tbuckley/cabot-search huggingface dataset:
Abstract 3307: Improved survival in AML by in vivo drug targeting of conserved regulatory pathways in phenotypically distinct tumor-initiating compartments
Authors: Kenneth D. Gibbs, Astraea Jager, Oliver Crespo, Yury Goltsev, Angelica Tejo, Chase Richard, Garry Nolan
Journal: Cancer Research (2012)

Abstract Increasing evidence suggests tumors are maintained by cancer stem cells, however their nature remains controversial. In a HoxA9-Meis1 (H9M) driven model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy–stem/progenitor cells (Lin−kit+), and committed progenitors of the myeloid (Gr1+kit+) and lymphoid lineages (Lym+kit+). Each compartment clonally recapitulated the original range of tumor cell immunophenotypes in vivo, including cells with a less-differentiated immunophenotype. These distinct populations largely shared signaling networks, and in vivo pharmacologic targeting of shared pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, these data show that H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, in some malignancies, tumor-initiation ability (or “cancer-stemness”) can represent a targetable, cellular state that can exithat exists independently of distinct immunophenotypic definition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3307. doi:1538-7445.AM2012-3307
Abstract 3634: Overcoming drug resistance to EGFR-tyrosine kinase inhibitors by FUS1 or FHIT-gene therapy in human lung cancer
Authors: Ryo Sakai, Kai Xu, Bingliang Fang, Jack A. Roth, Lin Ji
Journal: Cancer Research (2010)

Abstract Dysregulation of the epidermal growth factor receptor (EGFR) and apoptotic pathways is a hallmark of human lung cancer and regulate tumor cell proliferation, survival, angiogenesis, and metastasis. Inhibition of oncogenic EGFR activity is proving to be an effective therapeutic strategy for lung cancer. Though EGFR-tyrosine kinase inhibitors (TKIs) are promising drugs, resistance occurs frequently. ZD6474 is an orally available small-molecule that inhibits both EGFR and VEGFR2 tyrosine kinases. FUS1 and FHIT are novel tumor suppressor genes identified in the human chromosome 3p21.3 and 3p14.2 regions, respectively and have been shown to suppress tumor cell growth by induction of apoptosis and down-regulation of multiple oncogenic tyrosine kinase activities in human non-small-cell lung cancer (NSCLC) cells in vitro and in vivo. We evaluated the therapeutic effects of EGFR-TKIs at dose levels equivalent to those of steady-state serum levels achieved in the clinic as single agents and in combination with FUS1- or FHIT-nanoparticle-mediated gene therapy in NSCLC cells. We found that expression of wild type FUS1 or FHIT sensitized NSCLC cells to ZD6474 treatment (at 2µM), as shown by significantly enhanced inhibition of tumor cell growth in a cell proliferation assay. A combination treatment with FUS1-nanoparticles and ZD6474 also significantly enhanced inhibition on tumor cell-induced colony formation in H322 cells compared to treatment with either agent alone. Combination treatment with ZD6474 and FUS1 or FHIT-nanoparticles increased down-regulation of the EGFR signaling pathway and up-regulation of the apoptosis pathway as indicated by the reduced expression of the phosphorylated Akt and ERK1/2 and by enhanced expression of cleaved PARP on Western blots. We found that the expression level of p-Met, which is one of acquired resistant factors to EGFR-TKIs, was reduced by FHIT-gene therapy in H1975 cells. We evaluated the antitumor effects of combination therapy using a fluorometric migration assay and found that the migration of H1299-GFP cells were inhibited by co-treated with ZD6474 and FHIT-gene therapy. Our findings imply that a combination treatment with FUS1 or FHIT-gene therapy and ZD6474 may be a useful strategy for enhancing lung cancer therapy. (supported by NIH Lung SPORE P50CA70907 and RO1CA116322) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3634.
Racial Differences in the Use of Drug Therapy for HIV Disease in an Urban Community
Authors: Richard D. Moore, David Stanton, Ramana Gopalan, Richard E. Chaisson
Journal: New England Journal of Medicine (1994)

Guidelines for drug therapy in human immunodeficiency virus (HIV) disease are based primarily on the stage of the disease. To determine whether sociodemographic characteristics of patients influence drug therapy in practice, we analyzed the use of antiretroviral therapy and prophylactic therapy for Pneumocystis carinii pneumonia (PCP) in an urban population infected with HIV.All patients presenting for the first time to our HIV clinic from March 1990 through December 1992 were enrolled. Data on sociodemographic and clinical variables and on drug use were collected at the time of presentation and after six months. We asked whether patients with CD4+ cell counts of 500 or less per cubic millimeter were receiving antiretroviral therapy at the time of presentation, and whether patients with CD4+ cell counts of 200 or less per cubic millimeter were receiving PCP prophylaxis.Among the 838 patients enrolled, 656 (79 percent) were blacks, 167 (20 percent) were non-Hispanic whites, and 15 (2 percent) were Asian or Hispanic descent or were not racially classified. There were no racial differences in the stage of HIV disease at the time of presentation. However, there were racial disparities in the receipt of antiretroviral therapy: 63 percent of eligible whites but only 48 percent of eligible blacks received such therapy (P = 0.003). PCP prophylaxis was received by 82 percent of eligible whites but only 58 percent of eligible blacks (P < 0.001). There were no significant differences in the receipt of drug therapy with respect to age, sex, mode of HIV transmission, type of insurance, income, education, or place of residence. In a logistic-regression analysis, race was the feature most strongly associated with the receipt of drug therapy. When blacks were compared with whites, the adjusted relative odds were 0.59 (95 percent confidence interval, 0.38 to 0.93) for the receipt of an antiretroviral agent and 0.27 (95 percent confidence interval, 0.13 to 0.56) for the receipt of PCP prophylaxis.Among patients infected with HIV, blacks were significantly less likely than whites to have received antiretroviral therapy or PCP prophylaxis when they were first referred to an HIV clinic. This disparity suggests a need for culturally specific interventions to ensure uniform access to care, including drug therapy, and uniform standards of care.
Abstract 2334: TWIST1, a B-RAF effector, promotes melanoma cell invasion
Authors: Michele B. Weiss, Andrew E. Aplin
Journal: Cancer Research (2011)

Abstract Metastatic melanoma is the deadliest form of skin cancer and a paradigm for highly aggressive, chemotherapy-resistant tumors. Therefore, determining the factors impacting melanoma advancement toward metastasis is an important and clinically-relevant task. The TWIST1 protein is up-regulated in melanoma and its expression correlates strongly with poor clinical prognosis. We tested the role of high TWIST1 expression in traits associated with the progression of melanoma, as well as sought to delineate the mechanism underlying TWIST1 up-regulation. Our data shows that TWIST1 protein levels are higher in melanoma cells, especially invasive lines, compared to normal melanocytes. To evaluate the biological relevance of TWIST1 expression, we generated invasive melanoma cell lines depleted of TWIST1 by shRNA and non-invasive melanoma cell lines which constitutively overexpress TWIST1. First, we utilized these cell lines in standard Matrigel invasion assays through boyden chambers. Depletion of TWIST1 in several invasive melanoma cell lines significantly reduces Matrigel invasion by approximately 40-50%. The inverse phenotype is apparent when TWIST1 is overexpressed in low TWIST1-expressing, non-invasive melanoma cell lines. Additionally, we tested the effect of altered Twist expression in 3D collagen spheroid outgrowth assays, which mimic both tumor architecture and the in vivo collagen-rich dermal layer. We have found significant reduction of spheroid outgrowth when invasive cell lines are depleted for TWIST1 as well as increases in outgrowth when non-invasive cells overexpress TWIST1. Alterations to spheroid outgrowth were not as a result of apoptotic changes or proliferative rate as assessed by live/dead and EdU staining. Importantly, the mechanisms regulating high TWIST1 expression in melanoma are unclear. A comparison between wild-type and mutant B-RAF melanoma cell lines demonstrates that TWIST1 is more highly expressed in mutant B-RAF cells. We have found that disruption of B-RAF/MEK signaling, through siRNA/shRNA knockdown or pharmacological inhibition, strongly represses TWIST1 at the mRNA and protein level. An area of active investigation is the determination of the transcription factor responsible for TWIST1 regulation downstream of mutant B-RAF in melanoma. The data generated from these studies will allow for a greater understanding of the role and regulation of TWIST1 during the progression of melanoma towards metastasis. In addition, it may highlight TWIST1 as an attractive molecule/pathway for novel targeted therapies for melanoma. 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 2334. doi:10.1158/1538-7445.AM2011-2334
AB0728 Employment status and work disability in an asian cohort of systemic lupus erythematosus patients: Preliminary results
Authors: T.Y. Lian, K.O. Kong, K.P. Leong, J.C. Tan, B.Y.H. Thong, H.H. Chng, G.Y.L. Chan, E.T. Koh, W.G. Law, F.L.A. Chia, J.W.L. Tan, H.S. Howe
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> There is little data on work disability in Asian patients with SLE. Loss of work ability contributes to loss in productivity, increase in health care cost and also loss of self esteem which in turn can lead to anxiety and depression. <h3>Objectives</h3> To determine the employment status, prevalence of work disability in a cohort of Asian SLE patients and to identify its predictors. <h3>Methods</h3> We established our SLE registry in 2001. This follows about 1000 patients who are followed up according to a standard protocol by trained staff rheumatologists or trainees at regular 4-12 months. A cross-sectional questionnaire study was performed to evaluate the employment status of consecutive patients with SLE. The following parameters were collected: demographic, socioeconomic data, employment status including their history of having modified their job or having changed their job(s) and disease characteristics. Work disability was defined as failure to work due to SLE activity and its related complications. <h3>Results</h3> 323 patients were surveyed (mean age 45.5±12.1years, 92.4% women, 90% of Chinese descent, mean SLE duration 15.8±11.1years). Majority were married (65.8%) and 82.8% earned below the median Singapore income of $5000 per month (2010 census) More than half the patients (55.3%) did not have health insurance. There were 62 patients who were not in the workforce at time of questionnaire (30 housewives, 31 student, 1 retiree) and hence were excluded. Of the 261 who were in the workforce, 78((29.9%) lost their working ability. 52 of these patients (67.1%) reported they stopped work earlier than they had wanted to. The self reported causes of inability to work were fatigue (43.9%) and joint pains or aches (36.8%). A significant number of patients who were work disabled also modified their work or had to change jobs. Of the 78 patients who were unable to work, 47/78 (60%) modified their jobs by doing lighter duties (36.4%), or doing fewer hours or going part time (41.9%). Thirty one patients (39.7%) also changed jobs prior to stopping work with 60.5% of patients having changed 2 jobs. <h3>Conclusions</h3> Work disability is an important problem among SLE patients. The unemployment rate is high compared to the national unemployment rate of 2.2%. Majority of the the patients who were work disabled experienced a period of work instability before they stopped work. <h3>Disclosure of Interest</h3> None Declared
Zoo Animals Not Spared From Cancer
Authors: S. Kumar
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Zoo Animals Not Spared From Cancer Get access Seema Kumar Seema Kumar Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 22, 15 November 1989, Pages 1691–1692, https://doi.org/10.1093/jnci/81.22.1691 Published: 15 November 1989
AB0805 Low Grade Systemic Inflammation is Associated with Low Ultrasound Velocity in Older Men, A Population Based Study (LASA)
Authors: D. Den Uyl, N.M. van Schoor, N. Braveboer, P. Lips, W.F. Lems
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Elevated systemic levels of pro-inflammatory cytokines are likely involved in the pathogenesis of osteoporosis in healty individuals. <h3>Objectives</h3> To investigate whether low grade inflammation was associated with bone markers, bone quality, bone mass and fracture risk in a population of older persons. <h3>Methods</h3> Serum interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR) were measured in 1287 participants of the Longitudinal Aging Study Amsterdam (LASA), a population based study with healthy older men and women (age 76 (±6.7) years). Bone quality was measured by quantitative ultrasound measurements (QUS) at baseline and after 3 years at the calcaneus and bone mass was measured by dual-energy x-ray absorptiometry (DXA) at the spine and hips in a subpopulation. Furthermore, the bone markers osteocalcin (OC) and urinary excretion of deoxypyridinoline (DPD) were determined Incident fractures were recorded during 6 years of follow-up. IL-6 was dichotomized at the detection limit (5 pg/ml) because of the high number of participants (76%) with levels below the detection limit. hsCRP was categorized into 3 groups based on clinical relevant concentrations: &lt;3, 3-10, &gt;10 μg/ml. ESR was classified in tertiles (≤7, 8-16, 17-90). Multivariable linear regression analyses were used to evaluate the cross-sectional relation between inflammatory markers and bone mass and bone turnover. The longitudinal association of inflammatory markers and bone loss was evaluated by multivariable linear regression analyses with delta BMD as dependent variable and the association of inflammatory markers with time to fracture by Cox proportional hazard analyses. All multivariable analyses included adjustments for potential confounders. <h3>Results</h3> Multivariable regression analyses revealed that slightly elevated hsCRP plasma levels (3-10 μg/ml) were associated with low bone mineral density in the femoral neck in men (β= -0.126; 95%CI -0.07- -0.001, p&lt;0.05). After excluding participants with inflammatory diseases this was no longer significant. Increased IL-6 and ESR levels were associated with quantitative ultrasound measurements in healthy men (β=-0.98; 95%CI -57.72- -6.42, p&lt;0.05) and women (β= -0.221; 95%CI -15.39- -3.27, p&lt;0.05) respectively. No significant associations were found between inflammatory markers with bone markers, bone loss at the spine or hips, fracture rate or time to fracture. <h3>Conclusions</h3> Elevated inflammatory markers are associated with low quantitative ultrasound measurements, suggesting an impaired bone quality in healthy older men. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4641
Abstract 3330: Functional characterization of microRNAs identified in human acute myeloid leukemia stem cells
Authors: Karin G. Hermans, Eric R. Lechman, John E. Dick
Journal: Cancer Research (2012)

Abstract Human acute myeloid leukemia (AML) is organized as a functional cellular hierarchy and is sustained by a rare population of leukemia stem cells (LSC). AML is a heterogeneous disease with a relapse rate of up to 80% depending on age of the patient and AML subtype. Recent work suggests that leukemia stem cell properties influence therapy response, overall survival, and relapse of the disease. In order develop more effective novel therapies that target this rare cell population; it is imperative that we better understand LSCs at the molecular level. Although it is generally accepted that oncogenic mutations underlie cancer initiation and progression, most studies have focused on protein coding genes. However, there is increasing recognition that non-coding RNAs can also play a role in leukemogenesis. MicroRNAs (miRNAs) are a family of small non-coding RNAs that function as important regulators of the translation of protein-coding genes. In order to identify LSC specific miRNAs, we fractionated 16 primary human AML samples into four sub-populations, each of which were xenotransplanted into immune-deficient mice to evaluate in vivo leukemia initiating capacity. Global miRNA expression profiling was performed on each population and a LSC specific miRNA signature generated by supervised analysis guided by the ability to initiate leukemia in vivo. Similarly, a human cord blood derived hematopoietic stem cell (HSC) enriched miRNA signature was also established. From these lists, we selected ten promising candidate miRNAs to assess for biological function. We have initiated a functional screen to determine the role of the candidate miRNAs using both in vivo and in vitro assays. Preliminary results show that enforced expression of two miRNA candidates strongly reduced engraftment capability of HSCs over untransduced HSCs in immune-deficient recipients. Moreover, enforced expression of three additional miRNA candidates show a competitive growth advantage of transduced HSCs over untransduced HSCs and compared to controls. Also, enforced expression of one of these three miRNAs in the surrogate LSCs of a unique leukemia cell line induces a strong proliferative advantage over untransduced LSCs in an in vitro culture setting. In conclusion, thus far we have identified five miRNAs that affect hematopoietic stem cell properties. Further in vivo and in vitro analysis will determine whether these miRNAs are suitable targets for therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3330. doi:1538-7445.AM2012-3330
Treatment of Benign Nodular Thyroid Disease
Authors: Ad R. Hermus, Dyde A. Huysmans
Journal: New England Journal of Medicine (1998)

Nodular thyroid disease is common. Palpable thyroid nodules were detected in 0.8 percent of adult men and 5.3 percent of adult women in Whickham, northeast England,1 and in 1.5 percent of men and 6.4 percent of women between 30 and 59 years of age in Framingham, Massachusetts.2 In the latter population, new nodules appeared in 0.1 percent per year during a 15-year follow-up period.3 Thyroid nodules are even more commonly detected when the thyroid is examined by ultrasonography.4 The overwhelming majority of these nodules are benign. Several reviews describe diagnostic strategies to distinguish between benign and malignant nodules59 or . . .
Dynamic PET With FDG in Patients With Unresectable Aggressive Fibromatosis
Authors: Antonia Dimitrakopoulou-Strauss, Peter Hohenberger, Leyun Pan, Bernd Kasper, Safwan Roumia, Ludwig G. Strauss
Journal: Clinical Nuclear Medicine (2012)

Dynamic PET (dPET) studies with 18F-FDG were performed in patients with unresectable aggressive fibromatosis before imatinib therapy. The goal of the study was to evaluate the impact of regression-based parametric imaging on tumor diagnostics. A comparison between the regression-based quantitative data (slope and intercept values) with the compartmental data of FDG was performed.The evaluation includes 24 patients with recurrent disease (n = 14), residual tissue (n = 2), or primary disease (n = 8), who were scheduled for palliative treatment with imatinib. Parametric images were calculated based on the dPET data by fitting a linear regression function to the time-activity data and for each voxel. Images of the slope and the intercept of the time-activity data were calculated using a dedicated software. A volume-of-interest-based analysis was also performed by applying a 2-tissue compartment model to the dPET data. The resulting parameters of the FDG kinetics [blood volume (VB), k1-k4] were compared with the volume-of-interest-based slope and intercept data. The evaluation of the parametric images was performed visually and quantitatively.Twenty of 24 tumors could be visualized in the SUV images with a moderate uptake, in locations that were already known from the MR images. Most (16/24) of the tumors demonstrated a clear enhancement in the intercept images, whereas 4 of them showed an intermediate enhancement and only 4 did not show any enhancement in the intercept images. In contrast, only 10 of 24 tumors demonstrated a clearly enhanced slope, 3 of them revealed a slightly enhanced slope, and 11 of the 24 patients did not demonstrate any slope enhancement within the area of the known desmoid tumors. The comparison of slope revealed the highest correlation to the SUV (r = 0.56, P < 0.05), whereas the intercept values demonstrated the highest correlation to k1 (r = 0.794, P < 0.05), followed by the fractional VB (r = 0.709, P < 0.05), followed by SUV (r = 0.630, P < 0.05). The results indicate that slope images are related to the transport/phosphorylation-dependent part of FDG, whereas intercept images are related to the transport/perfusion part of FDG.These data demonstrate that the use of regression-based parametric imaging helps to differentiate between transport/perfusion- and transport/phosphorylation-dependent FDG uptake and demonstrate that the transport/phosphorylation rate is low in most of these tumors.