tbuckley/cabot-search huggingface dataset:
Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia
Authors: Lohith Bachegowda, Kerry Morrone, Shannon L. Winski, Ioannis Mantzaris, Matthias Bartenstein, Nandini Ramachandra, Orsi Giricz, Vineeth Sukrithan, George Nwankwo, Samira Shahnaz, Tushar D. Bhagat, Sanchari Bhattacharyya, Amer Assal, Aditi Shastri, Shanisha Gordon-Mitchell, Andrea Pellagatti, Jacqueline Boultwood, Carolina Schinke, Yiting Yu, Chandan Guha, James Rizzi, Jennifer Garrus, Suzy Brown, Lance Wollenberg, Grant Hogeland, Dale Wright, Mark Munson, Mareli Rodriguez, Stefan Gross, David Chantry, Yiyu Zou, Leonidas C. Platanias, Laurence E. Burgess, Kith Pradhan, Ulrich Steidl, Amit Verma
Journal: Cancer Research (2016)

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR.
THU0162 The Correlation Between Carotid Ultrasound, Coronary Artery Calcification Score and Lipid Profile in Patients with RA
Authors: O. Garmish, V. Levchenko, A. Romanovskiy
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> RA is a proatherogenic diseases, but detection of patients with moderate/high risk cardiovascular event has some differences with the general population. <h3>Objectives</h3> To determine the correlation between Coronary Artery Calcification Score (CACS), carotid intima-media thickness (cIMT), lipid profile and coronary risk evaluation by SCORE and mSCORE in detecting subclinical atherosclerosis in rheumatoid arthritis (RA) patients. <h3>Methods</h3> A set of 87 consecutive RA patients in the mean age 45,2±1,56 without history of cardiovascular (CV) events were studied to determine relationship between CACS, cIMT and carotid plaques (CP) and lipid profile. The mean disease duration was 7.9±0.7 years, 84,7% had rheumatoid factor and/or anti-CCP positivity and 33,8% extra-articular manifestations. 84.8% patients received biologic therapy more than one year. All subjects underwent CT imaging of coronary arteries using a 16-slice multi-detector computed tomography (MDCT) scanner (Lightspeed, 16, GE Healthcare, USA). Carotid ultrasonography examination included the measurement of cIMT in the common carotid artery, detection of focal plaques in the extracranial carotid tree, blood flow velocity and morphology of the intima. 40 healthy women in the mean age 32,8±1,56 was undergo carotid ultrasound by the same parameters. <h3>Results</h3> RA patients were stratified according to the cIMT and CPs. A cIMT&gt;0.90 mm was observed in 23 (26.4%) and CP in 25 (28.7%) patients. 57.7% of the patients with cIMT&gt;0.90 had unilateral and 30.8% bilateral CP, 7 (30.4%) categorized as having low, 10 (43.5%) moderate and 6 (26%) high CV risk. Only 1 patient has CACS ≥1, 6 patients had calcinosis of aorta and valves. The CPs was observed only in patients at age 50 and older. The patients with cIMT&gt;0.90 mm and CPs was significantly older (56.2±2.4 vs 40.53±1.6 years), but had no differences in diseases duration and level of total cholesterol. 67% of patients had fragmentation, induration and interruption of the layers differentiation of the intima. Any changes of the intima morphology in healthy women was observed. <h3>Conclusions</h3> The use of CACS does not allow identifying properly high/very high CV risk RA patients. Patient with cIMT&gt;0.90 mm had significantly high level of CRP, LDL cholesterol and TG in mouse macrophages. 67% of patients had abnormal of intima morphology by carotid ultrasound in comparison with control group. <h3>Disclosure of Interest</h3> None declared
Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral center in India
Authors: N. Ghadyalpatil, S. Banawali, P. Kurkure, B. Arora, S. Bansal, P. Amare, A. Choughule, L. Soy, R. Singh
Journal: Journal of Clinical Oncology (2009)

10047 Background: Chronic myeloid leukemia (CML) is a rare disease in children and there is limited data of safety and efficacy of imatinib mesylate (IM) in this age group. Methods: We analyzed the outcomes of 48 consecutive children (September 1998 to December 2008) in chronic phase (CP) or accelerated phase (AP) CML not eligible for Allo-SCT and were treated with IM [Glivec (Novartis), through patient assistance programme GIPAP or Veenat (NATCO), generic brand for GIPAP ineligible patients] within 12 months of diagnosis. The dose of IM was 260 mg/m 2 (maximum 400 mg) per day. Results: The median age at the time of diagnosis was 12 years (range 3–18 years). Of 48 patients, (34 males and 14 females) 46 were in CP and 2 in AP. Forty-three patients (89.5 %) achieved complete cytogenetic response (CCR) at median time of 10 months (range 3–31 months). Five patients (10 %) had hematological response but did not have CCR, of which 2 progressed to AP and 1 had hematological relapse. One patient had secondary IM resistance and had progressive disease even on dose escalation. Two patients in AP at diagnosis achieved CCR at 5 and 7 months and continue to be in CCR. Thirty-one out of 35 patients on Glivec and 12 out of 13 patients on Veenat achieved CCR. At a median follow up 29 months, the event free survival and overall survival was 74.1% and 100 % respectively. IM was well tolerated with grade III and IV neutropenia and thrombocytopenia seen in 2 and 7 patients respectively. Significant non hematological toxicities were uncommon except for hypopigmentation which was seen in more than half the cohort. Conclusions: Results from this largest single center study indicate that outcome of children with CML receiving IM is similar to adults. This data will be especially useful for financially challenged patients in developing countries where Allo-SCT is still not an affordable option while generic brand of IM seems to be feasible alternative. No significant financial relationships to disclose.
Effect of Ingestion of Strain C3H Milk in the Production of Mammary Tumors in Strain C3H Mice of Different Ages
Authors: H. B. Andervont, W. J. McEleney
Journal: JNCI Journal of the National Cancer Institute (1941)

Journal Article Effect of Ingestion of Strain C3H Milk in the Production of Mammary Tumors in Strain C3H Mice of Different Ages Get access H. B. Andervont, H. B. Andervont principal biologist Search for other works by this author on: Oxford Academic PubMed Google Scholar W. J. McEleney W. J. McEleney assistance of scientific aide National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 1, August 1941, Pages 13–16, https://doi.org/10.1093/jnci/2.1.13 Published: 01 August 1941
Bilateral Superior Venae Cavae With Crisscross Atrial Drainage
Authors: Sushil P. Tripathi, Ashish A. Nabar, Prafulla G. Kerkar, Hemant B. Telkar, Ashlesha S. Udare
Journal: Circulation (2015)

P ersistent left superior vena cava (PLSVC) is the most common thoracic systemic venous drainage anomaly, occurring in 0.5% of the general population and in ≈10% of patients with other congenital cardiac anomalies. 1Anomalous connection of the right superior vena cava (RSVC) to the left atrium (LA) is extremely rare.
FRI0093 The Framingham Score is a Useful Surrogate Marker of High Risk Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis
Authors: P.H. Dessein, A. Corrales, R. Lopez-Mejias, A. Solomon, A.J. Woodiwiss, J. Llorca, G.R. Norton, F. Genre, R. Blanco, T. Pina, C. Gonzalez-Juanatey, L. Tsang, M.A. Gonzalez-Gay
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Carotid artery plaque as identified by ultrasound represents very high risk atherosclerosis. <h3>Objectives</h3> We determined the performance of cardiovascular disease (CVD) risk equations including the Systematic COronary Risk Evaluation (SCORE) and Framingham score in predicting plaque presence in patients with rheumatoid arthritis (RA). <h3>Methods</h3> A cohort of 330 cases was assembled amongst 451 Spanish patients that underwent CVD risk screening and carotid ultrasound. Applied exclusion criteria were established CVD, diabetes and moderate or severe chronic kidney disease. The findings were validated in 90 black and 97 white African RA patients. <h3>Results</h3> Carotid plaque was present in 162 (49.1%) of the Spanish patients. The SCORE and Framingham score were each strongly associated with plaque (<i>P</i> &lt;0.0001). In predicting plaque presence, the area under the curve (AUC) (SE) of the receiver operator characteristic (ROC) curve for the Framingham score was larger than for the SCORE (0.799 (0.024) versus 0.747 (0.027), <i>P</i> =0.003). The optimal cut-off value and corresponding sensitivity and specificity for the Framingham score and SCORE were 11.0, 64% and 81% and 0.5, 86% and 58%, respectively. Based on optimal cut-off values, a high Framingham score but not SCORE was associated with carotid plaque independent of age, sex, erythrocyte sedimentation rate and C-reactive protein concentrations. Whereas a conventional Framingham score value of ≥20 correctly classified only 25% as being at high CVD risk, this proportion increased to 64% in those with a Framingham score of &gt;11; the percentage of patients without plaque incorrectly classified as being at high CVD risk increased from 17% in those with a Framingham score or ≥20 to only 23% in those with a Framingham score of &gt;11.0. External validation produced similar results in white but not black Africans with RA. <h3>Conclusions</h3> In this study, the Framingham score outperformed the SCORE in predicting plaque presence in RA. Upon CVD risk stratification, a Framingham score of &gt;11.0 comprises a measure that can reclassify about 40% of white RA patients without established CVD, chronic kidney disease or/and diabetes more accurately. Delineation of effective population specific CVD risk assessment strategies is needed in black African RA patients. <h3>Disclosure of Interest</h3> None declared
Is there a role for induction chemotherapy in the setting of concomitant chemoradiation in locally advanced head and neck cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Aron Popovtzer, Irit Ben-Aharon, Ezra E. W. Cohen, Liath Vidal
Journal: Journal of Clinical Oncology (2015)

6068 Background: :There is a controversy regarding the role of induction chemotherapy (IC) prior to concomitant chemoradiation (CCRT) in locally advanced head and neck cancer (LAHNC). We performed a systematic review and meta-analysis(MA) of all randomized controlled trials (RCTs) which assessed the addition of IC in this setting. Methods: We included RCTs that compared IC followed by CCRT to CCRT alone for LAHNC. The Cochrane Library, MEDLINE and conference proceedings were systematically searched (2000-11/2014). The primary outcome was overall survival (OS). Secondary outcomes were progression free survival (PFS), disease control (DC), complete response (CR) rate and adverse events. Relative risk (RR) for dichotomous data and hazard ratio (HR) for time to event data were estimated and pooled. Results: Five RCTs met the inclusion criteria, with a total of 1229 patients with stage III or IV LAHNC. Median age was 55y (35-75). IC consisted of docetaxel, platinum and 5FU (TPF) in 4 trials, and platinum-5FU (PF) in one trial. No statistically significant effect on OS was shown, though a trend towards the IC-CCRT group was observed - HR 0.85 (95%CI 0.71-1.02,p = 0.07). There was no significant difference in PFS HR 0.84 (0.57-1.24). Yet, patients treated with IC had a better DC compared to CCRT alone (HR of progression, treatment failure or death 0.64 (95%CI 0.52-0.8). The rate of CR improved with IC compared to CCRT, RR 1.66 (95%CI 1.02-2.69). The risk of any grade 3-4 adverse event, fever and neutropenia increased in the IC-CCRT group. The risk of mucositis (4 trials, 922 patients) increased with IC followed by CRT- RR 1.24 (95%CI 1.05-1.46, I2 of heterogeneity73%). In a sensitivity analysis using a random-effects model no such difference was shown RR 1.30 [0.91-1.85] Conclusions: MA of RCTs showed no significant effect on OS or PFS. However, the advantage in CR and DC, as well as a trend to improved OS in the IC group, imply that selected patients may benefit from the addition of IC. Since the patient population varied in the extent of disease, future studies are warranted to evaluate the role of IC in subpopulations of patients with LAHNC.
SP0091 Accuracy of Cardiovascular Risk Algorithms in Rheumatoid Arthritis and Its Management: Next Steps to a Targeted Approach
Authors: G.D. Kitas
Journal: Annals of the Rheumatic Diseases (2015)

People with Rheumatoid Arthritis (RA) have increased cardiovascular disease (CVD) morbidity and mortality. This appears to be due to increased prevalence, insufficient identification and poor control of classical CVD risk factors including dyslipidaemia, hypertension, physical inactivity, obesity and insulin resistance; and the presence of additional risk factors, particularly systemic inflammation (and its direct or indirect effects on the vasculature), and many of the anti-rheumatic drugs that have significant vasoactive and cardio-metabolic effects, amongst others. Their combination may lead to acceleration of atherosclerosis, plaque instability and rupture and pro-thrombotic phenomena expressed clinically as the whole range of syndromes, from stable ischaemia to acute CVD events and death. Processes other than atherothrombosis, including myocarditis, vasculitis, microvascular dysfunction, and cardiac autonomic dysfunction are now receiving increasing attention. At the clinical level, the question remains as to how we can identify early on the high-risk patients and what primary prevention strategies we can implement to reduce their risk. Algorithms developed in the general population appear to underestimate risk in people with RA, and development of RA-specific CVD risk algorithms has proven very challenging predominantly due to massive heterogeneity of data in different RA populations. The effects of primary prevention strategies including lifestyle modification, pharmacological reduction of classical CVD risk factors (mainly lipids and blood pressure) and of inflammation (using antirheumatic medications) on cardiovascular outcomes have not been assessed through randomised controlled trials; available data are limited to small interventional studies assessing surrogates of CVD and to retrospective analysis of observational studies. On such a backdrop, a practical approach will be presented that can be used in many different clinical settings. <h3>Disclosure of Interest</h3> None declared
Soundings: War and causality
Authors: Trisha Greenhalgh
Journal: BMJ (2003)

The kids are cross. They marched four miles and sat in the park on a freezing cold day listening to speeches they didn't understand, but Tony Blair didn't change his mind.

I tried to explain that the purpose of the peace march wasn't to cause a change of heart in the prime minister, but to register a protest and show comradeship with others who felt the same. In that case, said the kids, there was no point marching in the first place.

Occasionally in medicine we can say with confidence that a particular agent, event, or lifestyle choice has caused a particular condition. More often, the putative cause turns out, with the clarity of hindsight, to be the least significant of half a dozen influences—or merely a confounding variable. Acid and ulcers. Lead and underperformance. The pill and promiscuity. The fashion industry and anorexia nervosa.

Similarly with treatments. As an evidence based clinician I'm impressed with an intervention that has a number needed to treat of two, but half the patients so treated will return to demand their money back. “I came with problem X, you gave me medicine [or operation] Y, and I'm not cured.”

One of science's most pressing questions is how, having sold the public a clockwork universe for 600 years, to convey the fact that complex problems have multiple causes and no simple or predictable solutions. There is always uncertainty; there is always the need for the calculated guesswork we call judgment.

Whose acts, and whose omissions, have caused the high rates of childhood malnutrition in Iraq?

Where is the chain of events that caused a particular teenager to choose a short, vainglorious career in terrorism?

What combination of diplomacy and threat will cause a dictator to dismantle the weapons whose components we sold him?

At what point can lack of cooperation legitimately be said to have caused a final call to arms?

Even my children know that these are non-questions. There are no causes in war, nor are there testable hypotheses, confident forecasts, or reliable ways of resolving paradoxes. Let us brace ourselves for the sequence of consequences that none of us will have predicted.
Monoclonal Antibody Recognizing Human Melanoma-Carcinoma Cross-Reacting Oncofetal Antigen Epitopically Associated With Carcinoembryonic Antigen<xref ref-type="fn" rid="FN2">2</xref>
Authors: S K Liao, P C Kwong, B J Clarke, P B Dent, E D Ryan, M J Khosravi, S Laferte, M J Krantz
Journal: JNCI Journal of the National Cancer Institute (1985)

By fusion of mouse NS1 myeloma cells with splenocytes from a BALB/c mouse immunized with human melanoma cells, an IgG1 monoclonal antibody, designated as 140.72, was produced. By the mixed hemadsorption antibody binding assay, 140.72 was shown to react with 17 of 20 melanoma cell lines and with 5 of 14 carcinoma cell lines. This antibody also reacted with 3 of 3 normal melanocyte cultures in much lower titers. It did not react with any of 35 other normal and malignant lines, including neuroblastoma, glioblastoma, sarcoma, teratoma, fibroblast, and lymphoid cell lines. Absorption with fresh melanoma and carcinoma homogenates confirmed the results of direct tests. Fetal reactivity of antibody 140.72 was determined by positive absorption with 10 of 11 tissue homogenates derived from different fetuses of 10-16 weeks' gestation. The reactivity of this antibody was completely removed by absorption with a highly purified preparation of carcinoembryonic antigen (CEA) derived from a colon carcinoma. The antigenic activity was detected in the culture medium of reactive cell lines. Immunoprecipitation analyses of melanoma and carcinoma cells indicated that the antigenic determinant recognized by antibody 140.72 is on a glycoprotein with an apparent molecular weight of 95,000-150,000 common to both serologically reactive cell types. Additionally, a 200,000-molecular-weight glycoprotein corresponding to the CEA molecule was detected only on the reactive carcinoma cells. These data confirmed previous findings obtained with polyclonal anti-CEA antisera for the existence of shared CEA-related antigenic determinants on human carcinomas and melanomas and provided additional molecular characterization of these glycoproteins. Further characterization of the molecules bearing the antigenic determinant recognized by antibody 140.72 should be performed with a view to exploring its potential in the immunodiagnosis and immunotherapy of patients with melanoma.
AB0166 The Effect of a Treatment with Allogenic Mesenchimal Stromal Cells (MSCS) on Urinary Biomarkers in a Mouse Model of Systemic Lupus Erythematosus
Authors: C. Tani, S. Vagnani, L. Carli, F. Querci, M. Mosca
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Urine is a source of suitable biomarkers for Lupus nephritis (LN) because it is easily accessible and can directly reflect the status of local inflammation and damage in the kidney. In recent decades monocyte chemoattractant protein-1 (MCP-1) and neutrophil gelatinase-associated lipocalin (NGAL) have been proposed as potential biomarkers for renal involvement in patients with systemic lupus erythematosus (SLE). <h3>Objectives</h3> The present study is aimed at evaluating the trend of the urinary MCP-1 (uMCP-1) and NGAL (uNGAL) in a mouse model of SLE after administration of a systemic therapy with bone marrow derived allogenic mesenchimal stromal cells (MSCs) at different phases of the disorder and at different dosages. <h3>Methods</h3> 35 female New Zealand Black/New Zealand White F<sub>1</sub> (NZB/W) mice have been used as model of SLE and 10 C57BL/6J mice have been used as donors of allogenic bone marrow derived MSCs (BMMSCs). NZB/W mouse were divided into the following experimental groups: –5 NZB/W mouse treated with a single MSCs infusion at 20 weeks of age (NZB/W<sub>20</sub>) –5 NZB/W mouse treated with a single MSCs infusion at 24 weeks of age (NZB/W<sub>24</sub>) –5 NZB/W mouse treated with a single MSCs infusion at 32 weeks of age (NZB/W<sub>32</sub>) –5 NZB/W mouse treated with multiple MSCs infusions started at 20 weeks of age (NZB/W<sub>M20</sub>) –5 NZB/W mouse treated with multiple MSCs infusions started at 24 weeks of age (NZB/W<sub>M24</sub>) –10 NZB/W mouse not treated as Controls (C). Urine was weekly collected from mice by metabolic cages; urinary MCP-1 and NGAL were measured with immunoassorbent assay kits (MCP-1, Thermo Scientific; NGAL-2, Boster Biological Technology). <h3>Results</h3> In untreated mice uNGAL resulted 38.7±26.7 ng/ml at 18 weeks and it increased from 24 weeks of age (120±3.5 ng/ml) reaching a pick after 35 weeks of age (180.5±42.5 ng/mg). At 24 weeks uNGAL was 32.7±24.6 ng/ml in NZB/W<sub>20</sub>, 30.4±17 ng/ml in NZB/W<sub>M24</sub>. At 35 weeks of age uNGAL was 184.6±28.2 ng/ml in NZB/W<sub>20</sub>, 84.4±27.8 ng/ml in NZB/W<sub>24</sub> and 158±66.2 ng/ml in NZB/W<sub>32.</sub> At 35 weeks of age uNGAL was 152.5±99.5 in NZB/W<sub>M20</sub> and 49.5±8 ng/ml in NZB/W<sub>M24</sub> (p=0.009 if compared to untreated mice). No differences in uMCP-1 were detected into the different treatment arms if compared to the controls. <h3>Conclusions</h3> In our experiments, multiple infusions of allogenic bone marrow derived MSCs were associated with lower urinary levels of NGAL. On the other hand, this treatment does not seem to influence urinary MCP-1 concentrations in this model. Further investigations are ongoing to clarify the possible relationship between MSCs treatment and urinary NGAL in this model of lupus nephritis. <h3>Disclosure of Interest</h3> None declared