tbuckley/cabot-search huggingface dataset:
Abstract 2059: Kinase library siRNA screen identifies KSR1 as a synergistic therapeutic target in combination with TIC10.
Authors: Joshua E. Allen, Wafik S. El-Deiry
Journal: Cancer Research (2013)

Abstract Apo2L/TRAIL is an endogenous antitumor protein that possesses efficacy-limiting properties such as short serum half-life, stability, cost, and limitations in delivery when used as a recombinant protein therapeutic. TIC10 is a first-in-class small molecule inducer of the human TRAIL gene that improves these unfavorable drug properties to ultimately increase the efficacy and utility of TRAIL. TIC10 upregulates TRAIL gene transcription by activating the pro-apoptotic transcription factor Foxo3a, which is achieved through dual inhibition of Akt and MEK/ERK. We conducted a siRNA screen using a kinase library to identify kinases that affect TIC10 response in cancer cells assayed by cell viability assays to gain mechanistic insight into the molecular mechanisms of TIC10 and potentially identify a combinatorial target to improve the activity of TIC10. Execution and validation of the siRNA screen revealed 4 kinases (DGKD, SGKL, STK23, KSR) that improved the therapeutic response to TIC10 upon siRNA-mediated knockdown at 36 hours, but not 12 hours, post-treatment in HCT116 human colon cancer cells. We next assayed the effect of knocking down these 4 kinases on cancer cell cytotoxic response to recombinant human TRAIL. These studies revealed no effect with kinase knockdowns, suggesting that the mechanisms of sensitization lie upstream of TIC10-mediated TRAIL production. Network analysis of the “hit” kinases and the previously described mechanism of TIC10 revealed rational overlap of signaling pathways and kinetics. Among the 4 identified kinases, KSR1 possessed the most direct connection to the putative mechanism of TIC10 that involves the dual inhibition of Akt and the MAPK pathway. KSR1 is a MAPK scaffold protein that positively regulates the MAPK signaling pathway. Based on these observations, we are testing the hypothesis that inhibiting KSR1 in combination with TIC10 cooperatively inhibits MAPK signaling to increase TRAIL production. Together, these results suggest that KSR1 is a key player in the cytotoxic response to TIC10 and that combining TIC10 and an inhibitor of KSR1 may result in improved therapeutic response. Citation Format: Joshua E. Allen, Wafik S. El-Deiry. Kinase library siRNA screen identifies KSR1 as a synergistic therapeutic target in combination with TIC10. [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 2059. doi:10.1158/1538-7445.AM2013-2059
Abstract 1217: Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform
Authors: Nathan Anderson, Tin Khor, Andrew Feldhaus, Andreya Gatling, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer
Journal: Cancer Research (2014)

Abstract Cachexia is present in the majority of patients with advanced cancer progression and is not reversible through nutritional supplementation, leading to loss of skeletal muscle and adipose tissue. There are a lack of quality pre-clinical models for cachexia research. Previously, Champions Oncology reported a mouse cachexia model derived from a primary human renal cell carcinoma tumor implanted in immunocompromised mice. This model, CTG-0804, was developed using the innovative Champions TumorGraft™ platform, which preserves the biological properties of the original human tumor. The Champions TumorGraft platform demonstrated dramatic weight loss in these mice as the tumor grew. Plasma from these mice also showed elevated levels of human IL-6. We have now further characterized this TumorGraft model by evaluating standard of care (SOC) agents for renal cell carcinoma and anti-IL-6 compounds to determine the mechanism of cachexia. The SOC evaluation revealed that sorafenib, sunitinib, temsirolimus and bevacizumab as single agents provided a survival advantage by inhibiting tumor growth and preventing weight loss in these mice. Blockade of human IL-6 with tocilizumab or ALD518 did not inhibit tumor growth and weight loss still occurred, demonstrating the possibility of other pathways involved in the cachexia mechanism. In addition, the SOC data for sunitinib showed significant tumor growth inhibition, but no regression at the study end point. This correlated with the clinical profile, where sunitinib could not prevent metastasis and the patient eventually progressed. The TumorGraft model was molecularly characterized and mutation analysis revealed a KIT V530I mutation. This mutation has been reported in extra-abdominal aggressive fibromatosis (desmoid tumor) and acute myeloid leukemia patients that have responded to c-kit targeting therapies, such as imatanib and dasatinib. Further characterization of this TumorGraft is ongoing to include additional bioinformatics using gene expression and mutation pathway analyses. In summary, we have continued development of this cachexia model using the Champions TumorGraft platform, along with molecular evaluation, to produce a robust and well-characterized approach for cachexia investigation which can also be applied to other areas of drug development and cancer research. Citation Format: Nathan Anderson, Tin Khor, Andrew Feldhaus, Andreya Gatling, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform. [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 1217. doi:10.1158/1538-7445.AM2014-1217
S92 Epithelial mesenchymal transition occurs earlier than previously thought in the development of squamous cell carcinoma of the lung
Authors: N. M. Cummings, D. M. Rassl, H. C. Boobier, J. R. Gosney, A. G. Nicholson, L. D. Sharples, R. C. Rintoul
Journal: Thorax (2010)

<h3>Introduction</h3> Squamous cell carcinoma is believed to develop in a step-wise fashion from squamous metaplasia (SqMet), through low- and high-grade dysplasia (LGDys; HGDys) and carcinoma-in-situ (CIS) to invasive disease (InvSCC). Epithelial mesenchymal transition (EMT) is an important process by which epithelial cells shed their differentiated characteristics and acquire mesenchymal, fibroblast-like properties including increased motility and invasiveness. There is now convincing phenotypic, genetic and functional evidence that EMT plays a central role in carcinogenesis. To date, EMT is believed to occur during transition from pre-invasive disease to invasive disease. A hallmark of EMT is the down-regulation of E-cadherin, a cell adhesion molecule present in the plasma membrane of epithelial cells. We have examined the role of EMT during the progression of bronchial dysplasia. <h3>Methods</h3> Using immunohistochemistry, 170 formalin-fixed paraffin-embedded blocks from lung cancer biopsies and resection specimens were stained for epithelial markers E-cadherin and MNF116 and the mesenchymal marker S100A4. In each sample, areas of SqMet, LGDys, HGDys (incorporating CIS) and InvSCC were identified. Up to three representative areas were assessed for each lesion type present and an aggregate score assigned which took into account strength and extent of staining. Specimens were also stained for β-catenin which translocates from the membrane to the nucleus during EMT. One hundred cells per high power field were counted and the proportion of membranous, cytoplasmic and nuclear staining calculated. <h3>Results</h3> There was a progressive loss of epithelial markers and a concurrent gain in S100A4 with increasing dysplasia. The switch from expression of epithelial to mesenchymal markers began as early as SqMet and reached significance for all three markers between LGDys and HGDys. Likewise, β-catenin showed translocation from membranous to cytoplasmic expression; this also reached significance between LGDys and HGDys. The difference in nuclear expression between groups did not reach significance. <h3>Conclusions</h3> In order to improve lung cancer survival there is increasing interest in identifying early stage disease. The mechanisms underlying progression of bronchial dysplasia are poorly understood. Our results suggest that EMT is occurring much earlier in bronchial dysplasia than previously appreciated and this may have implications for the surveillance and treatment of pre-invasive disease.
Physicians: Check That Blood Pressure
Authors: Leon J. Warshaw
Journal: JAMA (1989)

<h3>To the Editor.—</h3> As one of the speakers at the 1972 meeting where Elliot Richardson, then Secretary of Health, Education, and Welfare, launched the National High Blood Pressure Education Program and who over the years has promoted the workplace as an arena for high blood pressure detection and intervention, it has been gratifying to note the progress that has been achieved. Now, the majority of people with high blood pressure are at least aware that they have it and, thanks to advances in treatment, a growing proportion of them have it under control. But the job is not finished. A cornerstone of the program has been the effort to see that a blood pressure check is incorporated into every medical encounter to identify those who are candidates for further evaluation and treatment. I was dismayed, therefore, to note in a recent report from the National Center for Health Statistics<sup>1</sup>
Neuropilin-2 Is a Receptor for Semaphorin IV Insight into the Structural Basis of Receptor Function and Specificity
Authors: Roman J Giger, Erica Rowe Urquhart, Susan K.H Gillespie, Dorothy V Levengood, David D Ginty, Alex L Kolodkin
Journal: Neuron (1998)

Neuropilins bind secreted members of the semaphorin family of proteins. Neuropilin-1 is a receptor for Sema III. Here, we show that neuropilin-2 is a receptor for the secreted semaphorin Sema IV and acts selectively to mediate repulsive guidance events in discrete populations of neurons. neuropilin-2 and semaIV are expressed in strikingly complementary patterns during neurodevelopment. The extracellular complement-binding (CUB) and coagulation factor domains of neuropilin-2 confer specificity to the Sema IV repulsive response, and these domains of neuropilin-1 are necessary and sufficient for binding of the Sema III semaphorin (sema) domain. The coagulation factor domains alone are necessary and sufficient for binding of the Sema III immunoglobulin- (Ig-) basic domain and the unrelated ligand, vascular endothelial growth factor (VEGF). Lastly, neuropilin-1 can homomultimerize and form heteromultimers with neuropilin-2. These results provide insight into how interactions between neuropilins and secreted semaphorins function to coordinate repulsive axon guidance during neurodevelopment.
False-positive Liver Scintigraphy Secondary to Posterior Sulcus Pulmonary Neoplasm
Authors: BERT R. CAROLLO, JOE C. LEONARD
Journal: Clinical Nuclear Medicine (1985)

Two cases of posterior sulcus tumors mimicking primary liver lesions on Tc-99m sulfur colloid imaging with correlative radiographs and CTs are presented to illustrate this potentially significant cause of false-positive liver scintigraphy.
BMA criticises latest plans for revalidation
Authors: R. Wilkins
Journal: BMJ (2010)

Doctors leaders have called for the latest plans for revalidation drawn up by the General Medical Council to be scrapped saying they seem both “threatening and disproportionate.”

The BMA says the GMC should “go back to the drawing board” to deal with fundamental problems in its consultation document Revalidation: the way ahead, which was launched in March.

Feedback from BMA committees led the BMA to conclude that its “confidence in the process [of revalidation] is seriously undermined.”

The BMA said that the current proposals for revalidation “appear designed to describe excellence as a doctor rather than …
An Investigation into a Panel of Isogenic Taxane Resistant Breast Cancer Cell Lines Using Transcriptomic and Genomic Methods.
Authors: J. Kenicer, M. Lambros, V. Sabine, J. Reis-Filho, J. Bartlett
Journal: Cancer Research (2009)

Abstract Background: Taxanes are a powerful chemotherapeutics used to treat breast cancer. Taxane resistance has become increasingly more prevalent in the clinic; This problem is exacerbated by a lack of understanding of mechanisms underlying taxane resistance.Materials and Methods: 3 isogenic breast cancer cell-line panels: paclitaxel resistant (PACR) MDA-MB-231s/ZR75-1s and docetaxel resistant (DOCR) ZR75-1s were derived by culturing cells in incrementally escalating doses of taxanes over time. MDA-MB-231: native, 5nM, 25nM and 100nM PACR cells, ZR75-1: native, and 5nM, 25nM, and 50nM PACR and ZR75-1: native, and 5nM, 25nM and 50nM DOCR cells were analysed. RNA from native and PACR MDA-MB-231 cell lines was analysed on the Illumina® human ref.8V2 chip. Data were analysed using IlluminaGui. For aCGH, DNA was extracted from MDA-MB-231 PACR, ZR75-1 PACR and DOCR and respective parental lines, labelled and hybridised to a tiling path BAC microarray (resolution ∼50kb). Each cell-line was tested against reference samples of DNA from pooled female blood. Taxane resistant cells were tested against their parental cell line.Results: Illumina data demonstrated that resistance to increasing doses of paclitaxel is associated with sequential increases in mRNA dysregulation in MDA-MB-231 cells.A number of comparisons between the illumina data of native and the PACR cells were made using a p value of P≤0.001. The first comparison made using the illumina data, was between the 5nM PACR cells and the native cell lines: 25 significantly up or downregulated genes were identified. When the 25nM PACR cells were compared to the native cell lines, 225 genes were found to be significantly up or downregulated. Finally, when 100nM PACR cells were compared to native cells, 425 genes were found to be significantly up or downregulated. A group of genes identified that were common to multiple paclitaxel resistant groups included candidates such as YY1, AURKA and CCND2. aCGH has identified significant differences in patterns of copy number loss, gain and amplification in the taxane resistant cell lines, including chromosome loss of 6p and gain of 2p. Illumina and aCGH data were overlaid using specially designed algorithms.Discussion: Both aCGH and expression arrays highlight a progressive acquisition of molecular and transcriptomic alterations in isogenic breast cancer cell lines resistant to increasing doses of taxanes. Further mapping of transcriptomic and genomic profiles will enable identification of key molecular targets for restoration of taxane sensitivity. Genes upregulated in taxane resistant clones identified in the illumina experiment, in particular those whose upregulation is underpinned by DNA copy number gains in resistant cells, may represent genes which may be targeted with inhibitors to test potential candidates for reversing taxane resistance. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1134.
Adenosine 3′–5′ monophosphate (cAMP) reduces neointima formation and smooth muscle cell proliferation after balloon injury
Authors: C. Indolfi, A. Rapacciuolo, E. Di Lorenzo, G. Esposito, L. Cavuto, E. Stabile, A. Cioppa, G. Tortora, F. Ciardiello, M. Chiariello
Journal: Journal of the American College of Cardiology (1998)
Exogenous Oxidized Low-Density Lipoprotein Injures and Alters the Barrier Function of Endothelium in Rats In Vivo
Authors: Shanthini Rangaswamy, Marc S. Penn, Gerald M. Saidel, Guy M. Chisolm
Journal: Circulation Research (1997)

Oxidation converts low-density lipoprotein (LDL) into a cytotoxin in vitro. Oxidized LDL exists in vivo in atherosclerotic lesions and possibly in plasma. Many cell functions are altered in vitro by oxidized LDL, but few have been examined in vivo. To test whether oxidized LDL could injure endothelial cells and alter endothelial permeability to macromolecules in vivo, we infused oxidized LDL, native LDL, or their solvent intravenously into rats. Subsequently, endothelial cell injury and proliferation were measured, and the transport into the aorta wall of the macromolecule horseradish peroxidase (HRP) was quantified. Transport data were analyzed using mathematical models of macromolecular transport; parameters were estimated by optimally fitting model-predicted HRP concentrations to experimental data. Compared with native LDL or solvent control infusion, oxidized LDL infusion increased (1) the number of injured aortic endothelial cells fivefold to sixfold at 36 hours, (2) proliferation of endothelial cells at 48 hours, (3) intimal and medial accumulations of HRP twofold to threefold at 48 hours, and (4) the permeability coefficient of the endothelium to HRP fourfold to fivefold at 48 hours. Hence, oxidized LDL administered in vivo can injure the endothelium, despite the presence of endogenous antioxidants, compromising the function of the endothelium as a permeability barrier.
The Clinical Management of Systemic Lupus Erythematosus
Authors: M. L. Snaith
Journal: Annals of the Rheumatic Diseases (1984)

Ankylosing spondylitis in North India: a clinical and iminunogenetic studly 385 patients with AS1 20 would suggest that ankylosing spondylitis is immunoinflammatory in nature.The authors thank Miss Vena Taneja for her help in tissue typing.
Diagnostic quantification of CASS (coronary artery surgery study) clinical and exercise test results in determining presence and extent of coronary artery disease. A multivariate approach.
Authors: L D Fisher, J W Kennedy, B R Chaitman, T J Ryan, C McCabe, D Weiner, F Tristani, M Schloss, H R Warner
Journal: Circulation (1981)

Multivariate linear discriminant function analysis on maximal exercise treadmill and angiographic data from 500 men with definite angina, 584 men with probable angina and 267 men with nonspecific chest pain identified independent predictors of presence and extent of coronary disease. We used the discriminant function to develop a clinical risk index and a clinical and exercise risk index for each patient subset. Probability curves were generated to predict the presence and extent of coronary disease. In definite angina cases, exercise testing provided more diagnostic information than clinical data alone. However, in the 10% of cases with the smallest risk indexes, half of the patients had coronary disease and one-quarter had multivessel disease. In men with probable angina, exercise testing added substantially more diagnostic information than clinical data. The probability of multivessel disease was reduced to less than 10% for 30% of patients with probable angina, an important diagnostic contribution. Exercise testing in men with nonspecific chest pain was of limited value because disease prevalence was already low.
NHS breast screening programme: is the high incidence of interval cancers inevitable?
Authors: D. Asbury, C. R M Boggis, D. Sheals, A. G Threlfall, C. B J Woodman
Journal: BMJ (1996)

In the NHS breast screening programme women are screened every three years; those presenting with breast cancer within three years of a negative test are considered to have an interval cancer. Unexpectedly high rates of interval cancers have been reported from the programme,1 2 but opinion is divided about what should be done.3 It is accepted that not all interval cancers could have been detected at the time of screening and that some will be true interval cancers, appearing de novo between screening rounds. We report how the occurrence of true interval cancers varies with time from screening.

Interval cancers occurring before 31 March 1994 in women screened from 1 April 1988 to 31 March 1993 at the Manchester and Wigan breast screening services were identified,1 and a mammogram taken at the time of diagnosis was …
Change of Heart Perhaps, but Not of Legislation
Authors: Charles Marwick
Journal: JAMA (1994)

SPEAKING at the National Press Club in Washington, DC, last December, the Surgeon General of the United States, Joycelyn Elders, MD, suggested that legalization of illicit drugs could lead to a significant decrease in violent crime.  deserves active examination, she said.  Elders' words set off spasms of political pain from the White House to Capitol Hill, and ripples of her remarks eddied from coast to coast. Much of the criticism mistakenly portrayed her as in favor of legalizing currently illegal drugs.  Elders had hardly returned to her office before White House press secretary Dee Dee Myers announced,  President is against legalizing drugs. It will not happen on his watch. [Elders] is not speaking for the administration on this issue.  The Surgeon General declined to be interviewed for this article, saying, through her spokesman, that her earlier remarks on the topic still stand. In response to the White House's
Evaluation of Association between Epicardial Adipose Tissue Volume and Coronary Artery Calcium Score with Multislice Computed Tomography
Authors: Müslüm Şahin, Mustafa Çetin, Zehra Güven Çetin, Emrullah Kızıltunç, Hülya Çiçekçioğlu, Ender Örnek, Feridun Vasfi Ulusoy
Journal: Journal of the American College of Cardiology (2013)
Exercise testing in patients with variant angina: results, correlation with clinical and angiographic features and prognostic significance.
Authors: D D Waters, J Szlachcic, M G Bourassa, J M Scholl, P Théroux
Journal: Circulation (1982)

Eighty-two patients with variant angina underwent a treadmill exercise test using 14 ECG leads, and 67 also underwent exercise thallium-201 scans. The test induced ST elevation in 25 patients (30%), ST depression in 21 (26%) and no ST-segment abnormality in 36 (44%). ST elevation during exercise occurred in the same ECG leads as during spontaneous attacks at rest, and was always associated with a large perfusion defect on the exercise thallium scan. In contrast, exercise-induced ST depression often did not occur in the leads that exhibited ST elevation during episodes at rest. The ST-segment response to exercise did not accurately predict coronary anatomy: Coronary stenoses greater than or equal to 70% were present in 14 of 25 patients (56%) with ST elevation, in 13 of 21 (62%) with ST depression and in 14 of 36 (39%) with no ST-segment abnormality (NS). However, the degree of disease activity did correlate with the result of the exercise test: ST elevation occurred during exercise in 11 of 14 patients who had an average of more than two spontaneous attacks per day, in 12 of 24 who had between two attacks per day and two per week, and in only two of 31 who had fewer than two attacks per week (p less than 0.005). St elevation during exercise was reproducible in five of five patients retested during an active phase of their disease, but not in three of three patients who had been angina-free for at least 1 month before the repeat test. Twelve patients wih exercise-induced ST elevation were retested during treatment with calcium antagonist drugs; in 10 of 12, ST elevation did not occur with the second test. During a mean follow-up of 20.3 +/- 14.5 months, death or myocardial infarction occurred in three of the 25 patients with ST elevation during exercise, none of 21 with ST depression and two of 36 with no ST abnormality. We conclude that in variant angina patients, the results of an exercise test correlate well with the degree of disease activity but not with coronary anatomy, and do not define a high-risk subgroup.