tbuckley/cabot-search huggingface dataset:
Pre-clinical safety assessment of VB4-845, an EpCAM binding immunoconjugate
Authors: Crystal Marlin, Jennifer Brown, Michele Rasamoelisoloa, Jeannick Cizeau, Denis Bosc, Joycelyn Entwistle, Nick Glover, Glen MacDonald
Journal: Cancer Research (2008)

2136  VB4-845 is a recombinant fusion protein, consisting of a tumor-targeting antibody fragment fused to a truncated form of Pseudomonas exotoxin A (ETA252-608) that specifically targets the epithelial cell adhesion molecule (EpCAM). EpCAM is highly expressed in a wide variety of epithelial carcinomas including squamous cell carcinoma of the head and neck (SCCHN). VB4-845 is currently being evaluated for this indication in a phase II/III clinical trial using an intratumoural route of administration. In order to select an appropriate animal model for pre-clinical studies, the EpCAM amino acid sequence and epitope binding site of VB4-845 were compared among various species (mouse, rat, dog, rhesus monkey, chimpanzee) to that of humans. Amino acid identity varied from 81.6% (mouse) to 97.6% (chimpanzee) to that of humans. The EpCAM epitope amino acid identity varied from 66.7% (mouse) to 100% (rhesus monkey and chimpanzee) to that of humans. However, immunohistochemistry studies showed that VB4-845 did not cross-react with any species other than chimpanzee, a species in which end-point toxicology studies are not possible. Initial safety studies were conducted in Sprague-Dawley rats. As VB4-845 is in advanced clinical trials, additional toxicology and safety pharmacology studies were carried out in a second species, Cynomolgus monkey. Animals were dosed over a range of 0.015 to 3.5 mg/kg which corresponds to 0.03 to 70 mg in humans, up to 100 times greater than the highest clinical dose. The maximum tolerated dose was determined to be 1 mg/kg based on skin lesions at the injection site associated with other localized or systemic findings suggestive of inflammation (limited usage of affected limb, elevated body temperature, neutrophilia). Potential toxicity of repeated doses of VB4-845 was assessed in a four week repeated-dose study (0.035, 0.175, 0.350 mg/kg) which corresponds to the human clinical dose (0.7 mg) up to 10 times (7.0 mg) the proposed clinical dose. The once weekly subcutaneous (SC) administration did not result in any changes in ophthalmoscopy, neurological assessments, electrocardiography, hematology, urinalysis, organ weight data, or macroscopic findings. Clinical signs were limited to reduced appetite that was dose related but did not result in body weight changes. Localized skin lesions at the treatment sites were also dose related but resulted in inconsequential microscopic changes (foci of minimal-slight chronic inflammation and/or hemorrhage) with no evidence of systemic inflammation. The NOEL was determined to be 0.350 mg/kg. Pharmacokinetic analysis indicated that the maximum drug exposure occurred just less than four hours after SC administration. Safety studies continue to support the use of VB4-845 for the treatment of SCCHN and preparation for market registration.
Abstract 1173: A novel high throughput platform for head &amp; neck cancer organoids drug screening
Authors: Karla Queiroz, Else Driehuis, Silvia Bonilla, Henriëtte Lanz, Hans Clevers, Jos Joore, Paul Vulto
Journal: Cancer Research (2019)

Abstract Head and neck (HN) cancer is a broad category of tumor types arising from various anatomic structures including the craniofacial bones, soft tissues, salivary glands, skin, and mucosal membranes. Treatment often involves an intensive combination of surgery, radiotherapy and chemotherapy. Despite this, tumour recurrence rates remain high and survival rates are relatively poor. Here, we describe a novel high throughput drug screening platform combining the OrganoPlate, a microfluidic based 3D culture plate, and HN cancer-derived organoids. MIMETAS develops Organ-on-a-Chip-based models for evaluation of new medicines. Our unique microfluidic technology enables testing of compounds on miniaturized 3D organ models in high-throughput. These models are expected to show better predictivity as compared to laboratory animals and conventional 2D cell culture models, without compromising throughput or ease of use. Hereby we show the establishment of HN cancer-derived organoids in 2-lane OrganoPlate, and its usefulness for phenotypic drug screenings. The aim of the study is to evaluate the 2-lane OrganoPlate as a platform for growing HN cancer organoids and drug screening. Organoid lines (T2, T3 and T4) were embedded in the 2-lane OrganoPlate as single cells in an Extracellular Matrix gel. At day 3, cultures were treated with Cisplatin or Carboplatin for 120 hours. Drug response was evaluated by assessment of morphology (phase contrast), Cell Viability (Alamar blue) and proliferation (EdU incorporation). Organoids cultures grow well under perfusion in the 2-lane OrganoPlate and different sensitivity to cisplatin is captured by the used readouts. The high-throughput, microfluidic 2-lane OrganoPlate platform offers an attractive method for growing HN cancer-derived organoids, supporting development of individualized tumour models for phenotypic drug screenings. Citation Format: Karla Queiroz, Else Driehuis, Silvia Bonilla, Henriëtte Lanz, Hans Clevers, Jos Joore, Paul Vulto. A novel high throughput platform for head &amp; neck cancer organoids drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1173.
Abstract 19264: Variable Pacemaker Dependency at 1 Year After Transcatheter Aortic Valve Replacement
Authors: Amer Hawatmeh, Gautam Visveswaran, Mohammad Thawabi, Hisham Hakeem, Prem Patel, Constantinos Costeas, Najam Wasty, Mark Russo, Marc Roelke, Marc Cohen
Journal: Circulation (2017)

Background: Transcatheter aortic valve replacement (TAVR) has emerged as an alternative for surgical replacement in patients with severe aortic stenosis (AS). Despite the clinical benefit of TAVR, ...
Abstract 17205: Contractility in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes is Highly Dependent on Stochastic Variability in Myofilament Development
Authors: Jonathan Hernandez, Akul Arora, Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Allen Liu, Adam S Helms
Journal: Circulation (2018)

Introduction: Modeling heart diseases using cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) enables direct study of cellular and molecular mechanisms. However, the variable phenotypes of individual cells has limited the reproducibility of contractile measurements. We hypothesized that variability in myofibrillar development in hiPSC-CMs influences the contractile kinetics and could be controlled for by visualizing and quantifying myofilaments in vitro . Methods and Results: Control hiPSCs were differentiated into cardiomyocytes (hiPSC-CMs) and purified. hiPSC-CMs were replated at day ~25 onto 8.7 kPa polyacrylamide gels containing fluorescent microbeads and micropatterned with fibronectin in 7:1 aspect ratio rectangles (1750 um 2 ). Single iPSC-CMs grew into the rectangular shapes and exhibited spontaneous contractions by day 2 of replating. hiPSC-CMs were stained with live-cell actin dye and imaged on day 5-7 for fluorescent bead displacements and actin videos depicting myofilaments. Traction force analysis of bead displacements was performed to calculate whole-cell force vs. time curves at 33 msec temporal resolution. Myofilament area was measured by thresholding a binary mask on the actin live cell images. Myofilament number varied markedly among individual iPSC-CMs. iPSC-CMs with few myofilaments (myofilament area / cell area &lt;30%) developed low force (&lt;400 uN per cell) and were not included in subsequent analyses. Among cells with myofilament area &gt;30%, the mean traction force was 1368±357 uN and the myofilament area demonstrated a linear correlation with maximum force (R 2 =0.19, runs test p=0.8) with slope of 0.8±0.2 uN/um 2 (p=0.002 vs zero slope). Maximum contraction velocity strongly correlated with maximum force (R 2 =0.31, runs test p=0.4) with slope of 3.9±0.9 sec -1 (p&lt;0.0001 vs zero slope), as did maximum relaxation velocity (R 2 =0.27, runs test p=0.6, slope 4.1+1.0 sec -1 , p=0.0003 vs zero slope). Similar results were observed in two control cell lines and with two different purification methods. Conclusion: Variability in myofilament development is a critical determinant of contractile force and kinetics in individual iPSC-CMs that should be accounted for in iPSC-CM contractile experiments.
Abstract 4714: Preclinical evaluation of a novel LSD1 inhibitor SYHA1807 for the treatment of small cell lung cancer
Authors: Lingyun Wu, Hanyu Yang, Lele Zhao, Jianjun Sun, Jian Liu, Yuanfeng Xia, Chichung Chan, Shuhui Chen
Journal: Cancer Research (2019)

Abstract Histone post translational modification is an important epigenetic regulation to activate or suppress specific gene expressions. Methylation which is dynamically regulated by methyltransferase and demethylase (e.g. lysine specific demethylase) is one of the mechanisms and is critical for cell cycle and differentiation. Lysine specific demethylase 1 (LSD1) is the first identified histone modifying enzyme that removes methyl from histone lysine and arginine residues. Its overexpression has been found in many human cancers, like blood, lung and breast cancers. Small cell lung cancer is a neuroendocrine cancer characterized as low differentiation, rapid metastatic spread and resistance to regular chemotherapy. Aberration of epigenetic regulation is a common feature in small cell lung cancer, like down regulation of tumor suppression gene and up regulation of oncogenes. LSD1 expression of small cell lung cancer patients is up regulated in tumor tissue but not in normal tissues. Dysregulated histone methylation may contribute to the tumor malignance and treatment resistance. Taken together, LSD1 activity inhibition may provide a promising treatment option for small cell lung cancer. A challenge in LSD1 drug development is how to maintain optimal therapeutic effects while reducing mechanism related hematological toxicity. Through scaffold hopping and thoroughly SAR exploration, a novel LSD1 inhibitor SYHA1807 has been identified. The exposure level of this candidate at lung tissue is about four times higher than in bone marrow. The ideal drug tissue distribution characteristics may provide further safety assurance in clinical application. Detailed ADME/PK, in vitro, in vivo properties and preliminary safety evaluation results will be presented. Note: This abstract was not presented at the meeting. Citation Format: Lingyun Wu, Hanyu Yang, Lele Zhao, Jianjun Sun, Jian Liu, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of a novel LSD1 inhibitor SYHA1807 for the treatment of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4714.
Abstract 4319: Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma
Authors: Jiajie Hou, He Zhang, Jun Liu, Zhenjun Zhao, Jianye Wang, Zhike Lu, Bian Hu, Jiankui Zhou, Zhicong Zhao, Mingxuan Feng, Haiyan Zhang, Bin Shen, Xingxu Huang, Beicheng Sun, Mark J. Smyth, Chuan He, Qiang Xia
Journal: Cancer Research (2019)

Abstract Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to ultimately stabilize the methylated oncogene mRNAs in inflammation-associated hepatocellular carcinoma (HCC). YTHDF2 silenced in human HCC cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed HCC progression. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer. Significance: We show that hypoxia induces downregulation of m6A-reader YTHDF2 and hyper-upregulation of m6A-mRNAs in human HCC, which adapts m6A decoration into a cancer-promoting mechanism. Thus we identify YTHDF2 as a suppressor in tumor growth and metastasis by targeting IL-11 and Serpin E2. Note: This abstract was not presented at the meeting. Citation Format: Jiajie Hou, He Zhang, Jun Liu, Zhenjun Zhao, Jianye Wang, Zhike Lu, Bian Hu, Jiankui Zhou, Zhicong Zhao, Mingxuan Feng, Haiyan Zhang, Bin Shen, Xingxu Huang, Beicheng Sun, Mark J. Smyth, Chuan He, Qiang Xia. Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4319.
Axillary implantation of Impella CP allows early rehabilitation of patients in cardiogenic shock bridged to heart transplantation
Authors: David Couto-Mallón, Francisco Estévez-Cid, Carlos Velasco-García, José M. Herrera-Noreña, Carmen Iglesias-Gil, Miguel Solla-Buceta, L. Seoane-Quiroga, V. Aller-Fernández, S. Fojón, M. Balsa-Canto, Eduardo Barge-Caballero, Gonzalo Barge-Caballero, María J. Paniagua-Martín, María Generosa Crespo-Leiro, José J. Cuenca-Castillo
Journal: European Journal of Heart Failure (2017)
Abstract 1934: Development of spectrally distinct silica coated gold nanorods for detection of cancer using MSOT
Authors: Karl N. Thomas, Abhilash Samykutty, Molly McNally, Lacey R. McNally
Journal: Cancer Research (2019)

Abstract Traditional cancer imaging devices are limited in their ability to screen for multiple contrast agents simultaneously in real time. Multispectral Optoacoustic Tomography (MSOT) is an emerging imaging modality capable of real-time imaging of numerous contrast agents with enhanced spatial resolution of 75µm at depths of 5 cm. The use of exogenous contrast agents in MSOT remains largely unexplored, so we developed two species of spectrally distinct gold nanorod as contrast agents for use in MSOT. Our goal was to evaluate the potential of MSOT to spectrally differentiate two exogenous contrast agents simultaneously. Two gold nanorod species were created using hydrogen peroxide (GNR-H2O2) or ascorbic (GNR-ASC) acid as reducing agents to modify the length of each species to create nanorods with individual light absorbance spectra in the IR range (680-900 nm). These gold nanorods were highly stabilized via encapsulation with mesoporous silica along with a subsequent chitosan capping. Human epidermal growth factor receptor 2 positive (HER2+) cells were specifically targeted by conjugating these mesoporous silica-coated chitosan capped gold nanorods (CMGs) to Trastuzumab resulting in TRA-CMG particles. Both TRA-CMG-ASC and TRA-CMG-H2O2 resulted in optoacoustic spectrally distinct signals when imaged in tissue phantoms both individually as well as mixed within the same well after multispectral processing using linear regression. Treatment of HER2+ breast cancer cell lines, DY36T2Q and SKBR3, with TRA-CMG-H2O2 resulted in 2.5x and 3.1x enhanced signal, respectively, as compared to HER2- MDA-MD468 cells. Treatment of DY36T2Q and SKBR3 cells with TRA-CMG-ASC demonstrated 3.7x and 6.9x, respectively, compared to MDA-MD468. In all three cell lines treated with a combination of TRA-CMG-H2O2’s and TRA-CMG-ASC’s clear and distinct signals were observed for each particle, demonstrating that each TRA-CMG possessed and maintained a detectibly distinct optoacoustic spectrum, in the IR range, allowing them to be detectable as separate contrast agents in MSOT while proximate to other targeted contrast agents. Both particles have demonstrated that they can be simultaneously administered and targeted at HER2+ cell while also maintaining distinct photoacoustic signals in MSOT upon consolidation. Each particle species, targeted to the same cells, were capable of being monitored individually in the presence of the other gold nanorod contrast agent. Citation Format: Karl N. Thomas, Abhilash Samykutty, Molly McNally, Lacey R. McNally. Development of spectrally distinct silica coated gold nanorods for detection of cancer using MSOT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1934.
Abstract LB-238: Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients
Authors: Xiaohe Liu, Zheng Ao, Jordan S. Preiss, Joel Neal, Lisa Ya Zhou, Lidia Sambucetti, Heather A. Wakelee
Journal: Cancer Research (2019)

Abstract Early detection and intervention are crucial for long-term survival of either primary or recurrent lung cancer patients. Circulating tumor cells (CTCs) could be powerful biomarkers for the diagnosis, prognosis, and treatment planning of cancer. In this work we applied our FAST cytometer, a fiber-optic array scanning technology (FAST) to develop a sensitive diagnostic blood tests (“liquid biopsies”) for NSCLC. This technology is based on the ultra-rapid, sensitive and accurate detection of rare circulating cells expressing the biomarker(s) of interest. By applying the FAST cytometer with a unique NSCLC specific cocktail, we were able to detect CTC in NSCLC setting with higher sensitivity as compared with traditional cytokeratin-based detection. In a pilot cohort of 51 NSCLS patients, we have detected CTC in 74.2% using our unique panel for NSCLC CTC, this has raised our sensitivity from 48.8% using traditional cytokeratin-based detection. In addition, we have also interrogated circulating cancer associated fibroblasts (cCAF) as an additional liquid biopsy marker for NSCLC. We detected cCAF in 67% NSCLC patients. When combined with our enhanced CTC detection method, addition of cCAF further increased our sensitivity to 88.5%. Moreover, using clinically validated PD-L1 antibody (Ventana SP263) as reference, we have demonstrated our capacity to analyze PD-L1 expression on CTC at protein level, we have shown detection of PD-L1+ CTC in 80% of the patients. To summarize, we have developed an unique panel to detect CTC with higher sensitivity using combinational detection and we have demonstrated that by combining CTC detection with cCAF detection, liquid biopsy sensitivity for cancer detection can be further increased without significant increase in false positive rates. Lastly, we developed a method to analyze the PD-L1 expression on CTC using clinically validated Ventana PD-L1 (SP263) rabbit monoclonal antibody as reference which can potentially serve as a companion diagnostics tool for NSCLC immunotherapy Citation Format: Xiaohe Liu, Zheng Ao, Jordan S. Preiss, Joel Neal, Lisa Ya Zhou, Lidia Sambucetti, Heather A. Wakelee. Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-238.
Serum B-cell maturation antigen as a prognostic marker for untreated chronic lymphocytic leukemia.
Authors: Camilia M Soof, Sameer Ashok Parikh, Susan L. Slager, Kari G. Rabe, Matthew Ghermezi, Tanya M. Spektor, Neil E. Kay, James R. Berenson
Journal: Journal of Clinical Oncology (2019)

7525 Background: New prognostic markers in chronic lymphocytic leukemia (CLL) are in demand. Different groups have developed models which combine multiple prognostic markers into a single index to classify CLL patients (pts). The CLL-International Prognostic Index (CLL-IPI) combines five parameters: age, clinical stage, TP53 status, IGHV mutational status, and serum β2 microglobulin levels. B-cell maturation antigen (BCMA) is a cell membrane receptor expressed exclusively on late stage B-cells and plasma cells with elevated serum (s) levels found in B-cell malignancies, such as multiple myeloma (MM). In MM, sBCMA levels can be used to monitor disease status and predict overall survival (OS). To further evaluate this biomarker in other hematologic malignancies, we studied it in CLL. Methods: Untreated (UNTX) CLL pts seen and consented at Mayo Clinic were identified. sBCMA levels were measured on stored sera of 331 UNTX CLL pts using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&amp;D Systems (Minneapolis, MN). The Mann-Whitney analysis was used to assess differences between CLL pts and healthy controls. The relationships between sBCMA and both time to first treatment (TFT) and OS were also assessed using Cox Regression models with an optimal sBCMA cutoff of 40.9 ng/mL. Results: The median age of pts was 61 years, and 71% were male. The distribution of CLL-IPI risk groups was as follows: 135 (41%) Low; 114 (34%) Intermediate; 67 (20%) High; 15 (5%) Very High. The median level of sBCMA in CLL pts (48.6 ng/mL) was higher (P &lt;0.0001) than those of healthy controls (n = 104; 36.03 ng/mL). In CLL pts, sBCMA is significant in univariable analyses of TFT (HR 2.9 (95%CI, 2.0-4.2); P &lt; 0.0001) and OS (HR 2.5 (95%CI, 1.5-4.0); P &lt; 0.0003), and remains significant when adjusting for sex and CLL-IPI factors (HR 2.3 (95%CI, 1.6-3.3), P &lt; 0.0001; HR 1.9 (95%CI 1.1-3.1), P = 0.01, respectively). Conclusions: sBCMA is elevated in CLL pts compared to healthy controls. After adjusting for CLL-IPI and sex, sBCMA levels provided independent prognostic value in predicting TFT and OS in this cohort. Measuring sBCMA with a readily accessible ELISA-based test, provides incremental value over the current CLL-IPI model in predicting prognosis of CLL.