified direct sequencing, transient expression of HBx led to an increase in methylation of the CpG island 1 up to 48.8 %. In addition, chromatin immunoprecipitation revealed that HBx recruited DNMT3A to CpG island 1 region of MTA1 promoter. In silico analysis of the CpG island 1 predicted an existence of putative p53 binding sequences. We demonstrated that p53 bound to the CpG island 1 by chromatin immunoprecipitation using specific anti-p53 antibody. Further, p53 was pull-downed by DNA probe encoding the p53 binding sequences. However p53 was not pull-downed by the methylated DNA probe using SssI DNA methyltransferase. These data showed that HBx induced methylation of CpG island 1, which interferes the DNA binding of p53 on the specific DNA region. This result may provide the molecular mechanism of how HBx induces the expression of MTA1 gene. 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 2433. doi:10.1158/1538-7445.AM2011-2433
AB0266 Characteristics of patients according to the two 2011 ACR/EULAR proposals of remission in rheumatoid arthritis
Authors: B. Rintelen, J. Sautner, P.M. Haindl, H.T. Mai, H.-P. Brezinschek, B.F. Leeb
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Recently an ACR/EULAR expert comity published new proposals of remission for rheumatoid arthritis (RA) [1]. Two propositions have been made: The Boolean based definition with ≤1 tender joint (TJ), ≤1 swollen joint (SJ), the patient global assessment on a 10cm visual analogue scale (PATGA) ≤1.0 and the C-reactive protein (CRP) in mg/dl ≤1.0 or the index based definition with a SDAI ≤3.3. The purpose of this investigation was to characterize patients according to both approaches. <h3>Methods</h3> 1844 assessments out of 720 long standing RA out-patients collected between 2007 and 2011 were enrolled (mean age 61.9 yrs. (95%CI 60.9-62.9), 76.7% female, 53.5% RF pos, mean disease duration 87.0 months (80.1-94.1), mean assessments per patient 2.5 (2.4-2.7), mean interval of assessments 6.7 months (6.39-7.03), mean DAS28 3.45 (3.39-3.51)). The assessments included a 28-joint count for TJ and SJ, evaluation of PATGA, CRP in mg/dl and physician’s global assessment (MDGA) to calculate the SDAI as described [2] but also to identify patients in remission according to the 2011 proposed ACR/EULAR remission definition. Moreover erythrocyte sedimentation rate first hour (ESR), patient’s pain perception on a 10cm VAS (VASpain) and the HAQ was recorded. The mean of each core set parameter and the 95% Confidence interval was calculated in the respective group of remission and student’s t-test was calculated for their relation. P&lt;0.05 was defined to be significant. <h3>Results</h3> 184 assessments were identified to be in remission according to the Boolean based definition, whereas 379 according to the index based definition. 181 assessments fulfilled both criteria. PGA, VASpain and the HAQ-score (all patient related parameters) were statistically different in both groups. <h3>Conclusions</h3> 198 more patients are identified to fulfil the index based definition than the Boolean based definition of remission. Patient’s related parameters as PGA, VASpain and the HAQ-score are statistically significantly different in both groups. The Boolean based definition is more stringent than the index based one. Both definitions are not interchangeable. <h3>References</h3> Felson DT et al. Arthritis Rheum. 2011 Mar;63(3):573-86. Smolen JS et al. Rheumatology (Oxford) 2003:42:244-57. <h3>Disclosure of Interest</h3> None Declared
Tc-99m Red Blood Cell Bleeding Scan in a Pregnant Woman Presenting With Hematemesis
Authors: Gonca Gul Bural, Michael Scheetz, Charles M. Laymon, James M. Mountz
Journal: Clinical Nuclear Medicine (2011)

A 6-month pregnant 35-year-old woman with hematemesis and dark blood in her stool was evaluated for location of an active gastrointestinal bleeding site. The findings from 2 esophagogastroduodenoscopies and a colonoscopy were negative. The patient was referred for a Tc-99m red blood cell scintigraphy, for location of an active bleeding site. As the patient was 6 months pregnant, the necessity of the case was discussed with the patient's referring physician and after determining that this study was necessary, the risk of radiation exposure to the fetus was discussed with the radiation safety officer and the patient. The procedure was performed after the patient signed informed consent regarding the considerations of radiation safety to the fetus. The Tc-99m red blood cell bleeding scan clearly shows activity in the fetus in addition to a large arteriovenous malformation in the patient. The visualized fetus prompted this report to discuss radiation risks concerns and a brief review of indications and guidelines for performing nuclear medicine procedures in pregnant patients.
Relationship of miR-101 and targeted epigenetic silencing of EzH2 on cell growth and invasiveness in ovarian cancer cells.
Authors: R. B. Batchu, A. Semaan, S. M. Seward, A. Qazi, S. Chamala, C. S. Bryant, C. Steffes, S. Kumar, M. A. Shammas, D. W. Weaver
Journal: Journal of Clinical Oncology (2010)

e15538 Background: Enhancer of zeste homolog 2 (EzH2), the catalytic subunit of Polycomb group (PcG) of the chromatin modifying complex, is abnormally elevated in several cancers. High levels of EzH2 correlate strongly with high-grade malignancies that are invasive, poorly differentiated and of advanced stage at presentation. miR-101 belongs to a family of micro-RNAs (miRNAs) that are short non-coding RNA sequences involved in epigenetic regulation of gene expression. miR-101 has been shown to bind to EzH2 mRNA inhibiting protein translation. Though recent reports demonstrate significant down regulation of microRNA-101 (miR-101) in several solid tumors suggesting that it might serve as a solid tumor signature, its role in ovarian cancer is not well defined. Methods: MDAH-2774 and SKoV3 cell lines were transfected with miR-101 expression plasmid (miR-101 sequence is as follows: 5' UAC AGU ACU GUG AUA ACU GAA G 3') using effectene (Qiagen Inc.,Valencia,CA). Standard protocols were followed for western blot analysis of EzH2 levels after EzH2 knockdown with miR-101 plasmid transfection. Triplicate growth curves were generated using Cell Counting Kit-8 (CCK-8) (Dojindo, Gaithersburg, MD). Eight week-old CB17/ICr-SCID mice were injected with 3 ×106 MDAH-2774 cells that were transfected with miR-101 plasmid. Results: miR-101 achieved more than 70% knockdown of the EzH2 protein 48 hrs after transfection in both SKoV3 and MDAH-2774 cell lines, demonstrating efficient inhibition of EzH2. Further, significant reduction in cell proliferation in both MDAH-2774 and SKoV3 cell lines was observed in response to EzH2 knock down. MDAH-2774 cells transfected with miR-101 showed 15% less growth than the control on day 3 after transfection, versus 48% for SKOV3 cells. EzH2 knockdown in CB17/ICr-SCID mice was associated with marked reduction in palpable tumor generation by MDAH-2774 cells, indicating that EzH2 promotes the growth of MDAH-2774 cell line in vivo. Conclusions: The results indicate that miR-101 mediated epigenetic silencing of EzH2 may be a potential therapeutic strategy for ovarian cancer. No significant financial relationships to disclose.
Experiences with the Surgical Treatment of Mitral Stenosis
Authors: John A. Williams, David Littmann, Richard Warren
Journal: New England Journal of Medicine (1958)

MITRAL-valve surgery within the Veterans Administration is performed almost wholly on men who were able to pass physical examinations for military service in the not too remote past. It is probable, although not certain, that the valvular disorders in these cases were acquired relatively late in life or were of such minimal degrees as to escape detection at the time of induction into the military service. As a result of this rather special selection of patients the pattern of rheumatic heart disease in Veterans Administration hospitals differs in several important respects from that encountered in civilian practice.This report is . . .
Real time in vivo analysis of granulomonocytic cell migration in the collagen induced arthritis model
Authors: Ruth Byrne, Eva Rath, Anastasiya Hladik, Birgit Niederreiter, Michael Bonelli, Sophie Franta, Michael Klimas, Josef S Smolen, Clemens Scheinecker
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Granulomonocytic cells (GMC) drive the inflammatory process at the earliest stages of rheumatoid arthritis (RA). The migratory behavior and functional properties of GMC within the synovial tissue are, however, only incompletely understood. This tempted us to study GMC in the murine collagen induced arthritis (CIA) model of RA with the help of multi-photon real time in vivo microscopy together with the subsequent and sequential ex vivo analysis of GMC on tissue sections. <h3>Methods</h3> CIA was induced in LysM-EGFP C57BL/6 transgenic animals that carry the EGFP fluorescence protein under the lysozyme promoter. Individual joints were prepared by surgical microscopy in healthy control and in CIA subjects and EGFP<sup>+</sup> GMC were analysed by 2-photon laser microscopy over 2 h. One group of animals received one single dose (0.25 mg) of prednisolone intravenously before in vivo imaging. Afterwards, the animals were killed and cryo-, and paraffin sections were prepared for immunofluorescence and histomorphological analysis, respectively. <h3>Results</h3> GMC were barely detectable in healthy animals but were abundant in the synovial tissue as soon as clinical arthritis was apparent. GMC were motile and migrated randomly through the synovial tissue with a reduced mean velocity (2.75±1.17 µm/min) of as compared to healthy controls (3.11±1.51 µm/min; p&lt;0.001). In CIA subjects, the frequent formation of dynamic cell clusters was observed that consisted of both EGFP<sup>high</sup> neutrophilic granulocytes and EGFP<sup>low</sup> monocytes. In addition EGFPl<sup>low</sup> F4/80<sup>+</sup> TRAP<sup>+</sup> osteoclast precursor cells were occasionally observed at the synovial-bone junction and areas of bone erosions.Prednisolone treatment reduced the mean velocity of cell migration (2.19±1.06 µm/min; p&lt;0.001) and significantly diminished the immigration of GMC into the synovial tissue, but did not affect GMC allocation within cell clusters or throughout the entire tissue. <h3>Conclusion</h3> The combined application of real time in vivo microscopy together with elaborate static postmortem analysis of GMC enabled the description of dynamic migratory characteristics of GMC together with their precise allocation in a complex anatomical environment. Moreover, this approach was found sensitive enough to detect subtle therapeutic effects within a very short period of time.
Abstract 2011: Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A against non-small cell lung cancer cells
Authors: Junko Kikuchi, Ichiro Kinoshita, Eiki Kikuchi, Yasushi Shimizu, Jun Sakakibara-Konishi, Satoshi Oizumi, Masaharu Nishimura, Hirotoshi Dosaka-Akita
Journal: Cancer Research (2011)

Abstract Background: The polycomb group gene, EZH2, mediates the histone methyltransferase activity, and functions as transcriptional repressor involved in gene silencing. It is involved in the malignant transformation and biological aggressiveness of several human cancers. We have previously shown that high EZH2 expression is correlated with tumor aggressiveness and is an independent unfavorable prognostic factor in non-small cell lung cancers (NSCLCs). However, the role of EZH2 in lung cancer cells has not been fully determined. Methods: In the present study, we evaluated the effect of a histone methyltransferase EZH2 inhibitor, 3-Deazaneplanocin A (DZNep), in NSCLC cell lines. Results: DZNep depleted cellular levels of EZH2 and SUZ12, and inhibited histone H3 lysine 27 trimethylation. DZNep inhibited proliferation of NSCLC cells dose- dependently through apoptosis and G1 cell cycle arrest which was partially associated with cyclin A decrease and p27Kip1 accumulation. Conclusion: Epigenetic therapy with the histone methyltransferase EZH2 inhibitor DZNep may constitute a novel approach for NSCLCs. 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 2011. doi:10.1158/1538-7445.AM2011-2011
Maternal Antibodies against Fetal Cardiac Antigens in Congenital Complete Heart Block
Authors: Pamela V. Taylor, James S. Scott, Leon M. Gerlis, Eva Esscher, Olive Scott
Journal: New England Journal of Medicine (1986)

An immunologic basis for congenital heart block has been proposed previously. To investigate the association between congenital heart block and maternal antibodies capable of crossing the placenta, we used immunofluorescence to examine serum samples from 41 mothers and 8 affected children, together with serum from controls, for antibodies to fetal cardiac tissue. Twenty-one mothers (51 percent) had IgG antibody reactive with fetal heart tissue, as compared with only 9 of 94 controls (10 percent; P less than 0.001). Three of 8 affected babies, but none of 50 healthy babies, had similar antibodies. The antibodies reacted with all myocardial tissue and were not directed specifically to the conduction system. They also reacted with other fetal tissues and could be distinguished from nuclear and smooth-muscle autoantibodies. We also observed a higher occurrence of antibodies to cytomegalovirus, but not to Epstein-Barr virus, in these mothers. Autopsy specimens from babies with congenital heart block examined by immunoperoxidase staining showed deposition of immunoglobulin and complement components in all cardiac tissues. These findings strengthen the case implicating immune reactivity related to maternal antibody in the development of some but not all cases of congenital heart block.
Cerebral palsy linked to maternal fever
Authors: A. Boulton
Journal: BMJ (1997)

Babies of normal birth weight who are exposed to infection and maternal fever while in the uterus seem to have a ninefold increased risk of developing cerebral palsy.

Maternal or placental infection had been associated with an increased risk of cerebral palsy in low birthweight babies. In a recent study American researchers studied the records of babies born in hospital in California between 1983 and 1985, all of whom weighed at least 2500g at birth. In all, 46 children …