tbuckley/cabot-search huggingface dataset:
Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level
Authors: De-Gang Song, Qunrui Ye, Mathilde Poussin, Jessica A. Chacon, Mariangela Figini, Daniel J. Powell
Journal: Journal of Hematology & Oncology (2016)

The poor prognosis and the limited efficacy of targeted therapy in patients with triple-negative breast cancer (TNBC) have raised the need for alternative therapies. Recent studies have demonstrated that folate receptor-alpha (FRα) may represent an ideal tumor-associated marker for immunotherapy for TNBC. The aim of the present study was to apply a chimeric antigen receptor (CAR) approach for the targeting of FRα expressed on TNBC cells and evaluate the antitumor activity of CAR-engineered T cells in vitro and in vivo. We found that human T cells expressing a FRα-specific CAR were potent and specific killers of TNBC cells that express moderate levels of FRα in vitro and significantly inhibited tumor outgrowth following infusion into immunodeficient mice bearing an MDA-MB-231 tumor xenograft. However, the antitumor activity of the FRα CAR T cells was modest when compared to the same CAR T cells applied in an ovarian tumor xenograft model where FRα expression is more abundant. Notably, FRα CAR T cells induced superior tumor regression in vivo against MDA-MB-231 that was engineered for overexpression of FRα. Taken together, our results show that FRα CAR T cells can mediate antitumor activity against established TNBC tumor, particularly when FRα is expressed at higher levels. These results have significant implications for the pre-selection of patients with high antigen expression levels when utilizing CAR-based adoptive T cell therapies of cancer in future clinical trials.
Abstract 3337: Targeting acute myeloid leukemia via anti-IL1RAP antibodies
Authors: Ping Jiang, Bob Y. Liu, Jen Huang, Jennifer Lu, Sharmili Roy, Madhavi Mishra, Xiaoxian Zhao, Jeffrey Lin, Eric D. Hsi, Jagath R. Junutula
Journal: Cancer Research (2016)

Abstract The current standard of care for Acute Myeloid Leukemia (AML) is largely ineffective in terms of achieving long term remission. This is mostly due to inability to remove all of the leukemic cells, and there is accumulating evidence to support the remaining leukemic cells are Leukemic Stem Cells (LSC) which are resistant to standard chemotherapy. We and others (Barreyro L. et. al. 2012) have discovered that IL-1 receptor accessory protein (IL1RAP) is overexpressed on LSC and their progenitors, but not on normal hematopoietic stem cells (HSC). Moreover, knockdown/knockout of IL1RAP expression greatly decreases growth/survival of AML cells. Thus, we have screened anti-IL1RAP therapeutic antibodies by applying FACS based analysis and Complement-Dependent Cytotoxicity (CDC) assays on both AML cell lines and primary patient samples. In a parallel effort, we also applied a functional IL-1β-induced NF-κB signaling assay to identify function-blocking anti-IL1RAP antibodies. Colony Formation Cell (CFC) assay results demonstrated that lead IL1RAP antibodies can significantly impede growth of both AML blast cells and leukemic stem cell-like cells. In contrast, normal HSCs are unaffected by these antibodies. Lead anti-IL1RAP antibodies also showed tumor growth inhibition in an established EOL-1 orthotopic tumor model. One major challenge of targeting IL1RAP by an antibody is that a large amount of IL1RAP protein is secreted into human serum, serving as a potential “sink” that inhibits IL1RAP antibody efficacy. We addressed this by developing a novel IL1RAP antibody that binds preferentially to the membrane-bound IL1RAP protein as compared to the secreted form. We will discuss different therapeutic development strategies to further advance the utilization of these lead anti-IL1RAP therapeutic antibodies for treating AML and other myeloid leukemic indications. Citation Format: Ping Jiang, Bob Y. Liu, Jen Huang, Jennifer Lu, Sharmili Roy, Madhavi Mishra, Xiaoxian Zhao, Jeffrey Lin, Eric D. Hsi, Jagath R. Junutula. Targeting acute myeloid leukemia via anti-IL1RAP antibodies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3337.
Standardized pathologic evaluation of the esophagus after neoadjuvant chemoradiation.
Authors: Christina T. Muijs, Justin K. Smit, Arend Karrenbeld, Jannet C Beukema, Johannes A. Langendijk, John Theodorus Plukker
Journal: Journal of Clinical Oncology (2012)

136 Background: The main objective of this study was to develop and validate a method to reconstruct the gross and clinical tumor volume (GTV and CTV) on the esophageal specimen in order to facilitate a good pathologic examination of the original tumor area after neo-adjuvant chemoradiation (CRT). Methods: The GTV and CTV borders of 25 patients were defined by a radiation oncologist on the planning CT in relation to 5 anatomical reference points. After CRT, the GTV and CTV borders were marked in vivo on the esophagus during surgical resection. Finally, the pathologist evaluated the presence of macroscopic and microscopic tumor in- and outside the GTV and CTV. The radiation tumor response was scored according to the standardized 5-tier Mandard classification. Radiation induced side effects were scored as well. Results: The Mandard classification could be scored on basis of the GTV alone in 68% of the cases (N=17). For the other patients (N=8), the GTV and the CTV should both be incorporated for correct evaluation of the tumor response. Five patients (20%) showed complete tumor response (Mandard 1), 68% (N=17) showed partial response (Mandard 2-3) and 12% (N=3) showed hardly any response (Mandard 4-5). In the partial responders, macroscopic tumor was found within the delineated GTV and microscopic tumor remained within the CTV both in 100% of the cases. In two patients (40%) with hardly any response, microscopic tumor was also found outside the CTV. This might be caused by tumor growth during the neo-adjuvant treatment or by geographical miss. Nine patients turned out to have positive lymph nodes. On average 18 (range 8-30) lymph nodes were evaluated per patients. Giant cell reactions, lymphocyte infiltration, and fibrosis, which indicate tumor regression were seen in the CTV and GTV, and were most pronounced in the GTV. Conclusions: This study suggested that demarcation of the GTV and CTV on the esophagus in vivo is important for standardized pathologic evaluation of the esophagus after neo-adjuvant chemoradiation. Furthermore using this method we determined microscopic tumor outside the CTV in 40% of the cases (N=2) of the bad responders (Mandard 4-5), illustrating the importance of our method in this patient category.
Hypertension Screening
Authors: WILLIAM J. MROCZEK
Journal: Annals of Internal Medicine (1975)

Letters1 March 1975Hypertension ScreeningWILLIAM J. MROCZEK, M.D., MARGENE MARTIN, R.N.WILLIAM J. MROCZEK, M.D.Search for more papers by this author, MARGENE MARTIN, R.N.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-82-3-384 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptMay 1974 was designated National Hypertension Month, and widespread screening for hypertension was encouraged by nearly all health care agencies. Plans are currently being made for National Hypertension Month in May 1975, and many community groups are planning blood pressure screening programs. Although hypertension screening accomplishes the first goal of the "Report of the Inter-Society Commission for Heart Disease Resources" (1), namely the identification of individuals with high blood pressure, there has been little published in the way of assessment of the results of hypertension screening procedures. In order to assess the results of screening for hypertension at our hospital,...Reference1. WOODBARROWFREIS JJE: Guidelines for the detection, diagnosis, and management of hypertensive populations. Circulation 44:A263-A272, 1971 MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Georgetown Medical Division District of Columbia General Hospital Washington, D. C. 20003 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByDesign and synthesis of novel nonpeptide CCK-B receptor antagonistsHypertension: Spectrum of problems and guidelines for management 1 March 1975Volume 82, Issue 3Page: 384-385KeywordsBlood groupsBlood pressureCardiovascular therapyHealth careHypertensionPrimary hypertension Issue Published: 1 March 1975 PDF DownloadLoading ...
P226 Impaired respiratory health status in the UK HIV infected population despite the use of antiretroviral therapy: Abstract P226 Table 1
Authors: JP Brown, J McGowan, H Chouial, S Capocci, C Smith, D Ivens, F Lampe, M Johnson, L Sathia, A Rodger, M Lipman
Journal: Thorax (2015)

<h3>Background</h3> The widespread use of antiretroviral therapy (ART) has led to a reduction in HIV related opportunistic infections. An increase in chronic non-HIV related co-morbidities has been observed in stable HIV positive individuals receiving ART. The extent to which HIV infection remains an independent risk factor for respiratory disease despite the use of antiretroviral therapy is uncertain and few studies have systematically evaluated respiratory disease in HIV-infected populations with access to antiretroviral therapy. <h3>Aims</h3> We sought to evaluate the frequency of (a) smoking and (b) respiratory symptoms and (c) spirometric impairment in the ambulatory UK adult HIV infected population, compared to HIV uninfected controls. <h3>Methods</h3> HIV-positive participants were recruited from a large HIV care service, HIV uninfected participants were recruited from Sexual Health services (where recruitment was stratified by age to approximate that of the HIV positive subjects). Participants completed a questionnaire which included questions on smoking history and respiratory health status using the St George’s Respiratory Questionnaire (SGRQ), and undertook spirometry without bronchodilation. <h3>Results</h3> 249 participants were recruited between April and July 2015 (Table 1). 28% of HIV positive and 33% of HIV negative participants were current smokers (p = 0.22). 9% of HIV positive and 7% of HIV negative participants had an FEV<sub>1</sub>/FVC of &lt;0.7 (p = 0.38). 92% of HIV positive participants were using antiretroviral therapy, 86% had an undetectable plasma HIV viral load and mean CD4 count was 684 cells/µL. Significantly higher SGRQ scores were observed in HIV positive participants than HIV-negative participants with a median total SGRQ score of 12 for those with HIV infection and 8 for the HIV negative participants (p = 0.03). In a linear regression (log scale) model, HIV infection was associated with a 62% increase (95% CI 1.19–2.21, p &lt; 0.01) in SGRQ in unadjusted analysis and 48% increase (1.08–2.02, p = 0.01) in a multivariable analysis adjusting for age, gender and smoking status. <h3>Conclusions</h3> Despite widespread use of ART, HIV infection is independently associated with impaired respiratory health status. This does not appear to result from current smoking or obstructive lung disease.
Abstract 3277: Prion-like protein “Doppel” is a selective therapeutic target for tumoral angiogenesis
Authors: Taslim Al-Hilal, Yoosoo Yang, In-San Kim, Youngro Byun, Fakhrul Ahsan
Journal: Cancer Research (2016)

Abstract Regulating growth factor signaling in a controlled and site-specific manner is the main hurdle that current antiangiogenic treatment modalities face. Here we show that the prion-like protein, doppel, is uniquely found in tumoral endothelial cells (TEC) but not in the normal ECs. Tissue sections containing primary human tumor (lung and colon) and normal tissues were used to study doppel protein expression. Strong expression and clear co-localization of doppel protein with CD34, a classical endothelial marker, was observed in both lung and colon cancer tissues compared to normal tissues. To evaluate doppel expression at the molecular level, we isolated TECs from different tumors derived from mouse xenografts. Extensive analysis showed that doppel was highly and ubiquitously expressed in the vasculature of squamous, breast, lung, and colon cancers. To elucidate the role of doppel in TEC during tumor angiogenesis, we generated a gain-of-function EC model to express doppel in ECs. Inducible overexpression of doppel in ECs correlates with high vessel formation in a spheroid-based EC transplantation technique. To integrate doppel expression with the canonical angiogenic circuits, we studied the mechanism by which doppel regulates angiogenesis. We evidently observed that doppel co-localized and formed complexes with vascular endothelial growth factor receptor 2 (VEGFR2). Also, doppel prolonged the surface residency of VEGFR2 and amplified the responsiveness of VEGF to VEGFR2. Genetic deletion of doppel in TEC not only depleted membrane residency but also induced internalization and degradation of VEGFR2. This indicates that doppel blocking can lead to effective control of VEGF-signaling in TECs and selective inhibition of tumor angiogenesis. Based on the functional role of doppel in angiogenesis and tumor growth inhibition, we generated doppel knockout mice on immunogenic C57BL6 mice. Tumor growth was inhibited in both hetero (Dpl+/-) and homo (Dpl-/-)-type mice compared to their wild-type littermate controls when syngeneic cancer cell lines including melanoma (B16f10) and lymphoma (EL4) or allogeneic colon cancer CT26 cell line were inoculated. Moreover, we developed doppel targeting monoclonal antibodies. Anti-doppel antibodies, 5C7 and 4D6, were effective against both murine CT26 and human HCT116 colon cancer cell lines. Our studies thus demonstrate the success of doppel targeting in inhibiting pathological tumor growth and establish doppel-VEGFR2 interactions as a specific molecular and therapeutic target in tumoral angiogenesis. Citation Format: Taslim Al-Hilal, Yoosoo Yang, In-San Kim, Youngro Byun, Fakhrul Ahsan. Prion-like protein “Doppel” is a selective therapeutic target for tumoral angiogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3277.
Abstract 692: Identifying genes that regulate bladder cancer progression and invasion
Authors: Amy L. Han, Brendan Veeneman, Scott A. Tomlins, Evan T. Keller
Journal: Cancer Research (2016)

Abstract Transitional cell carcinoma (TCC) is the most common type of bladder cancer and can be categorized as either non-muscle invasive (Ta-T1) or muscle invasive (≥T2). Approximately 50% of bladder cancers are T1 at initial diagnosis; however, the recurrence rate for these tumors is high and they may progress into T2. In this study, we aimed to determine if there are specific gene expression differences between T1 vs. T2 bladder cancer that can help identify key regulators in bladder cancer progression and invasion. T1 and T2 bladder cancer tissues were subjected to RNA-Seq to evaluate for differences among these stages. Additionally, the Oncomine database was examined to further narrow down potential candidates that differentiate T1 from T2. These efforts led to the identification of an extracellular matrix glycoprotein, fibulin-3 (FBLN3), as being highly expressed in T2 compared to T1 tissues. To validate these findings, FBLN3 expression was measured using qRT-PCR from formalin fixed and paraffin embedded tissues from patient bladder samples ranging from stages Ta-T4. These studies confirmed that FBLN3 expression was elevated in muscle-invasive compared to non-muscle invasive bladder cancer. Consistent with these findings, FBLN3 expression level correlated with the invasive ability of several bladder cancer cell lines. Specifically, FBLN3 expression was determined using both qRT-PCR and western blotting amongst the T24, UMUC-13, UMUC-3, RT4, and 5637 bladder cancer cell lines. The most invasive cell lines, T24 and UMUC-13, demonstrated the highest FBLN3 expression. In contrast, the least invasive cells, RT4 and 5637, demonstrated the least FBLN3 expression. To determine a functional role for FBLN3 in bladder cancer invasion, we knocked down or increased FBLN3 expression in bladder cancer cell lines using lentiviral transduction. Knockdown of FBLN3 expression in the T24 and UMUC-13 cells inhibited the invasion and migration of these bladder cancer cells; whereas, FBLN3 overexpression in the 5637 cells promoted the invasiveness of the bladder cancer cells. Furthermore, cell viability and growth rates were not affected by manipulation of FBLN3 expression. Our results indicate that FBLN3 serves as a pro-invasive factor in bladder cancer. These findings suggest that FBLN3 could serve as (1) a biomarker to differentiate T1 from T2 bladder cancers and (2) a promising therapeutic target. Citation Format: Amy L. Han, Brendan Veeneman, Scott A. Tomlins, Evan T. Keller. Identifying genes that regulate bladder cancer progression and invasion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 692.
Abstract 4333: Identification and optimization of the first highly selective GLUT-1 inhibitors
Authors: Marcus Bauser, Bernd Buchmann, Holger Siebeneicher, Arwed Cleve, Hartmut Rehwinkel, Roland Neuhaus, Iring Heisler, Thomas Mueller, Charlotte Christine Kopitz
Journal: Cancer Research (2016)

Abstract Increased glycolysis rates combined with an insufficient cellular respiration in tumor cells have been known for decades as the Warburg effect (1930). One of the key players in this metabolic alteration of cancer cells is glucose transporter 1 (or GLUT-1), which facilitates the transport of glucose across the plasma membranes of mammalian cells. Many tumor biopsies underline the crucial importance of GLUT-1 overexpression for the vitality of many tumor entities. Moreover the glucose uptake dependency of cancer cells can be visualized by the widespread clinical application of 18fluorodeoxyglucose (FDG) uptake in PET tumor imaging. Therefore, inhibition of glucose uptake for the treatment of cancer seems to be an interesting approach. Based on our first identified GLUT-1 inhibitors (1H-pyrazolo[3,4-d]pyrimidines) with modest selectivity profile, a high throughput screen (HTS) was performed to identify new potent lead structures with unique selectivity against the other members of the GLUT-1 family (GLUT-2,-3 and -4). Among several lead structures we identified from the HTS the quinoline carboxamides with the most promising selectivity profile. Extensive SAR elaboration by synthesizing more than 1600 new derivatives of the lead structure clearly revealed the essential moieties for high activity, potency, and selectivity. Additionally, we were able to improve the in vitro and in vivo PK properties permitting in vivo animal studies. We are able to report for the first time the preclinical profile and structure of the very potent and highly selective GLUT-1 inhibitor BAY-876 representing an ideal tool to further evaluate the scope and limitations of GLUT-1 inhibition as new therapeutic option. Citation Format: Marcus Bauser, Bernd Buchmann, Holger Siebeneicher, Arwed Cleve, Hartmut Rehwinkel, Roland Neuhaus, Iring Heisler, Thomas Mueller, Charlotte Christine Kopitz. Identification and optimization of the first highly selective GLUT-1 inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4333.
TG02: A novel, multi-kinase inhibitor with potent activity against solid tumors.
Authors: F. Burrows, K. Goh, V. Novotny-Diermayr, S. Hart, H. Hentze, M. Goh, Y. Tan, L. Cheetham, S. L. Zaknoen, J. Wood
Journal: Journal of Clinical Oncology (2010)

e13549 Background: Kinase inhibitors have found applications in oncology due to their ability to target key signaling pathways in many different cancers. In general, broad-spectrum kinase inhibitors have yielded better clinical outcomes than more selective ones because they block more than one pathway critical for tumor growth. We describe herein the pharmacological profile of TG02, a multi-kinase inhibitor being developed by Tragara Pharmaceuticals, which combines cell cycle regulatory and transcriptional CDK inhibition with activity against kinase targets involved in antiapoptotic signaling and other aspects of the malignant phenotype. Methods: In vitro potency was evaluated using kinase assays, Western blot analyses of the pathway components, FACS-based cell cycle analyses and proliferation and apoptosis assays in human tumor lines. Evaluation of in vivo PK, PD biomarkers and antitumor efficacy was in nude mouse xenograft models of solid tumors. Results: TG02 was shown to be a 10-50nM inhibitor of CDKs 1,2,7 and 9 and other ongogenic kinases, including FLT3, JAK2 and ERK5. TG02 potently inhibits proliferation across a broad panel of human solid tumor cell lines (n = 15, IC50 from 64 to 504 nM). This potency exceeded that of other pan-CDK inhibitors currently in clinical development (SNS-032 and seliciclib) and other drugs that block FLT3 and JAK2 but lack CDK activity (sunitinib and TG101348), suggesting that the unique spectrum of kinases inhibited by TG02 may provide enhanced antitumor activity in solid tumors. TG02 potently induced G2/M cell cycle arrest that rapidly progressed to robust apoptosis in HCT116 cells and synergized with doxorubicin in pancreatic and breast cancer cell lines and with gemcitabine in ovarian carcinoma cells. TG02 was cleared from the blood within 8 hours of PO dosing but was retained in tumor masses at supratherapeutic levels for 24-48 h, depending on dose. Accordingly, pathway-related biomarkers were markedly suppressed for 24-72 h after dosing. In mice bearing SC HCT116 xenografts, TG02 inhibited tumor growth by 82% (p<0.001) at 75 mg/kg PO Q2D. Conclusions: TG02 is a multi-kinase inhibitor with a previously unreported spectrum of targets that shows promising preclinical activity for the treatment of solid tumors in man. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration S*BIO Pte Ltd, Tragara Pharmaceuticals S*BIO Pte Ltd, Tragara Pharmaceuticals