tbuckley/cabot-search huggingface dataset:
Abstract 39: Discovery of PEN-221, an SSTR2-targeting maytansinoid conjugate with potent activity in vitro and in vivo
Authors: Brian H. White, Patrick Bazinet, Kerry Whalen, Michelle DuPont, James M. Quinn, Rossitza Alargova, Tsun Au Yeung, Adam Brockman, James Gifford, Haley Oller, Kristina Kriksciukaite, Charles-Andre Lemelin, Patrick Lim Soo, Benoit Moreau, Samantha Perino, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Mary Simcox, Richard Wooster, Mark T. Bilodeau
Journal: Cancer Research (2017)

Abstract Here we describe the discovery and the structure of PEN-221, a somatostatin receptor 2 (SSTR2) targeting peptide conjugated to DM1. PEN-221 is the first clinical compound from Tarveda’s Pentarin platform, which utilizes miniaturized drug conjugates that diffuse rapidly and deeply into solid tumors. Antibody drug conjugates (ADCs) have garnered a significant amount of attention in their ability to direct cytotoxic drugs to cancer cells; however, the efficacy of ADCs in solid tumors is limited by the slow diffusion of such large molecules through solid tumor tissue. Pentarins are designed to improve the efficacy of targeted therapies through effective tumor cell targeting and enhanced tumor penetration. SSTR2, a GPCR overexpressed in multiple types of neuroendocrine tumors, including small cell lung cancers, internalizes rapidly upon agonist stimulation, making it an ideal vector for delivering cytotoxic payloads. Examination of a variety of SSTR2 targeting ligands, as well as several potential conjugation sites, led to the identification of the C-terminal side chain of [Tyr3]-octreotate amide as the best conjugation site for a lipophilic payload. The use of DM1 as a payload afforded superior receptor affinity and receptor internalization when compared to other similarly potent microtubule-targeting agents. In vitro studies show that PEN-221 has receptor-dependent cytotoxic effects, and preclinical studies demonstrate PEN-221 induces tumor regression in several SSTR2 expressing xenograft models. Citation Format: Brian H. White, Patrick Bazinet, Kerry Whalen, Michelle DuPont, James M. Quinn, Rossitza Alargova, Tsun Au Yeung, Adam Brockman, James Gifford, Haley Oller, Kristina Kriksciukaite, Charles-Andre Lemelin, Patrick Lim Soo, Benoit Moreau, Samantha Perino, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Mary Simcox, Richard Wooster, Mark T. Bilodeau. Discovery of PEN-221, an SSTR2-targeting maytansinoid conjugate with potent activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 39. doi:10.1158/1538-7445.AM2017-39
Abstract 2114: Targeting invasive and drug-resistant PDAC with photodynamic therapy
Authors: Gwendolyn Cramer, Seyedehrojin Jafari, Hamid El-Hamidi, Dustin Jones, Jonathan Celli
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with an extensive desmoplastic reaction and a characteristic extracellular matrix (ECM)-rich stromal microenvironment which is a major determinant of disease progression and therapeutic response. Using 3D cell culture models of PDAC, we recently showed that an invasion-promoting ECM composition leads to differential response to chemotherapy agents and photodynamic therapy (PDT), in which cytotoxic response is triggered by light activation of a photosensitizing agent. In particular, ECM-infiltrating populations with characteristic mesenchymal phenotype display a marked increase in sensitivity to PDT (using the photosensitizer verteporfin), while the same cells exhibit increased chemoresistance. Here, motivated by these findings we systematically disentangle influences associated with the physical and biochemical properties of ECM as regulators of PDAC growth behavior and treatment response. In 3D tumor spheroids transplanted into invasion-promoting type 1 collagen gels, we use riboflavin-mediated photocrosslinking as a tool to regulate ECM stiffness (independent of its concentration), combined with high-content imaging to co-register invasive progression and differential response to chemotherapy and PDT. Increased extent of photocrosslinking correlates with increased collagen stiffness as confirmed by bulk oscillatory rheology, and is associated with a decrease in the invasive velocity (migration speed directed away from the primary transplanted spheroid) of ECM-infiltrating PDAC cells. Preliminary comparisons of PDT and oxaliplatin chemotherapy in low and high collagen crosslinking conditions show that PDT is significantly more effective than oxaliplatin in ECM-invading populations regardless of collagen stiffness. We also compare oxaliplatin chemotherapy and PDT before and after PDAC invasion into Matrigel ECM, and find that PDT efficacy is only enhanced after extensive invasion into the surrounding matrix. These results support the efficacy of PDT in targeting locally invasive PDAC while stressing the importance of elucidating how both biochemical and biophysical ECM interactions regulate therapeutic susceptibilities. Citation Format: Gwendolyn Cramer, Seyedehrojin Jafari, Hamid El-Hamidi, Dustin Jones, Jonathan Celli. Targeting invasive and drug-resistant PDAC with photodynamic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2114. doi:10.1158/1538-7445.AM2017-2114
Abstract 540: Deep learning to determine breast cancer estrogen receptor status from nuclear morphometric features in H&amp;E images
Authors: Rishi R. Rawat, Daniel Ruderman, David B. Agus, Paul Macklin
Journal: Cancer Research (2017)

Abstract We hypothesized that the spatial arrangement of nuclei in a hematoxylin and eosin (H&amp;E) stained image contains a vast quantity of latent information that is currently underutilized. We tested this hypothesis on the classification of breast cancer biopsies as estrogen receptor (ER) positive or negative. While determining ER status typically requires immunohistochemistry (IHC) staining, we aimed to recapitulate this step by predicting ER status directly from H&amp;E stained slides. By training a deep neural network on nuclear-morphometric features, we demonstrate the power of machine learning to provide insights about cancer biology, and aim to scale precision oncology for the developing world. We constructed a learning pipeline that segments nuclei from H&amp;E stained slides scanned into digital images, extracts shape and orientation descriptors, and uses a deep neural network to learn spatial features to predict ER status. After training the pipeline on 57 tissue cores of invasive ductal carcinoma (IDC), we were able to predict ER status in patients with IDC in a statistically significant manner (AUC=0.72, 95%CI=0.55-0.88, n=56) and ductal carcinoma in situ (AUC=0.82, 95%CI=0.74-0.89, n=106). To our knowledge, this is the first work to show that nuclear morphometric information can be used to predict the molecular status of a breast cancer tumor. An initial analysis of the features learned by the deep neural network provides a glimpse into the mechanistic differences between ER+ and ER- cancers: suggesting the importance of spatial heterogeneity in distinguishing between ER+ and ER-. We anticipate that further analysis will provide deeper insights about the morphological differences between ER+ and ER- cancers, and that this type of analysis can be applied to other markers and cancers. Moreover, an optimized version of this pipeline may serve patients in the developing world by providing a means to predict marker status directly from H&amp;E images. Citation Format: Rishi R. Rawat, Daniel Ruderman, David B. Agus, Paul Macklin. Deep learning to determine breast cancer estrogen receptor status from nuclear morphometric features in H&amp;E images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 540. doi:10.1158/1538-7445.AM2017-540
Abstract 1618: Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma
Authors: Po-Hao Feng, Kang-Yun Lee
Journal: Cancer Research (2017)

Abstract Background: Host immunity affect treatment effect of lung cancer. Peripheral blood S100A9+ monocytic myeloid derived suppressor cells (MDSCs) is a predictive factor for treatment response of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) of lung adenocarcinoma patients. Bevacizumab have immune-modulating effect, including decreasing MDSCs, and improve treatment effect in combination with immunotherapy. However, the effect of immune modulation in combination of bevacizumab and EGFR-TKI in EGFR mutated lung adenocarcinoma patients is not clear. Methods: Stage IV lung adenocarcinoma harboring sensitive EGFR mutation patients receiving first line EGFR-TKI or combination EGFR-TKI and bevacizumab were enrolled. The peripheral blood mononuclear cell (PBMCs) were collected, and S100A9+ MDSCs percentage was calculated by flow cytometry from CD14+S100A9+ in PBMC. Clinical data was collected. Results: Eight patients receiving EGFR-TKI and bevacizumab, as combination group, and twenty patients received EGFR-TKI alone, as control group, were enrolled. PBMC S100A9+ MDSC decreased in combination group (decrease 39±18% from baseline), but not in control group. Combination group had longer progress free survival (PFS) comparing with control group. (Median PFS combination vs control group: 15.2 vs 9.9 months, Log Rank test, p=0.05) Increased of peripheral blood cytotoxic T cells also had trend in combination group but not in control group. Conclusion: Besides the anti-angiogenesis effect, bevacizumab had immune modulated effect, especially in decreasing circulating S100A9+ MDSC in EGFR mutated lung adenocarcinoma patients. This might partially explain the longer PFS in combination of EGFR-TKI of anti-angiogenesis agent treatment. Citation Format: Po-Hao Feng, Kang-Yun Lee. Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2017-1618
Abstract 5481: Role and regulation of Peroxiredoxin antioxidant proteins in K562 leukemia cells
Authors: Elizabeth Szabo, Shelley A. Phelan
Journal: Cancer Research (2017)

Abstract Peroxiredoxins are a family of antioxidant proteins that have found to play a key role in many diseases, including cancer. A wide number of studies have found that Peroxiredoxin levels are elevated in several cancers, and reducing these levels can aid in inhibiting cell growth of cancer cells, suggesting that Peroxiredoxins confer resistance to reactive oxygen species (ROS)-induced cellular toxicity in cancer cells. Specific research has demonstrated that Peroxiredoxin levels are elevated in leukemia cells, and that targeting and inhibiting Peroxiredoxins in these cells can induce differentiation. Studies have also shown the use of doxorubicin as an effective chemotherapy treatment to significantly decrease cell proliferation and viability in leukemia. The purpose of this study is to examine Peroxiredoxin levels in K562 cells, a human chronic myelogenous leukemia cell line, and determine if high levels of Peroxiredoxins have the ability to protect cells from chemotherapy-induced death and possibly aid in chemoresistance. We first demonstrated that serum-deprived K562 cells exhibited significant growth inhibition over a 72 hour time period, but had no significant effect on viability. We also showed that treating K562 cells with 50 nM doxorubicin significantly decreased proliferation and viability. Corresponding changes in Peroxiredoxin protein levels are currently being analyzed to determine the effect of both growth-inhibition and chemotherapy-induced cytotoxicity on the Peroxiredoxin family in K562 cells, and siRNA experiments are being conducted to examine the protective role of Peroxiredoxins in these cells. Based on previous studies on MCF-7 cells conducted in our lab, we predict that Peroxiredoxin levels will be modified under both conditions, and that suppression of Prdxs by siRNA will increase chemotherapy susceptibility. Citation Format: Elizabeth Szabo, Shelley A. Phelan. Role and regulation of Peroxiredoxin antioxidant proteins in K562 leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2017-5481
Abstract 431: IDH1-mutated gliomas rely on anaplerosis of glutamate and lactate whereas IDH1 wild-type gliomas rely on glycolysis and acetate anaplerosis
Authors: Mohammed Khurshed, Krissie Lenting, Remco J. Molenaar, William P. Leenders, Cornelis J. van Noorden
Journal: Cancer Research (2017)

Abstract Hotspot mutations in isocitrate dehydrogenase 1 (IDH1MT) initiate low grade glioma (LGG) and secondary glioblastoma and induce neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). This causes metabolic rewiring that is not fully understood and in vitro studies have shown that IDH1MT cancer cells rely on glutaminolysis, providing cells with α-KG via activities of glutaminase (GLS) and glutamate dehydrogenase (GLUD). Here, we first show by in silico analysis of 269 IDH1 wild-type (IDH1WT) and 408 IDH1MT gliomas, obtained from the The Cancer Genome Atlas (TCGA) database, that IDH1WT gliomas have high expression levels of genes encoding for enzymes that are involved in glycolysis and acetate anaplerosis. On the other hand, the tricarboxylic acid (TCA) cycle, rather than glycolytic lactate production, is the predominant metabolic pathway in IDH1MT gliomas and is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. IDH1WT- and IDH1MT-related differences in expression were found in both LGG and glioblastoma. Furthermore, via in situ enzymatic activity mapping, we show in human gliomas and in xenocraft models that GLUD activity is increased and GLS activity is decreased in IDH1MT glioma, indicating that IDH1MT gliomas depend on glutamatolysis, rather than glutaminolysis. We show that transcript levels in our xenocraft models are in good agreement with our in silico analysis of the TCGA database. Finally, we confirmed the glutamate dependency of IDH1MT gliomas by MRS-flux analysis, whereas IDH1WT gliomas show high lactate production. Taken together, we show that IDH1WT gliomas have a typical Warburg phenotype and rely on acetate anaplerosis whereas IDH1MT gliomas are glutamate and lactate dependent. This metabolic rewiring in IDH1MT glioma, enables targeting of glutaminolysis rather than direct inhibition of IDH1MT for therapy. It diminishes the supply of glutamate-derived α-KG and directly inhibits the production of D-2-HG and simultaneously worsen the redox status of the glioma cells by inhibiting NAD(P)H production by GLUD. A candidate drug to inhibit GLUD is epigallocatechin-3-gallate gallate, a component of green tea that is currently receiving high interest as anti-cancer agent. Note: This abstract was not presented at the meeting. Citation Format: Mohammed Khurshed, Krissie Lenting, Remco J. Molenaar, William P. Leenders, Cornelis J. van Noorden. IDH1-mutated gliomas rely on anaplerosis of glutamate and lactate whereas IDH1 wild-type gliomas rely on glycolysis and acetate anaplerosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 431. doi:10.1158/1538-7445.AM2017-431
Abstract LB-034: MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in hepatocellular carcinoma
Authors: Jung Hsien Hung
Journal: Cancer Research (2017)

Abstract Glycine N-methyltransferase (GNMT) is a tumor suppressor and frequently down-regulated in hepatocellular carcinoma (HCC). However, the mechanism is not fully understood. MicroRNAs are gene regulators and play important roles in tumorigenesis. In this study, we used both miRWalk and miRTar programs to search for microRNAs that may target at GNMT. Among several candidates, we found that microRNA-224 (miR-224) can bind to the GNMT transcript of the coding region. In addition, mutation of miR-224 seed sequences prevented its binding and subsequently repression activity in the reporter assay. The GNMT-MT plasmid containing GNMT mRNA with miR-224 seed sequence silent mutation can escape the suppression of miR-224 in HEK293T cells. Both exogenous and endogenous GNMT expression were suppressed by miR-224, while miR-224 inhibitors enhanced GNMT expression. In addition, miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. We further demonstrated a significant inverse correlation of miR-224 and GNMT mRNA levels in HCC samples. In conclusion, miR-224 is the first reported miRNA that directly targets the GNMT mRNA coding sequence and plays an important role in GNMT suppression during hepatocarcinogenesis. Citation Format: Jung Hsien Hung. MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-034. doi:10.1158/1538-7445.AM2017-LB-034
Abstract 4218: Racial similarities in the effects of depression on hospital cost of breast cancer
Authors: Baqar A. Husaini, Oscar Miller, Meggan Novotny, Robert Levine
Journal: Cancer Research (2017)

Abstract Objective: Breast cancer (BC) incidence is reported to have declined in the nation. However, the role of depression on hospital costs for BC by race remains unknown. In this presentation, we examine two issues: (i) prevalence of BC with comorbid depression among discharged hospital patients; (ii) racial variation in the effect of co-morbid depression on hospital costs of BC patients. Methods: We extracted data on depression and breast cancer from the 2008 Tennessee Hospital Discharge Data System (HDDS). The BC sample (n=2,523) patients were mostly white (86%) with an average age of 63 years. We computed age-adjusted BC prevalence rates per CDC methodology, and compared the hospital costs for BC patients with vs. without depression. Results: Age adjusted BC rates (per 100,000) were higher among white than black patients (92.2 vs. 43.3, p&amp;lt;.000). Nearly one-fourth (23%) of BC patients had depression (no racial differences: (25% white vs. 24% black BC patients). Hospital costs for BC patients were 17% higher compared to non-BC patients, and cost was 55% higher among BC patients with co-morbid depression compared to non-depressed BC patients ($64,439 vs. $41,344). The higher cost for depressed BC patients was similar across both white and black BC females. Conclusion: BC is higher among white females compared to black females. BC patients cost with depression tended to be significantly higher compared to non-depressed patients regardless of race. Since nearly one-fourth of BC patients were depressed with higher hospital cost, these results point to possible significant costs savings by treating depression before the need for hospitalization among BC patients. Citation Format: Baqar A. Husaini, Oscar Miller, Meggan Novotny, Robert Levine. Racial similarities in the effects of depression on hospital cost of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4218. doi:10.1158/1538-7445.AM2017-4218
Allergy to buckwheat: an emerging clinical problem. Clinical and laboratory analysis of 24 consecutive patients
Authors: Enrico Marco Heffler, Riccardo Asero, Federica Nebiolo, Stefano Pizzimenti, Savino Sciascia, Iuliana Badiu, Giuseppe Guida, G Mistrello, S Amato, C Marchese, Giovanni Rolla
Journal: Allergy (2009)
Ambient Coarse Particulate Matter and the Right Ventricle: The Multi-Ethnic Study of Atherosclerosis
Authors: Jennifer C. D’Souza, Steven M. Kawut, Laura R. Elkayam, Lianne Sheppard, Peter S. Thorne, David R. Jacobs, David A. Bluemke, Joao A.C. Lima, Joel D. Kaufman, Timothy V. Larson, Sara D. Adar
Journal: Environmental Health Perspectives (2017)

Background: Coarse particulate matter (PM10–2.5) is primarily mechanically generated and includes crustal material, brake and tire wear, and biological particles. PM10–2.5 is associated with pulmonary disease, which can lead to right ventricular (RV) dysfunction. Although RV characteristics have been associated with combustion-related pollutants, relationships with PM10–2.5 remain unknown. Objectives: To quantify cross-sectional associations between RV dysfunction and PM10–2.5 mass and components among older adults and susceptible populations. Methods: We used baseline cardiac magnetic resonance images from 1,490 participants (45–84 y old) from the Multi-Ethnic Study of Atherosclerosis and assigned 5-y residential concentrations of PM10–2.5 mass, copper, zinc, phosphorus, silicon, and endotoxin, using land-use regression models. We quantified associations with RV mass, end-diastolic volume, and ejection fraction after control for risk factors and copollutants using linear regression. We further examined personal susceptibility. Results: We found positive associations of RV mass and, to a lesser extent, end diastolic volume with PM10–2.5 mass among susceptible populations including smokers and persons with emphysema. After adjustment for copollutants, an interquartile range increase in PM10–2.5 mass (2.2 μg/m3) was associated with 0.5g (95% CI: 0.0, 1.0), 0.9g (95% CI: 0.1, 1.7), and 1.4g (95% CI: 0.4, 2.5) larger RV mass among former smokers, current smokers, and persons with emphysema, respectively. No associations were found with healthy individuals or with ejection fraction. Conclusions: Alterations to RV structure may represent a mechanism by which long-term PM10–2.5 exposure increases risks for adverse respiratory and cardiovascular outcomes, especially among certain susceptible populations. https://doi.org/10.1289/EHP658