tbuckley/cabot-search huggingface dataset:
Abstract 4428: Oncogenic ERBB3 mutations in human cancers
Authors: Bijay S. Jaiswal, Noelyn M. Kljavin, Eric Stawiski, Steffen Durinck, Subhra Chaudhuri, Charles Eigenbrot, Gabriele Schaefer, Frederic J. de Sauvage, Somasekar Seshagiri
Journal: Cancer Research (2014)

Abstract The human epidermal growth factor receptor (HER) family of tyrosine kinases are deregulated in multiple cancers either through amplification, overexpression or mutation. ERBB3/HER3, the only ERBB family member with an impaired kinase domain, upon ligand binding heterodimerizes with ERBB2 to promote signaling. While amplification and overexpression of ERBB3 is observed in some cancers, occurrence and relevance of ERBB3 somatic mutations in oncogenesis is not established. Here we report the identification of ERBB3 somatic mutations in ∼11% of colon and gastric cancers. We found that the ERBB3 mutants together with ERBB2 promote oncogenic signaling and transformed colonic and breast epithelial cells in a ligand independent manner. Further, we found that multiple target therapeutics that acts on ERBB3, ERBB2 or their downstream signaling components are effective in blocking ERBB3-mutant mediated oncogenic signaling and disease progression in vivo. Identification of activating ERBB3 mutations along with the established contribution of ERBB3 to acquired resistance to EGFR/ERBB2-targeted drugs provides a rational to therapeutically target ERBB3. Citation Format: Bijay S. Jaiswal, Noelyn M. Kljavin, Eric Stawiski, Steffen Durinck, Subhra Chaudhuri, Charles Eigenbrot, Gabriele Schaefer, Frederic J. de Sauvage, Somasekar Seshagiri. Oncogenic ERBB3 mutations in human cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4428. doi:10.1158/1538-7445.AM2014-4428
Fusion of NUP214 to ABL1 on Amplified Extrachromosomal Elements in T-ALL.
Authors: Jan Cools, Carlos Graux, Cindy Melotte, Hilmar Quentmeier, Adolfo A. Ferrando, Ross Levine, Joris R. Vermeesch, Michel Stul, Binita Dutta, Nancy Boeckx, Andre Bosly, P. Heimann, Anne Uyttebroeck, Nicole Mentens, Riet Somers, Roderick A.F. MacLeod, Hans G. Drexler, A. Thomas Look, D. Gary Gilliland, Lucienne Michaux, Peter Vandenberghe, Iwona Wlodarska, Peter Marynen, Anne Hagemeijer
Journal: Blood (2004)
CPOD and lung function parameters as predictors of mortality: Results from the Latin American PLATINO cohort study
Authors: Ana M.B. Menezes, Rogelio Perez-Padilla, Fernando C. Wehrmeister, Maria Victorina Lopez-Varela, Adriana Muiño, Gonzalo Valdivia, Carmem Lisboa, José R. Jardim, Maria Montes de Oca, Carlos Talamo, Renata Bielemann, Mariana Gazzotti, Ruy Laurentu, Bartolomé Celli, Cesar Victora
Journal: European Respiratory Journal (2014)

Rationale : There is evidence from high-income countries that low lung function and COPD predict subsequent mortality. Little is known about lung function as predictors of mortality in low- and middle income countries.  Aims : To describe mortality rates according to COPD and lung function in cohorts from three Latin American (LA) cities.  Methods : Prospective population based adult cohorts were followed up in Montevideo, Santiago and Sao Paulo during 5, 6 and 9 years, respectively. The outcomes included all-cause, cardiovascular, respiratory and cancer mortality; exposures were COPD (according to different criteria), FEV 1  and FVC. Cox regression models were used in confounder-adjusted analyses. Sensitivity, specificity, positive and negative predictive values, ROC curves and Youden9s index were calculated.  Results : The main causes of death were cardiovascular, respiratory and cancer. In the adjusted models, baseline COPD was associated with overall mortality (HR 1.43 for FEV1/FVC 1 /FVC 1 /FEV 6  1  was associated with an increased risk for overall and respiratory mortality in both sexes. FVC did not show a significant association with overall mortality. For most COPD criteria sensitivity was lower than specificity. The area under the curve for FEV 1  was greater than for FVC for overall and cardiovascular mortality.  Conclusions : COPD and low FEV 1  are important predictors for overall and cardiovascular mortality in LA.
Abstract 997: Innate Immune Adaptor MyD88 Mediates Myocardial Inflammation And Infarction In A Mouse Model Of Ischemia-reperfusion Injury
Authors: Huailong Zhao, Xinhua Xu, Ulrich Schmidt, Wei Chao
Journal: Circulation (2007)

INTRODUCTION: The innate immune response to ischemia-reperfusion (I/R) is, by far, the most common cause of myocardial inflammation and contributes to ischemic myocardial injury. MyD88 is an adaptor protein critical for transducing signals from most innate immune receptors and plays an important role in host defense against microbial infection; but its role in non-infectious myocardial inflammation and injury following I/R is unclear. METHODS: I/R injury was studied in wild-type (WT) and MyD88-deficient (MyD88−/−) mice. Mice were anesthetized and mechanically ventilated. The heart was exposed via intercostal thoracotomy. The left coronary artery was ligated for 30 min followed by reperfusion. The coronary artery was re-ligated at 24 hours and fluorescent microsphere was injected into LV to detect area-at-risk (AAR). The hearts were harvested, sectioned, and examined for inflammation or infarct size. Myocardial neutrophil infiltration [GR-1 immunohistochemistry and myeloperoxidase activity] and NF-kB signaling (I-kBa degradation and NF-kB binding activity) were examined to assess myocardial inflammation. In ex vivo studies, isolated mouse hearts were exposed to global ischemia for 20 min followed by reperfusion for 30 min. RESULTS: In vivo I/R induced significant neutrophil infiltration and NF-kB activation in myocardium in WT mice compared with the sham-operated mice. However, in MyD88−/− mice subjected to the same I/R, the level of neutrophil recruitment and NF-kB signaling was significantly lower compared with WT mice. The ratio of AAR to LV was similar in WT and MyD88−/− mice (34 +/− 3% vs. 41 +/− 3%). However, the ratio of MI to AAR was 58% less in MyD88−/− than in WT mice (14 +/− 2% vs. 33 +/− 6% (p &lt; 0.014, n = 11–12). In a Langendorff model of I/R injury, a system devoid of circulating blood components, global I/R induced similar MI sizes, as a fraction of LV size (MI/LV), in MyD88−/− and WT mice (34 +/− 6% and 25 +/− 7%, respectively, p = 0.3, n = 8). CONCLUSIONS: These studies demonstrate that systemic MyD88 deficiency decreases myocardial inflammation and infarction after ischemia-reperfusion in vivo and support the hypothesis that MyD88 mediates ischemic myocardial injury via mechanisms that are dependent upon circulating blood components.
Abstract 2851: Reduced Tip60 expression in human gastric cancer
Authors: Guangdi Chen, Rongpan Bai, Zhongsheng Zhao, Jianwei Zhou, Yu Weng
Journal: Cancer Research (2014)

Abstract The tumor suppressor Tip60 plays a major role in gene transcription, DNA damage response, apoptosis and cancer development, but its role in gastric cancer is unknown. In this study, we investigated the role of Tip60 in gastric cancer pathogenesis and assessed its prognostic value. Using tissue microarrays consisting of 567 cases of gastric cancers (78 for training set and 489 for validation set), we found that Tip60 expression was significantly reduced in advanced gastric cancer compared to early stages of gastric cancer (P &amp;lt; 0.001). Reduced Tip60 was correlated with gastric cancer lymph node metastasis (P &amp;lt; 0.001) although no significant correlation was found between Tip60 expression and gastric cancer distant metastasis. Kaplan-Meier survival curve analysis showed that reduced Tip60 expression was associated with a poorer five-year overall survival in gastric cancer patients from both training set (P = 0.010) and validation set (P &amp;lt; 0.001). Our data indicate that Tip60 may play an important role in gastric cancer metastasis and serve as a potential biomarker for gastric cancer patient outcome. Note: This abstract was not presented at the meeting. Citation Format: Guangdi Chen, Rongpan Bai, Zhongsheng Zhao, Jianwei Zhou, Yu Weng. Reduced Tip60 expression in human gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2851. doi:10.1158/1538-7445.AM2014-2851
Abstract 1909: Identification and characterization of microRNA-134 as a novel receptor tyrosine kinase-regulated tumor suppressive hub in glioblastoma
Authors: Ying Zhang, Jungeun Kim, Adam C. Mueller, Bijan Dey, Yanzhi Yang, Daehee Lee, Jan Hachmann, Sanjo Finderle, Deric M. Park, James Christensen, David Schiff, Benjamin Purow, Anindya Dutta, Roger Abounader
Journal: Cancer Research (2014)

Abstract Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. In this study, we uncovered microRNA-134 (miR-134) as a novel tumor suppressive hub that is co-regulated by multiple RTKs via MAPK and KLF4 and that acts via regulation of KRAS and STAT5B expressions. Using microRNA microarrays and qRT-PCR, we screened for microRNAs that are co-regulated by multiple RTKs in GBM. We found that miR-134 was one such microRNA that is downregulated by the activation of MET, EGFR, and PDGFR, the three most commonly deregulated RTKs in GBM. Using a combination of pharmacology, promoter analysis, transcription factor functional and rescue approaches and ChIP/qPCR, we uncovered the MAPK pathway and the transcriptional repressor KLF4 as mediators of the effects of RTKs on miR-134 repression. We then measured the expression of miR-134 and found that it was downregulated in human GBM tumors and GBM stem cells (GSCs) and that it inversely correlated with the activation levels of MET, EGFR, and PDGFR in the tumors. We demonstrated that miR-134 inhibits GBM cell and GSC proliferation, survival, and in vivo xenograft growth, as well as GSC self-renewal and stemness. We uncovered the oncogenes KRAS and STAT5B as direct targets of miR-134 with immunoblots and 3′UTR reporter assays, and showed with rescue experiments that they mediate miR-134 tumor suppressive effects. Thereafter, using a series of molecular and functional assays we established direct links and dependencies between RTKs, KLF4, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. Importantly, we also found that miR-134 induction is required for the anti-tumor effects of small molecule RTK inhibitors. Altogether, our extensive study identified miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B. These findings shed new light onto the molecular and functional interactions between RTKs and microRNAs and uncover opportunities for exploiting these interactions for therapeutic purposes. Citation Format: Ying Zhang, Jungeun Kim, Adam C. Mueller, Bijan Dey, Yanzhi Yang, Daehee Lee, Jan Hachmann, Sanjo Finderle, Deric M. Park, James Christensen, David Schiff, Benjamin Purow, Anindya Dutta, Roger Abounader. Identification and characterization of microRNA-134 as a novel receptor tyrosine kinase-regulated tumor suppressive hub in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1909. doi:10.1158/1538-7445.AM2014-1909
Measles and rubella misdiagnosed in infants as exanthem subitum (roseola infantum)
Authors: D. R Tait, K. N Ward, D. W G Brown, E. Miller
Journal: BMJ (1996)

with allowing more protected time for training to encourage more London principals to become trainers; providing more political solutions for primary care in London; and improving the marketing of general practice to medical students and junior doctors in London.Thirdly, recommendations from the course organisers included increasing the general practice component of training to 18 months; encouraging more flexibility in part-time training; making it possible for all registrars to undertake a component of their general practice time in an urban practice; and creating more academic and research posts in London to encourage registrars not currently wanting to become principals to continue working in the inner city.Government funding for educational flexibility in the London initiative zone over the next two years will enable some of these issues to be addressed.In addition, data on numbers of general practice registrars need to be collected and collated in a more uniform way; this should be partially addressed by the new reporting mechanism, but this will need to be moni- tored.Finally, any recommendations for vocational training cannot be viewed in isolation from the wider demands of general practice in inner London, in par- ticular immediate improvements in safety for doctors in high risk areas and long term measures to tackle inner city social deprivation.We thank the four Thames regional advisers in general practice-Drs Homung, Josse, Ruben, and Styles-and all the respondents to our questionnaires.
BMA Annual Representative Meeting: BMA secretary threatens to sue representatives
Authors: Annabel Ferriman
Journal: BMJ (2003)

BMA secretary Jeremy Strachan threatened to sue the chairman of the representative body and members of the meeting's agenda committee during the association's annual meeting because, he claimed, the wording of one of the motions criticising him was libellous.

The motion, from the Eastern regional junior doctors' committee, criticised Mr Strachan for proposing to change the terms and conditions of staff, against the wishes of the 2002 annual meeting. It was due to be debated on the second afternoon of the meeting, but was withdrawn in the morning without an explanation.

Representatives at the meeting revealed what had happened when they were speaking to another motion, criticising the BMA for alienating grass root doctors by manipulating the meeting's agenda to ensure that contentious issues were not debated. The motion, from Buckinghamshire division, also said that the council and executive committees failed to act on policies not to their liking.

Speaking in favour of that motion, Dr Paddy Glackin, a GP who until recently was working abroad, told the meeting that Mr Strachan had threatened legal action against the chairman of the representative body and the agenda committee, if the motion from the junior doctors was not withdrawn.

Mr Paul Flynn, a consultant obstetrician from Swansea and a member of the agenda committee, confirmed that the agenda committee was only told that Mr Strachan was considering taking legal action the night before the motion was due to be debated. The committee itself then took legal advice and the motion was withdrawn. The agenda committee thought it had been subject to “inappropriate pressure.”

The meeting showed further support for BMA staff by criticising attempts by the association to introduce performance related pay for its staff, when it had resisted it for doctors.
Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing
Authors: Veronica R. Placencio, Yves A. DeClerck
Journal: Cancer Research (2015)

Abstract Despite its function as an inhibitor of urokinase and tissue-type plasminogen activator (PA), PA inhibitor-1 (PAI-1) has a paradoxical protumorigenic role in cancer, promoting angiogenesis and tumor cell survival. In this review, we summarize preclinical evidence in support of the protumorigenic function of PAI-1 that has led to the testing of small-molecule PAI-1 inhibitors, initially developed as antithrombotic agents, in animal models of cancer. The review discusses the challenges and the opportunities that lay ahead to the development of efficacious and nontoxic PAI-1 inhibitors as anticancer agents. Cancer Res; 75(15); 2969–74. ©2015 AACR.
Effects of vitamin D on alveolar epithelial wound repair and cell survival
Authors: Rachel Dancer, Shengxing Zheng, Vijay D'Souza, Fang Gao, David Thickett
Journal: European Respiratory Journal (2011)

It is increasingly recognised that vitamin D is important in both adaptive and innate immunity with significant immunomodulatory effects. Patients undergoing oesophagectomy are at significant risk of post-operative Acute Lung Injury. They are severely vitamin d deficient and those with the lowest levels of vitamin D have a greater systemic inflammation with increased epithelial damage and extra-vascular lung water. We hypothesised that vitamin d has a trophic role to protect against alveolar epithelial damage.   Methods:  A549 cells were mechanically wounded using a pipette tip and then wound repair after 24 hours culture with or without 25 D3 was assessed by videomicroscopy. Cell proliferation was measured by BRDU incorporation. Cells were incubated with FasL alone or with 25 D3 for 24 hours. Cell viability was measured using a Celltiter Aqueous solution (Promega).   Results:  A549 and primary alveolar type II cells increased wound repair in response to a physiological dose of vitamin 25D3. BRDU incorporation was similarly increased supporting proliferative effect of vitamin D. sFasL induced cell death was reduced by addition of 50nmol/L 25-OH vitamin D (p=0.001) when added before or up to 1.5 hours after addition of sFasL suggesting that vitamin d reduced apoptotic cell death. sFasl inhibited proliferation of ATII in actions that were blocked by vitamin d.   Conclusions:  Our data suggests that Vitamin D plays a role in the maintenance of an intact alveolar epithelial barrier through effects on wound repair and is protective against apoptotic cell death.
Recent Advances in Targeted, Self‐Assembling Nanoparticles to Address Vascular Damage Due to Atherosclerosis
Authors: Eun Ji Chung, Matthew Tirrell
Journal: Advanced Healthcare Materials (2015)

Self‐assembling nanoparticles functionalized with targeting moieties have significant potential for atherosclerosis nanomedicine. While self‐assembly allows the easy construction (and degradation) of nanoparticles with therapeutic or diagnostic functionality, or both, the targeting agent can direct them to a specific molecular marker within a given stage of the disease. Therefore, supramolecular nanoparticles have been investigated in the last decade as molecular imaging agents or explored as nanocarriers that can decrease the systemic toxicity of drugs by producing accumulation predominantly in specific tissues of interest. In this Progress Report, the pathogenesis of atherosclerosis and the damage caused to vascular tissue are described, as well as the current diagnostic and treatment options. An overview of targeted strategies using self‐assembling nanoparticles is provided, including liposomes, high density lipoproteins, protein cages, micelles, proticles, and perfluorocarbon nanoparticles. Finally, an overview is given of current challenges, limitations, and future applications for personalized medicine in the context of atherosclerosis of self‐assembling nanoparticles.
Diagnosis of Coronary Embolism: A Review<sup>1</sup>
Authors: R G Charles, E J Epstein
Journal: Journal of the Royal Society of Medicine (1983)

Coronary embolism is an uncommon but distinct clinical entity. It can be diagnosed clinically, and should be suspected when acute myocardial infarction occurs in association with an underlying condition which predisposes to embolism. The most common are valvular heart disease, a prosthetic heart valve, infective endocarditis, cardiomyopathy with mural thrombus and arrhythmia. The diagnosis may be obscured by atypical symptoms and transient ECG changes. The diagnosis is supported by the demonstration of normal coronary arteries by selective coronary arteriography. Treatment with long-term anticoagulants may prevent further emboli. Additional antiplatelet drugs are also necessary in patients with prosthetic heart valves.
Abstract 5215: Loss of Rpl22 promotes tumor progression through regulation of angiogenesis
Authors: Shuyun Rao, Jason E. Stadanlick, Kathy Q. Cai, David L. Wiest
Journal: Cancer Research (2015)

Abstract Mutations in ribosomal proteins (RP) often cause bone marrow syndromes associated with increased risk for cancer development. We have shown that Rpl22 is a haploinsufficient tumor suppressor in T acute lymphoblastic leukemia (T-ALL). Indeed, loss of one Rpl22 allele accelerates T-cell lymphomagenesis in the murine Akt transgenic mouse model, by inducing the stem cell factor Lin28B in an NFκB-dependent manner. Moreover, mice lacking both Rpl22 alleles exhibited significantly increased thymic tumor size, which was associated with poor survival and markedly enhanced angiogenesis relative to Rpl22 heterozygous mice or wild type. The increased angiogenesis in the mediastinal mass was linked to upregulation of VEGFA and downregulation of S1P1. Loss of S1P1 is sufficient to block egress of lymphoma cells from thymus. Rpl22-deficient thymic lymphoma lines also exhibit enhanced growth upon adaptation to growth in vitro, and this is reversed by ectopic expression of Rpl22. Rpl22 expression also represses the expression of proteins that promote traversal of the cell cycle. Collectively, the increased tumor growth and angiogenesis, and the blockade of thymic egress contribute to the enlarged mediastinal masses observed in Rpl22-deficient mice. Rpl22-mutant T-ALL are a molecularly distinct subtype exhibiting increased aggression and treatment resistance. Accordingly, our identification of a number of signaling pathways controlled by Rpl22 may enable the development of novel strategies, such as targeting angiogenesis, in such cases of T-ALL. Citation Format: Shuyun Rao, Jason E. Stadanlick, Kathy Q. Cai, David L. Wiest. Loss of Rpl22 promotes tumor progression through regulation of angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5215. doi:10.1158/1538-7445.AM2015-5215