tbuckley/cabot-search huggingface dataset:
Abstract 376: Limits of [18F]-FLT PET as a predictive imaging biomarker of proliferation in oncology
Authors: Eliot T. McKinley, Gregory D. Ayers, Ralph A. Smith, Mary K. Washington, Robert J. Coffey, Henry C. Manning
Journal: Cancer Research (2012)

Abstract Background: Surrogate, non-invasive imaging biomarkers of cellular proliferation hold great promise for quantifying response to personalized medicine in oncology. An emerging imaging approach to assess tumor proliferation utilizes the positron emission tomography (PET) tracer 3′-deoxy-3′[18F]-fluorothymidine, [18F]-FLT. Though several studies have associated serial changes in [18F]-FLT-PET with elements of therapeutic response, the degree to which [18F]-FLT uptake quantitatively reflects proliferative index has been continuously debated for more that a decade. The goal of this preclinical study was to elucidate quantitative relationships between [18F]-FLT-PET and cellular, proteomic, and genomic metrics proliferation in treatment naive tumors. Methods and Findings: [18F]-FLT-PET imaging was conducted in mice bearing human colorectal or breast cancer cell line xenografts. Quantitative relationships between PET imaging, thymidine kinase 1 (TK1) protein and RNA levels, and immunostaining for proliferation markers (Ki67, TK1) were evaluated using imaging-matched tumor specimens. Overall, we found that [18F]-FLT-PET reflects TK1 protein levels in tumors. However, the cell cycle specificity of TK1 expression and the variable degree to which tumors utilize thymidine salvage for DNA synthesis tend to decouple [18F]-FLT-PET data from estimates of proliferation by standard, clinically employed means. Conclusions: Our findings illustrate that [18F]-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization. Therefore, unlike more generalizable proliferation markers, such as Ki67 immunostaining, tumor uptake of [18F]-FLT reflects proliferative indices to variable and potentially unreliable extents. [18F]-FLT-PET can not discriminate moderately proliferative, thymidine salvage driven disease from highly proliferative tumors that rely primarily upon de novo thymidine synthesis. For those reasons, the magnitude of [18F]-FLT uptake in treatment naive tumors should not be considered a surrogate of proliferative index. These data provide rationale for the diversity of correlative results reported, both positive and discordant, comparing [18F]-FLT-PET and tumor proliferation across numerous single-center clinical studies and provide a basis for future clinical best-practices when this imaging biomarker is employed in oncology. 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 376. doi:1538-7445.AM2012-376
Combined Probiotic and Peanut Oral Immunotherapy for the Treatment of Peanut Allergy: A Randomised Trial
Authors: Mimi L.K. Tang, Anne-Louise Ponsonby, Francesca Orsini, Dean Tey, Marnie Robinson, Ee Lyn Su, Paul Licciardi, A. Wesley Burks, Susan Donath
Journal: Journal of Allergy and Clinical Immunology (2015)
A LONG-TERM INVESTIGATION OF CHLORPROMAZINE
Authors: N. WILLIAM WINKELMAN
Journal: American Journal of Psychiatry (1960)

1. The paper is a concise summary of what has been learned and how our thinking has evolved during a 6 year experience with chlorpromazine. It also reports the results of 75 patients who have been on the drug for 6 years. The discussion is divided into 3 areas: 1. Technique of treatment, 2. Results of treatment, and 3. Theory of treatment. 2. Theory of treatment is discussed first. Our present concept of the psychologic actions of chlorpromazine we explain by using the concept of psychic energetics. We feel it is from our understanding of the patient's conflicts and an understanding of the struggle of opposing forces and not merely evaluating the degree of his motor agitations that, in the long run, will help us treat him effectively. It has, therefore, been our main thesis that optimum therapeutic results can be achieved only by understanding of the patient's personality and by understanding how a drug can influence this structure. 3. All psychiatric treatment is divided into two categories: 1. Helping the patient suppress and repress painful conflicts, and 2. Helping the patient recall and relive the memory and emotions of the conflict with feeling and understanding and more successfully. It is pointed out that chlorpromazine can be utilized in either of these basic techniques, and each is described separately. 4. It sumarizes how chlorpromazine affects intra-psychic activities and how, in turn, these can help the psychiatrist predict results and treat patients. The orientation of treatment, accordingly, must be the patient, not the chemical compound; the psychiatrist is concerned with psychology, not with chemistry. 5. The orientation of all treatment is an ego orientation, and optimum treatment is achieved by following the status of the ego and doing everything to strengthen that structure. The therapeutic attitude should be less of treating the illness and its symptoms and more of helping the recuperative powers of the patient cure himself. 6. It is suggested that optimum therapy is carried out by those who are well trained in understanding the patient's psycho-dynamic make up, who have experience in the use of the compounds, and apply this combined knowledge in treatment.
Abstract PL04-02: Synthetic lethality: Targeting DNA repair mechanisms in clinical trials
Authors: Andrew Tutt
Journal: Cancer Research (2011)

Abstract Epithelial carcinomas are in general diseases occurring as a result of the acquisition of and selection for multiple mutations in a parental somatic cell clone in the tissues of the primary site. In the last two decades the role of genome caretakers, which function in key areas of the DNA damage response, have been recognized as important tumor suppressor genes. Inactivating mutations in these genes occur as germline and /or as somatic mutations. In either event, loss of function in a tumor cell precursor clone leads to accelerated mutation acquisition and underpins the etiology of the tumor. As an understanding of the complex network that is the DNA damage response matures additional roles for signaling pathways, already recognized to be central to the establishment of the cancer phenotype, as controllers of DNA repair are being discovered. This has relevance to identification of wider populations of patients with tumors susceptible to approaches that target DNA repair deficiency. These have claissically been with DNA damaging chemotherapy but recently the development of small molecule inhibitors of DNA repair enzymes such as Poly-ADP polymerases PARP-1 and PARP-2 have been shown to target deficiencies in DNA repair as well as sensitize to DNA damaging therapeutics such as radiation and chemotherapy. Early-phase trials with efficacy endpoints have been presented for the PARP inhibitors AG014699, Olaparib, Veliparib, Iniparib and MK4827 have all been presented. The results of the first phase II trials that explore monotherapy PARP inhibitor strategies, based on revisiting the concept of synthetic lethality, have emerged and will be reviewed. PARP inhibitors are also being explored as sensitizers to DNA damaging therapies. The phase II and III trials that have or are exploring combinations with DNA damaging therapy in these contexts will be discussed. I will then discuss biomarkers that have been proposed and are being investigated to develop optimum drug schedule and optimize patient selection for PARP inhibitor therapy approaches. 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 PL04-02. doi:10.1158/1538-7445.AM2011-PL04-02
FDG Uptake in Splenic Epidermoid Cyst With Hemorrhage
Authors: Aisheng Dong, Yang Wang, Jianping Lu, Changjing Zuo
Journal: Clinical Nuclear Medicine (2013)

Splenic epidermoid cyst is a rare entity and rarely becomes complicated by hemorrhage. We present a case of splenic epidermoid cyst with old hemorrhage showing strong FDG uptake in the cyst wall. Histopathology revealed granulation tissue with abundant inflammatory cells, including many hemosiderin-laden macrophages, in the inner layer of the cyst wall. The abundant inflammatory cells in the granulation tissue may contribute to the strong FDG uptake of the cyst wall. This case highlights that a benign lesion with hemorrhage should be included in the differential diagnosis of abnormal splenic FDG uptake along with tumor and inflammatory processes.
Abstract 3641: The predictive and prognostic roles of DNA damage response genes in epithelial ovarian cancer
Authors: Nicolette G. Alkema, Marieke Everts, Ate G.J. van der Zee, Klaske A. ten Hoor, Harry Hollema, Steven de Jong, Marcel A.T.M. van Vugt, Bea G.B.A. Wisman
Journal: Cancer Research (2012)

Abstract Background: Despite platinum-based chemotherapy, 5-year survival of advanced stage ovarian cancer patients is only 15-30%. Exposure to platinum-based chemotherapeutics induces double strand DNA breaks (DSBs) and subsequently leads to activation of the DNA damage response (DDR). Therefore inhibition of components of the DDR may lead to better response to therapy. Aim of this study was to investigate in a large series of ovarian cancer patients the predictive and prognostic role of the activation status of four DDR-proteins- ATM, a key controller in the DDR, and three ATM substrates, including Chk2, 53BP1 and γ-H2AX, of which the latter is a direct readout for DNA damage. Methods: Expression of phospho-ATM, Chk2, phospho-Chk2, 53BP1, phospho-53BP1 and γ-H2AX was immunohistochemically assessed in 309 patients with chemo-naive ovarian cancer. Expression levels were related to clinicopathological characteristics and survival. Response to platinum-based chemotherapy was analyzed by defining two populations with either an optimal therapy response or a very poor therapy response. Both groups consisted of patients with advanced stage ovarian cancer, &amp;gt;2 cm residual disease after primary surgery and were all treated with platinum-based chemotherapy. The responder group had a well-defined PFS of more than 18 months while the non-responder group had a PFS of less than 6 months. Results: In the two well-defined groups with the largest contrast regarding response to treatment, positive γ-H2AX expression (OR=0.193; p=0.036) and positive Chk2 expression (OR=0.149; p=0.011) were related to a good response to platinum-based chemotherapy. In advanced stage patients, phospho-53BP1 expression was independently related to a worse disease-specific survival (HR=1.905; p= 0.044). Conclusion: High DDR protein expression in advanced stage ovarian cancers suggests a high degree of genomic instability, while the negative prognostic impact of phospho-53BP1 may be due to enhanced repair capacity of chemotherapy-induced DSBs on the long term. 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 3641. doi:1538-7445.AM2012-3641
Abstract 692: Drug treatment causes evolution
Authors: Edward Flach, Inna Fedorenko, Kim Paraiso, Keiran SM Smalley, Alexander RA Anderson
Journal: Cancer Research (2011)

Abstract A targeted drug treatment, PLX40720, eliminates the bulk of melanoma tumours, but there is always regression. We assert that the tumour population is heterogenous. Then the drug treatment is a selection process, targeting specific subpopulations. When the treatment ends, phenotypic drift causes reversion towards the original wild-type population. Our model is a discrete population of cells. The cells each have a distinct phenotype. This phenotype determines their fitness. The fitness changes under drug conditions: we define a fitness landscape for both drug and drug-free conditions. We validate the model using population experiments on four melanoma cell lines (1205Lu, WM164, WM793, WM983A). We find initial growth curves, death rates and regrowth curves under drug treatment. Matching the clinical approach, we treat the cell lines chronically with drug for six months. We then stop treatment and examine the reversion of the resistant cell lines to wild-type over a period of several weeks. There is only partial reversion to wild-type. We return to the model to incorporate this experimental data. We extend the complexity of the fitness landscape to multiple fitness “wells". Reversion after drug treatment only populates one of these wells. This more complex landscape reproduces the experimental observations. The model concept extends naturally to considering combination therapies. We also discuss the effect of modifying the local environment of the tumour: the drug treatment may become more effective. This approach gives a quantitative assessment of treatment strategies. 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 692. doi:10.1158/1538-7445.AM2011-692
A Cooperative Double-Blind Evaluation of Gastric Freezing in the Treatment of Duodenal Ulcer
Authors: Julian M. Ruffin, James E. Grizzle, Nicholas C. Hightower, Gordon McHardy, Harrison Shull, Joseph B. Kirsner
Journal: New England Journal of Medicine (1969)

A double-blind evaluation of gastric "freezing" in the treatment of duodenal ulcer was initiated in 1963 and conducted simultaneously in five institutions. One group of patients had the true "freeze" with the temperature of the coolant at -10°C and another group had a sham procedure with the temperature of the coolant at 37°C. The results of this study demonstrate conclusively that the "freezing" procedure is no better than the sham in the treatment of duodenal ulcer, confirming the work of others. There was no significant difference in relief of pain, secretory suppression, the number and severity of recurrences, or the development of end points in the two groups. It is reasonable to assume that the relief of pain and subjective improvement reported by early investigators were probably due to the psychologic effect of the procedure.
IDENTIFICATION OF GATA4-INDUCING MEDIATORS FOR CARDIAC LINEAGE SPECIFICATION IN MESENCHYMAL STEM CELLS
Authors: Young Keun Ahn, Dong Im Cho, Moon Hwa Hong, Hye Jin Kang, Mi Ra Kim, Hye-Yun Jeong, Wan Seok Kang, Meeyoung Cho, Ju Hee Kim, Su Yeon Lim, Yong Sook Kim
Journal: Journal of the American College of Cardiology (2016)
EFFICACY AND SAFETY OF RIVAROXABAN COMPARED WITH WARFARIN IN PATIENTS WITH CAROTID ARTERY DISEASE AND NONVALVULAR ATRIAL FIBRILLATION: INSIGHTS FROM THE ROCKET AF TRIAL
Authors: Ajar Kochar, Anne Hellkamp, Yuliya Lokhnygina, William Jones, Richard Becker, Scott Berkowitz, Guenter Breithardt, Keith Fox, Jonathan Halperin, Graeme Hankey, Kenneth Mahaffey, Christopher Nessel, Daniel Singer, Jonathan Piccini, Manesh Patel
Journal: Journal of the American College of Cardiology (2016)
Double-Phase Scanning of the Thyroid Gland With Tc-99m MIBI in a Patient With a Malignant Nodule:
Authors: OMAR ALONSO, FERNANDO MUT, GRACIELA LAGO, MARGARITA NUÑEZ, EDUARDO TOUYA
Journal: Clinical Nuclear Medicine (1997)

The authors report on a patient with a malignant papillary thyroid nodule that was "cold" with Tc-99m pertechnetate and evaluated by double-phase thyroid scintigraphy with Tc-99m sestamibi (MIBI). The images were taken at 15 minutes and 2 hours postinjection. Although nodular MIBI uptake on the early scan was present, it was less intense than the extranodular thyroid tissue. The delayed image showed an inverse relation of uptake, being more intense in the nodular lesion. This scintigraphic pattern could be explained by a slower washout rate of the malignant lesion. However, delayed tracer accumulation cannot be excluded.
Abstract 5614: Legumain protease substrate modified TAT-liposome cargo: an efficient tool for targeting malignant diseases.
Authors: Ze Liu, Min Xiong, Debbie Liao, Dan Lv, Ralph A. Reisfeld, Wolfgang Wrasidlo, Si Chen, Dwayne G. Stupack, Peiqing Sun, Xiaoyue Tan, Rong Xiang
Journal: Cancer Research (2013)

Abstract Tumor targeting specificity and efficacy of the internalization of macro-biomolecular drugs have emerged as two major obstacles hampering the application of liposome-based delivery system against tumor. Trans-activating transcriptional activator (TAT) is a member of the cell-penetrating peptides which enhance the penetration of various macro-biomolecular cargos. In this study, we developed a modified TAT-Liposome cargo in which the activation of TAT peptide was blocked by Legumain protease substrate Ala-Ala-Asn-(AAN). Firstly, we confirmed the extremely high level of Legumain expression in a variety of solid tumors, as well as its specific effect on recognition and digestion of AAN. Then we conjugated AAN with the TAT peptide and constructed the modified liposome (AAN-TAT-Lipo) cargo. Flow-cytometry assay showed the internalization of AAN-TAT-Lipo was significantly higher than that of AAN-Lipo in 4T1 cells which expressed active Legumain. In vivo, the concentration of Dox encapsulated in AAN-TAT-Lipo was significantly higher in the tumor sites and lower in normal tissues compared with Free-Dox, AAN-Lipo-Dox and TAT-Lipo-Dox groups after administration in mouse model of orthotopic breast cancer. Luciferase assay showed that the AAN-TAT-Lipo-Dox dramatically inhibited tumor growth compared with other groups. TUNEL staining demonstrated that the apoptotic cells in tumor sites were significantly increased in the group of AAN-TAT-Lipo-Dox, compared with other groups. Whereas, the apoptotic cells in the heart, liver, spleen and kidney were decreased in the group of AAN-TAT-Lipo-Dox. Taken together, the modified TAT-lipo cargo via blocking TAT peptide activation with a Legumain specific substrate, AAN, is proven effective for improving the efficacy of internalization, and reducing the systemic toxicity of the tumor targeting delivery system as well. Citation Format: Ze Liu, Min Xiong, Debbie Liao, Dan Lv, Ralph A. Reisfeld, Wolfgang Wrasidlo, Si Chen, Dwayne G. Stupack, Peiqing Sun, Xiaoyue Tan, Rong Xiang. Legumain protease substrate modified TAT-liposome cargo: an efficient tool for targeting malignant diseases. [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 5614. doi:10.1158/1538-7445.AM2013-5614
No bootstrapping without semantic inheritance
Authors: Julian Kiverstein
Journal: Behavioral and Brain Sciences (2010)

Abstract Anderson's massive redeployment hypothesis (MRH) takes the grounding of meaning in sensorimotor behaviour to be a side effect of neural reuse. I suggest this grounding may play a much more fundamental role in accounting for the bootstrapping of higher-level cognition from sensorimotor behaviour. Thus, the question of when neural reuse delivers semantic inheritance is a pressing one for MRH.
P5-01-01: Identification, Validation and Assessment of Transcriptional Relevance of a PDGFR-Activation Signature in (Inflammatory) Breast Cancer.
Authors: Laere SJ Van, Golen KL Van, M Joglekar, NT Ueno, P Finetti, Dam PA Van, P Viens, D Birnbaum, F Bertucci, PB Vermeulen, LY Dirix
Journal: Cancer Research (2011)

Abstract Introduction. Breast cancer can be divided into several subgroups characterized by unique patterns of pathway activation. Platelet-derived growth factor receptor (PDGFR) signalling has not yet been included in this classification scheme, although it has been reported to be a potential target for therapy. In this study, we have constructed a PDGFR-activation signature and investigated its relevance in breast cancer. Materials and Methods. Sixteen PDGFR-modulated genes were identified by intersecting two published PDGFR-modulated gene lists. The resulting gene signature was applied onto a publicly available gene expression data set of GIST (GSE17743) using principle component analysis. The segregation of PDGFR- and KIT-mutated GIST samples was investigated using permutation analysis and classification sensitivity and specificity were assessed. Using the regression coefficients from the first principal component, a PDGFR-activation score was constructed and applied onto a second data set in order to validate the score (GSE1923). Finally, the score was applied onto a gene expression data set of 389 breast cancer ***samples, including 137 samples from patients with IBC. Results. Sixteen PDGFR-modulated genes (NR4A1, EGR3, JUNB, IER3, TIEG, JUN, BCL3, MYC, NR4A3, PLAU, MCL1, DUSP1, DUSP5, DUSP6, SGK, GADD45A) were able to discriminate PDGFR-mutated GIST samples from KIT-mutated GIST samples with a sensitivity of 75% and a specificity of 85%. Application of the PDGFR-activation score onto a data set of control and PDGF-treated glioblastoma cells showed a significant increase in the PDGFR-activation score in the treated condition (P=0.0302). Application of the PDGFR-signature onto our series of IBC and nIBC samples demonstrated a significant and molecular subtype-independent increase in PDGFR-activation in IBC (P=0.0015; FDR=3%). In addition, in our series of nIBC samples only, PDGFR-activation was associated with decreased DMFS and RFS (P=0.0038 and P=0.0137 respectively). In fact, PDGFR-activation was an independent prognosticator in a multivariate model incorporating the molecular subtypes. Discussion. We identified a gene signature composed of 16 genes able to predict PDGFR-activation in tissue samples by gene expression analysis. PDGFR-activation is significantly increased in samples from patients with IBC, an aggressive form of locally advanced breast cancer. In addition, in nIBC, PDGFR-activation is associated with DMFS and RFS, independently of the molecular subtypes suggesting that PDGFR-activation might add another level of clinically relevant heterogeneity in breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-01.