tbuckley/cabot-search huggingface dataset:
INFLUENCE OF DRUG DELIVERY ON THERAPEUTIC BENEFIT IN GBM-CDK4 AND MDM2 INHIBITOR COMPARISON IN FLANK VERSUS ORTHOTOPIC MODELS AND COMPARISON OF BRAIN PENETRANT VERSUS IMPENETRANT PI3K/MTOR INHIBITORS
Authors: J. N. Sarkaria, J. L. Pokorny, A. C. Mladek, K. Parrish, R. Oberoi, T. Sio, R. K. Mittapalli, W. F. Elmquist
Journal: Neuro-Oncology (2014)

BACKGROUND: Insufficient drug delivery across an intact blood-brain barrier (BBB) may limit the efficacy of therapeutic strategies. This study tested whether penetration across the BBB in glioblastoma could affect the efficacy of promising therapies. METHODS: The efficacy of a CDK4 inhibitor (PD0332991) and an MDM2 inhibitor (SAR405838), both with limited brain penetration, were tested singly in flank and orthotopic xenograft models in Mayo GBM22 and GBM108 lines, respectively. Structurally similar PI3K/mTOR inhibitors with limited (GDC-0980) and robust (GNE-317) brain penetration were tested in combination with bevacizumab in an orthotopic model of GBM10. Integrity of the BBB was assessed by injection of TexasRed-dextran conjugate 10 minutes prior to sacrifice. Drug concentrations were assessed by mass spectrometry. RESULTS: PD0332991 was effective in GBM22 flank tumors with a median time to reach the 1500mm3 endpoint of 116 days compared to 32 days for placebo (p < 0.05), while the same drug was ineffective in an orthotopic model (median survival 43 days vs. 44 days for placebo). Brain-to-plasma ratios for PD0332991 were 0.12 in wild-type mice compared to 10.3 in BBB-deficient mice. Similar results were obtained with the MDM2 inhibitor in GBM108 with profound effects on flank tumor growth (median time to 1500mm3 62 days for placebo versus 132 days with SAR405838; p < 0.05) but provided no survival benefit in an orthotopic model (median survival 38 days vs. 39 days). The effects of disrupting the BBB on the efficacy of SAR405838 in GBM108 orthotopic tumors will be reported. The clinical use of bevacizumab in GBM results in reduced contrast enhancement on MRI. Similarly, bevacizumab treatment of GBM10 orthotopic tumors results in a marked reduction in TexasRed-dextran accumulation within orthotopic tumors. Using this model, we compared the time to reach a moribund state following treatment with bevacizumab combined with either GDC-0980 or GNE-317. Compared to placebo (median survival 26 days), treatment with either GDC-0980 (29 days) or GNE-317 (33 days) did not significantly extend survival. However, when compared to bevacizumab alone (55 days), the combination of GNE-317 + bevacizumab significantly extended survival (71 days; p < 0.05) while GDC-0980 + bevacizumab did not (50 days). The brain-to-plasma AUC ratio for GNE-317 was 0.75 while GDC-080 was 0.07 in wild-type mice. The impact of bevacizumab therapy on tumor drug delivery will be reported. CONCLUSIONS: The efficacy of promising therapeutic strategies against relevant targets may be significantly compromised if tested using drugs that have limited penetration across the BBB. SECONDARY CATEGORY: Tumor Biology.
Abstract 3043: Akt-mTorc2 signaling underlies cellular addiction to HER3 signaling in HER2-amplified cancers.
Authors: Dhara N. Amin, Deepika Ahuja, Gregory S. Ducker, Paul Yaswen, Kevan Shokat, Mark Moasser
Journal: Cancer Research (2013)

Abstract HER2 amplified breast cancers are characterized by constitutive HER3 phosphorylation. Efforts to target the functionally relevant HER2-HER3 signaling complex in these tumor cells has proven difficult due to robust feedback signaling mechanisms that restore its signaling in the face of anything short of the complete inactivation of HER2 kinase activity. To study this in more depth, we used a combination of genetic and chemical genetic approaches designed to study the cellular adaptational responses to network perturbation. We find that positive or negative perturbation of any signaling node from upstream HER2 or HER3 down to the two mTor complexes results in compensatory responses that function to maintain homeostasis. The responses to various perturbations are mechanistically distinct, but taken together reveal an uncompromising core topology driven by a concentric Akt-mTorc2 positive-feedback loop buffered by HER3 and PHLPP nodes. While mTorc1 signaling is also subject to feedback regulation, it is not involved in the core topology and its output is not always protected in these tumors. The central role of mTor is consistent with its known functions as a master regulator of cellular homeostasis highly conserved across eukaryotes. But the inclusion of HER3 in this central homeostatic network is a tumor cell anomaly. To better delineate how this homeostatic network is altered in tumor cells, we compared and contrasted the network topology in a panel of HER2-amplified cancer cells with a panel of immortalized breast epithelial cells. Much of the feedback circuitries are preserved across tumor and untransformed cells. But the driving Akt-mTorc2 positive-feedback loop is lacking in untransformed cells. This is due to the fact that Akt drives mTorc2 signaling in tumor cells but not in untransformed cells. Consistent with a central role of mTorc2 in these tumors, knockdown of Rictor, but not Raptor, is lethal in HER2-amplified SkBr3 tumor cells. These studies reveal a key alteration of Akt-mTor signaling in HER2 driven tumors that underlies the pathological incorporation of HER3 into an mTor-driven network, thus putting the HER2-HER3 tumor driver under the protection of this evolutionarily ancient pathway, highly competent at homeostasis. Citation Format: Dhara N. Amin, Deepika Ahuja, Gregory S. Ducker, Paul Yaswen, Kevan Shokat, Mark Moasser. Akt-mTorc2 signaling underlies cellular addiction to HER3 signaling in HER2-amplified cancers. [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 3043. doi:10.1158/1538-7445.AM2013-3043
Tips for Leaders, Part III
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2011)

Good leaders anticipate the need for change and manage change well. However, the members of an organization generally oppose major change. There are many risks for the people and the group during a period of significant change. It is important that the leader communicates the reasons for the changes, involves as many people as possible in the process, develops a clear plan for implementation, and communicates well with the followers.
Imaging assessment of desmoid tumours in familial adenomatous polyposis: is state of the art 1.5T MRI better than 64-MDCT?
Authors: Santosh Bhandari, Ashish Sinha, Anika Hansmann, Arun Gupta, David Burling, Robin Phillips, Susan Clark, Vicky Goh
Journal: International Journal of Surgery (2012)

Objective: Desmoid tumour is a common extraintestinal manifestation of patients with familial adenomatous polyposis (FAP) who have undergone prophylactic colectomy. We aimed to determine whether MRI provides equivalent or better assessment of desmoid tumours than CT, the current first-line investigation. Methods: Following ethics approval and informed consent, FAP patients with known desmoid tumour underwent contrast-enhanced 64-slice multidetector CT (MDCT) and 1.5 T MRI (incorporating T1 weighted, T2 weighted, short tau inversion–recovery and T1 weighted with contrast, axial, sagittal and coronal sequences). The number, site, size, local extent, tumour signal intensity and desmoid-to-aorta enhancement ratio were analysed. Results: MRI identified 23 desmoid tumours in 9 patients: 9 intra-abdominal desmoid (IAD) tumours, 10 abdominal wall desmoid (AWD) tumours and 4 extra-abdominal desmoid (EAD) tumours. CT identified only 21 desmoids; 1 EAD and 1 AWD were not identified. The two modalities were equivalent in terms of defining local extent of desmoid. Five IAD tumours involved the bowel, six caused ureteric compression and none compromised the proximal superior mesenteric artery. There was no difference in median desmoid size: 56.7 cm (range 2–215 cm) on MDCT and 56.3 cm (3–215 cm) on MRI (p50.985). The mean MRI enhancement ratio, at 1.12 (standard deviation 0.43), was greater than the CT enhancement ratio, which was 0.48 (0.16) (p,0.0001). High signal intensity on T2 MRI was associated with increased MRI enhancement ratio (p50.006). Conclusions: MRI is at least equivalent (and may be superior) to MDCT for the detection of desmoid tumours in FAP. Coupled with the advantage of avoiding radiation, it should be considered as the primary imaging modality for young FAP patients. Received 11 December 2010 Revised 22 January 2011 Accepted 16 March 2011
Treatment with Histamine H<sub>2</sub>Antagonists in Acute Upper Gastrointestinal Hemorrhage
Authors: Rory Collins, Michael Langman
Journal: New England Journal of Medicine (1985)

Histamine H2 antagonists are widely used in treating patients with hematemesis and melena, despite the lack of reliable evidence of benefit from any of the randomized trials, considered separately. Examination of the data from all 27 available randomized trials, in which over 2500 patients were entered, suggests that treatment may reduce the rates of rebleeding, surgery, and death by about 10,20, and 30 per cent, respectively, although these results were only marginally significant for surgery and death. Any benefit appeared to be confined to patients with bleeding gastric ulcers, but since this subgroup analysis was prompted by preliminary examination of the data in some of the individual trials reviewed here, it should be treated with particular caution. The implications of this overview are that treatment with histamine H2 antagonists appears to be moderately promising, but its effects on important end points, such as death, still need to be assessed reliably. Prevention of "only" about 20 per cent of all deaths could well be worthwhile, for the condition is common, and the treatment widely practicable. To detect such a moderate effect reliably, however, might require the randomization of 10,000 patients (or more), which would be possible only in an extremely simple multicenter collaborative trial. (N Engl J Med 1985; 313: 660–6.)
Abstract 2743: Accelerating the exploration of novel gene fusion events in prostate cancer
Authors: Dorothee Pflueger, Stephane Terry, Andrea Sboner, Lukas Habegger, Raquel Esgueva, Maria A. Svensson, Pei-Chun Lin, Naoki Kitabayashi, Benjamin J. Moss, Ashutosh K. Tewari, Mark S. Chee, Francesca Demichelis, Mark B. Gerstein, Mark A. Rubin
Journal: Cancer Research (2010)

Abstract Gene fusions are regarded as cancer defining and often proven causative for cancer development. Up to 50% of prostate cancers harbor recurrent gene fusions, most often the TMPRSS2-ERG fusion. Other ETS gene fusions have been described involving ETV1, ETV4, and ETV5. The remaining prostate cancers are considered gene fusion negative based on fluorescence in-situ hybridization (FISH) or RT-PCR for known fusion specific transcripts. Paired-end RNA-sequencing is a novel approach to systematically interrogate for fusion transcripts in a global and un-biased manner. Herein, we exploit FusionSeq, a computational tool specifically developed to nominate chimeric transcripts from paired-end RNA-seq data, with the goal of identifying new gene fusions. Using FusionSeq we identified the androgen-induced genes FKBP5 and KLK2 as two novel 5′ fusion partners for the ETS genes ERG and ETV1, respectively. General transcriptional chimerism (e.g. read-through transcripts) without evidence of underlying genomic rearrangements is not restricted to prostate cancer but also occurs in the patient's matched benign prostate tissue, providing evidence for an extended complexity of the cellular transcriptome and supporting the notion that a gene's definition might have to be considered flexible. Finally, we report the identification and the validation of two novel gene fusions: i) the tumor suppressor and cell cycle regulator CDKN1A (p21WAF, CIP1) is fused to CD9; besides down-regulating p21 gene expression, the CDKN1A-CD9 fusion also alters the CD9 protein. ii) by fusing IKBKB (IKK2, IκB kinase beta subunit) to TNPO1 (transportin 1), IKBKB gene expression increases over other prostate cancers, suggesting a pronounced activation of the NFκB complex. Our results show that a small subset of prostate cancers may harbor private gene fusions involving tumor suppressors and regulators of pathways implicated in cancer development. 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 2743.
A9.02 Heat shock protein 90 plasma levels correlate with disease activity, skeletal muscle, lung and heart involvement in idiopathic inflammatory myopathies
Authors: H Storkanova, O Krystufkova, M Klein, H Mann, L Vernerova, M Spiritovic, J Zamecnik, K Pavelka, L Senolt, J Vencovsky, M Tomcik
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Heat shock proteins (Hsps) are molecular chaperones playing a key role in muscle physiology, adaptation to exercise or stress, and in activation of inflammatory cells. Increased Hsp90 expression was demonstrated in regenerating and atrophic muscle fibres, and in inflammatory infiltrates. The aim of this study was to evaluate Hsp90 in the circulation of patients with idiopathic inflammatory myopathies (IIM) and characterise its potential association with IIM-related features. <h3>Methods</h3> A total of 277 patients with IIM (198 females, 79 males; mean age 54.8; disease duration 4.1 years; dermatomyositis (DM, 104), polymyositis (PM, 104) cancer associated myositis (CAM, 42), necrotizing myopathy (IMNM, 27)) and 100 healthy individuals matched by age/sex were included. Plasma levels of Hsp90 were measured by ELISA (eBioscience, Vienna, Austria). Data are presented as median (IQR). <h3>Results</h3> Extracellular Hsp90 was increased in IIM patients compared to healthy controls (20.2 (14.3–40.1) vs. 9.2 (7.2–12.6) ng/ml, p &lt; 0.0001), and between individual subsets of IIM and healthy controls (PM: 19.4 (14.5–40.4), DM: 22.4 (14.3–43.5), CAM: 19.1 (12.3–29.8), IMNM: 19.6 (15.7–50.0) ng/ml, p &lt; 0.0001 for all). Hsp90 levels in all patients positively correlated with levels of LD (r = 0.551, p &lt; 0.0001), AST (r = 0.372, p &lt; 0.0001), ALT (r = 0.158, p = 0.009). Increased Hsp90 was associated with decreased MMT8 values (r=-0.136,p = 0.029), in particular with proximal muscles. Hsp90 positively correlated with patient and doctor disease activity (r = 0.222, p = 0.0004; r = 0.217, p = 0.0005, respectively), pulmonary (r = 0.201, p = 0.001) and muscle disease activity (r = 0.146, p = 0.018), MITAX (r = 0.175, p = 0.005), MYOACT (r = 0.159, p = 0.012), and with MDI extent (r = 0.215, p = 0.003)/severity (r = 0.120, p = 0.041). Higher Hsp90 was found in patients with IIM-associated interstitial lung disease, cardiac involvement and dysphagia (25.4 vs. 18.9, p = 0.004; 27.5 vs. 19.3, p = 0.004; 25.0 vs. 18.2, p = 0.018, respectively). Increased Hsp90 was associated with higher prednisone equivalent dose (r = 0.180, p = 0.007) and treatment with DMARDs (22.0 vs. 18.9, p = 0.013). <h3>Conclusions</h3> We demonstrate increased extracellular Hsp90 in IIM patients that is associated with damage and disease activity, with the involvement of proximal skeletal muscles, the heart and lungs. Hsp90 might become a useful biomarker of disease activity and muscle involvement in IIM. <h3>Acknowledgement</h3> Supported by BT Cure and MHCR 023728.
Serum Mass-Spectrometry Test in First Line Advanced Nsclc Patients Treated with Standard Chemotherapy Regimens
Authors: F. Grossi, C. Genova, E. Rijavec, M.G. Dal Bello, G. Barletta, G. Burrafato, F. Biello, C. Sini, J. Grigorieva, K. Meyer, H. Roder
Journal: Annals of Oncology (2014)
Abstract 1013: Hepatic stellate cells promote progression of cholangiocarcinoma <i>in vitro</i> and <i>in vivo</i>
Authors: Hirohisa Okabe, Toru Beppu, Hiromitsu Hayashi, Takatoshi Ishiko, Toshiro Masuda, Ryu Otao, Masayuki Watanabe, Hiroshi Takamori, Hideo Baba
Journal: Cancer Research (2010)

Abstract Background: Although tumor-stroma interaction has been discussed, the role of hepatic stellate (HS) cells against cancer, especially cholangiocarcinoma, has not been clarified. Although hepatic stellate cells have been known to have a pivotal role in fibrogenesis in liver, the influence of them on liver cancer has been poorly investigated. We previously reported hepatic stellate cells may exist in cancer stroma of intrahepatic cholangiocarcinoma and interact with cancer cells in vitro. The aim of this study was to investigate the effect of HS cells on cholangiocarcinoma cells progression in vitro and in vivo and to identify key proteins which regulate their interaction. Methods: The effects of cholangiocarcinoma cells’ conditioned medium (CC-CM) on activation and proliferation of HS cells (LI90 and LX-2), the influences of HS cells conditioned medium (HS-CM) on in vitro proliferation and invasion of cholangiocarcinoma cells (HuCCT-1 and RBE), and the effects of their interaction on human umbilical venous endothelial cells (HUVECs) tube formation were assessed using each of conditioned medium. The effect of HS cells on tumor growth was examined in vivo by subcutaneous co-injection of them. To clarify the factors inducing their interaction, cytokine array was performed to assess the secreted proteins induced by co-culture of cholangiocarcinoma and HS cells. Results: CC-CM activated HS cells and increased their proliferation. HS-CM dose-dependently increased cholangiocarcinoma cell proliferation and invasion. Chemotherapy to cholangiocarcinoma cells was less effective treated with HS-CM. HS-CM activated the mitogen-activated protein kinase (MAPK) and Akt pathways in tumor cells. The indirect interaction of cholangiocarcinoma and HS cells promote the tube formation of HUVECs. Subcutaneous co-injection of tumor cells with HS cells in nude mouse resulted in increased tumor size and weight. There found to be several proteins including interleukin-1β (IL1β) that remarkably increased by co-culture of them in culture medium and they were thought to be key proteins which regulated tumor-stromal interaction. Conclusions: This study indicated that HS cells have an important role in accelerating cholangiocarcinoma progression. Several proteins including IL1β induced by co-culture model may be therapeutic targets which focus tumor-stromal interaction in cholangiocarcinoma. 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 1013.
AUTOMATED CHARACTERIZATION OF DEGENERATIVE AND FUNCTIONAL MITRAL VALVE PATHOLOGY USING MORPHOLOGICAL ANALYSIS OF 3D ECHOCARDIOGRAPHIC DATASETS
Authors: Karima Addetia, Lynn Weinert, Sonal Chandra, Masaaki Takeuchi, Kikuko Obase, Ivan Salgo, Victor Mor-Avi, Roberto Lang
Journal: Journal of the American College of Cardiology (2015)
Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis
Authors: Daniel J. Lovell, Edward H. Giannini, Andreas Reiff, Gail D. Cawkwell, Earl D. Silverman, James J. Nocton, Leonard D. Stein, Abraham Gedalia, Norman T. Ilowite, Carol A. Wallace, James Whitmore, Barbara K. Finck
Journal: New England Journal of Medicine (2000)

We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate.
Abstract 4286: Modulation of T cell activation by malignant melanoma initiating cells
Authors: Tobias Schatton, Ute Schütte, Natasha Y. Frank, Qian Zhan, Andre Hoerning, Susanne C. Robles, Jun Zhou, F. Stephen Hodi, Giulio C. Spagnoli, George F. Murphy, Markus H. Frank
Journal: Cancer Research (2010)

Abstract Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. This raises the possibility that only a restricted minority of tumorigenic malignant cells might possess the phenotypic and functional characteristics to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis, by demonstrating that tumorigenic ABCB5+ malignant melanoma-initiating cells (MMICs) possess the capacity to preferentially inhibit interleukin (IL)-2-dependent T cell activation and to support, in a B7.2-dependent manner, regulatory T (Treg) cell induction. Compared to melanoma bulk populations, ABCB5+ MMICs expressed lower levels of the major histocompatibility complex (MHC) class I, showed aberrant positivity for MHC class II, and exhibited lower expression levels of the melanoma-associated antigens (MAAs) MART-1, ML-IAP, NY-ESO-1, and MAGE-A. In addition, tumorigenic ABCB5+ subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1 in both established melanoma xenografts and clinical tumor specimens in vivo. In immune activation assays, ABCB5+ melanoma cells inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5− populations. Moreover, coculture with ABCB5+ MMICs increased, in a B7.2 signalling-dependent manner, CD4+CD25+FoxP3+ Treg cell abundance and IL-10 production by mitogen-activated PBMCs. Consistent with these findings, ABCB5+ melanoma subsets also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T cell-modulatory functions of ABCB5+ melanoma subpopulations and suggest specific roles for MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance. 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 4286.