tbuckley/cabot-search huggingface dataset:
Abstract 2804: Identifying an optimal site for linker conjugation of the taccalonolides, novel microtubule stabilizing drugs
Authors: April L. Risinger, Lin Du, Antonius Ola, Robert H. Cichewicz, Susan L. Mooberry
Journal: Cancer Research (2018)

Abstract The taccalonolides are a structurally distinct class of microtubule stabilizers purified from the roots and rhizomes of plants of the genus Tacca. The covalent binding of taccalonolides bearing a C-22,23 epoxide to β-tubulin generates a distinct profile of microtubule stabilization that results in a high level of cellular persistence and the ability to circumvent multiple mechanisms of clinically relevant drug resistance, including expression of P-glycoprotein. The biological effects of 121 structurally distinct taccalonolides, including 23 isolated natural products and 98 semi-synthetic derivatives have been evaluated. These compounds range in potency from 0.6 nM to over 50 µM, allowing for detailed structure activity relationship studies. Some of the most potent taccalonolide derivatives include semi-synthetic modifications at C-6, C-7, or C-15 in combination with C-22,23 epoxidation. While these compounds did not have an acceptable therapeutic window for in vivo antitumor activity by systemic administration, they demonstrated highly effective and exquisitely persistent antitumor activity in a drug-resistant tumor model when delivered directly into the tumor. Additional studies were undertaken to see whether large chemical moieties could be added at these sites to facilitate targeted delivery of these compounds. In contrast to C-7 and C-15 derivatives, which are cleaved, C-6 modifications are stable and retain microtubule stabilizing and cytotoxic activities. In particular, fluorescent C-6 taccalonolide conjugates allowed, for the first time, direct visualization of these compounds in live cells, which co-localized with bundled microtubules. Further probing of the functionality at taccalonolide C-6 will allow for more detailed mechanistic studies of drug transport and distribution as well as optimization of a linker that could be used for antibody-based drug delivery. Citation Format: April L. Risinger, Lin Du, Antonius Ola, Robert H. Cichewicz, Susan L. Mooberry. Identifying an optimal site for linker conjugation of the taccalonolides, novel microtubule stabilizing drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2804.
Abstract 15866: Incidence and Severity of Left Atrial Scar in Older Patients With and Without Atrial Fibrillation
Authors: Sanghamitra Mohanty, Chintan Trivedi, Carola Gianni, Mahmut F Gunes, Yalcin Gokoglan, Rong Bai, John David Burkhardt, Javier Sanchez, Patrick Hranitzky, G. J Gallinghouse, Amin Al-Ahmad, Rodney Horton, Richard Hongo, Steven Hao, Salwa Beheiry, Michela Casella, Antonio Dello Russo, Claudio Tondo, Luigi Di Biase, Andrea Natale
Journal: Circulation (2015)

Background: Atrial fibrosis or scar is considered a substrate change related to atrial fibrillation (AF); by slowing conduction and increasing heterogeneity it could provide a substrate for AF. However, it is still not known whether AF causes the profibrotic changes in the left atrial wall or simply facilitates the manifestation of an existing aging-related structural remodeling in older patients. We examined scar prevalence and severity in patients aged ≥ 75 years with and without AF to address this question. Method: Five hundred seventy one patients undergoing radio-frequency catheter ablation for AF or supraventricular tachycardia (SVT) were included in this prospective analysis and classified into 2 groups; group 1: patients with AF (n=308, 62% male, median 77.8 (75 to 91) years, 46% paroxysmal and 64% persistent AF) and group 2: patients with diagnosis of SVT (n=263, 56% male, median 80 (75 to 88) years). Left atrial (LA) scarring was determined by three-Dimensional (3D) voltage mapping. Scar was defined as an area with a bipolar voltage amplitude ≤ 0.05 mV, indistinguishable from noise. The degree of scar was described as a percentage of the LA area (mild &lt;20%, moderate 20-60%, and severe &gt;60%) involved. Results: Age and gender distribution was similar in both groups. Left atrial scar was detected in 172 (56%) patients in group 1 and 134 (51%) in group 2 (p=0.24). After adjusting for age and gender in multivariable logistic model, diagnosis of AF or SVT did not show to have any association with the incidence of scar (p=0.22). Based on the 3D mapping, 52(30%) patients were classified as having mild LA scarring, 88(51%) moderate scar and 32(19%) with severe scar in group 1. Distribution of scar severity in group 2 was: mild 50(37%), moderate 67(50%), and severe in 17(13%), which was similar to that of AF patients (p=0.248). Conclusion: Similar prevalence and distribution of severity of the left atrial scarring in elderly patients with and without atrial fibrillation suggest age-dependent substrate remodeling to be the major contributor of scar formation. Our results indicate that scar could facilitate atrial fibrillation in predisposed subjects only.
MicroRNA Regulation and Cardiac Calcium Signaling
Authors: MasahideHarada, XiaobinLuo, ToyoakiMurohara, BaofengYang, DobromirDobrev, StanleyNattel
Journal: Circulation Research (2014)

MicroRNAs (miRNAs) are emerging as key control molecules in the regulation of gene expression, and their role in heart disease is becoming increasingly evident. Given the critical role of Ca2+ handling and signaling proteins in the maintenance of cardiac function, the targeting of such proteins by miRNAs would be expected to have important consequences. miRNAs have indeed been shown to control the expression of genes encoding important Ca2+ handling and signaling proteins, and are themselves regulated by Ca2+-dependent processes. Ca2+-related miRNAs have been found to be significant pathophysiological contributors in conditions like myocardial ischemic injury, cardiac hypertrophy, heart failure, ventricular arrhythmogenesis, and atrial fibrillation. This review is a comprehensive analysis of the present knowledge concerning miRNA regulation of Ca2+ handling processes, the participation of Ca2+-regulating miRNAs in the evolution of heart disease, the mutual relationship between Ca2+ signaling and miRNAs in...
The Orphan Nuclear Receptor Nur77 Suppresses Endothelial Cell Activation Through Induction of IκBα Expression
Authors: BeiYou, Yuan-YingJiang, ShaopingChen, GuijunYan, JianxinSun
Journal: Circulation Research (2009)

Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. Nur77 is highly expressed in vascular endothelial cells (ECs) and plays a role in the regulation of cell proliferation and angiogenesis; its role in vascular inflammation, however, remains unknown. Treatment of human umbilical vein ECs (HUVECs) with tumor necrosis factor (TNF)-α substantially increased the transcription and protein expression of Nur77 in a dose and time-dependent manner, as determined by Northern blot and Western blot analysis. Adenovirus mediated overexpression of Nur77 markedly increased the intracellular levels of IκBα by approximately 4-fold, whereas overexpression of dominant negative Nur77 (DN-Nur77), which lacks its transactivation domain, had no effect on IκBα expression, suggesting that Nur77 is an important transcriptional factor in controlling IκBα expression in ECs. Furthermore, overexpression of Nur77 significantly inc...
Effects of Adenosinetriphosphate and Potassium Chloride on Ventricular Fibrillation Induced by Lack of Substrates
Authors: MarioPenna, AlejandroIllanes, MarcosPupkin
Journal: Circulation Research (1962)

The perfusion of the isolated guinea pig or cat heart with a substrate-free Tyrode solution induces a decrease in rate, a lengthening of the P-R interval, a decreased amplitude of the R wave, ventricular premature contractions, A-V dissociation, insignificant changes of the Q-T interval, and, finally, ventricular fibrillation with a regular atrial rhythm. In isolated hearts of both species, the reversal of ventricular fibrillation induced by lack of metabolites was attempted as follows: in guinea pig hearts, increasing the potassium chloride concentration of the Tyrode solution without glucose to 5.4 mM/L. reversed ventricular fibrillation in all cases. Adenosinetriphosphate (ATP) reversed this arrhythmia in only two of seven cases. However, in the isolated cat heart, potassium chloride in the same concentration (5.4 mM/L.) reversed ventricular fibrillation only in three out of seven cases. ATP did not reverse ventricular fibrillation in any cases, but potassium given with ATP reversed this arrhythmia in ...
Abnormal Automaticity in Canine Purkinje Fibers Focally Subjected to Low External Concentrations of Calcium
Authors: ToyomiSano, TohruSawanobori
Journal: Circulation Research (1972)

The false tendon was isolated from the dog heart and mounted under a partition plate in the center of a chamber which was filled with Tyrode's solution. Two microelectrodes were positioned closely on either side of the plate and inserted into the false tendon. The partition did not alter repolarization of the action potential in normal Tyrode's solution. When EDTA was added to one side of the preparation, a low-plateau potential appeared after repolarization on the other side, which contained normal Tyrode's solution. This change occurred concurrently with a prolongation of the action potential in the calcium-free Tyrode's solution. The low-plateau potential was a reflection of the electrotonic potential from the nearby cells whose action potentials were prolonged. Repetitive firing of the action potential was frequently observed when abrupt differences in repolarization were recorded at close interelectrode distances. These results suggest that differences in repolarization of closely apposed cells can i...
Abstract 1763A: Single-cell RNA-sequencing reveals the immune contexture of triple-negative breast cancer tumors
Authors: Si Qiu, Ruoxi Hong, Zhenkun Zhuang, Shusen Wang
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is aggressive and associated with a higher risk of early relapse. The lack of estrogen receptor, progesterone receptor, and HER2 expression precludes the use of targeted therapies, and the high level of immune cell infiltration suggests that TNBC patients may benefit from immunotherapy. The design of immunomodulatory strategies for the TNBC treatment will tremendously benefit from a comprehensive understanding of the tumor infiltrated immune cell landscape of this cancer. To this end, we performed deep single cell RNA sequencing to 7,066 immune cells collected from 8 TNBC patients using the MIRALCS platform. We identified 13 immune cell subsets according to their transcriptome features. We found that the frequency of identified T cells and macrophages varied greatly across patients. We explored the diversity of tumor-infiltrating T lymphocytes and their functional states, and described the complicated and patient specific macrophage phenotypes. We also examined the single-cell expression level of immunotherapeutic target molecules in different immune cell subgroups. Our study gives an insight into the heterogeneity of the immune cell contexture of TNBC tumors, provides a valuable resource to understand the immune ecosystem of TNBC and may accelerate immunotherapies development on this breast cancer subtype. Citation Format: Si Qiu, Ruoxi Hong, Zhenkun Zhuang, Shusen Wang. Single-cell RNA-sequencing reveals the immune contexture of triple-negative breast cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1763A.
Abstract 3439: GATA3 mutation of luminal-type breast cancer patients in Taiwan
Authors: Shih Feng Tsai
Journal: Cancer Research (2018)

Abstract To investigate the mutation landscape of luminal-type breast cancer in Taiwan, we have conducted whole-genome sequencing on 20 cases of breast cancer, including 15 cases of those positive for estrogen receptor and 5 cases negative for estrogen receptor. Specifically, we searched for mutations in TP53, GATA3, and ESR1 genes. Additionally, we designed an amplificon sequencing scheme to interrogate the GATA3 coding sequences. GATA3 mutation has been previously reported to be correlated with suppression of proliferation upon aromatase inhibitor treatment. Also, the prevalence and clinical significance of GATA3 mutation-positive breast cancer differed between the TCGA cohort and the Fudan cohort. In our current series that focuses on breast cancer patients of Han Chinese living in Taiwan, we have identified 21 GATA3 mutations among 72 breast cancer tumor specimens screened by the amplicon sequence, and another 3 samples with GATA3 mutation by whole-genome sequencing. Notably, Pro409Alafs mutation occurred in six cases and this truncation mutation showed an average VAF of 0.155. A specific antibody was raised against the additional c-terminal amino acid sequence for the detection of the abnormally expressed proteins in these cases. As GATA3 is required for epithelial cell differentiation and as both normal breast luminal epithelium and estrogen-receptor-positive tumors showed high GATA3 expression, we are conducting further studies to demonstrate the clinical relevance of GATA3 mutation and the potential value of the Pro409Alafs as an outcome predictor for luminal-type breast cancer. Citation Format: Shih Feng Tsai. GATA3 mutation of luminal-type breast cancer patients in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3439.
MRX34, a liposomal miR-34 mimic and potential first-in-class microRNA therapeutic: activity in animal models of liver cancer.
Authors: Chris Daige, Leslie Priddy, Jason Wiggins, Terri Nelligan-Davis, Danlee Enzler, Komal Vadnagara, David Brown
Journal: Journal of Clinical Oncology (2016)

e14076 Background: Each miRNA modulates the expression of hundreds of genes across distinct cellular pathways, giving miRNA-based cancer therapy the potential to simultaneously repress multiple oncogenic processes in the tumor microenvironment, including growth and proliferation, resistance, cancer stem cells, metastasis, and immune evasion. The naturally occurring tumor suppressor miR-34a has been shown to down-regulate expression of > 30 oncogenes, as well as genes involved in tumor immune evasion (eg, PD-L1). MRX34, a liposome-encapsulated miR-34a mimic, is a potential first-in-class miRNA therapy for cancer. Methods: MRX34 activity was characterized in NOD/SCID mice with orthotopic liver tumors (Hep3B, HuH7, C3A, BN118, BN124). Biodistribution and biological activity were assessed using qRT-PCR and mRNA array analyses of tumor and tissues harvested 24 h after single IV injections of MRX34. In further experiments, we used serum AFP levels and recovered tumor weights to measure MRX34 efficacy, both as a single-agent and in combination with sorafenib. Results: miR-34a levels were significantly and dose-dependently elevated in liver tumor, liver, and lung samples from mice dosed with MRX34. Compared to mRNA levels in tumors from mice dosed with controls (empty liposomes, dilution buffer), levels of > 600 mRNAs were reduced by ≥ 30% in tumors from MRX34-treated mice. Single-agent MRX34 consistently inhibited tumor growth across the HCC models, with full tumor regression observed in > 70% of MRX34-treated animals. Therapeutic activity appeared to result from miR-34a repression of genes related to apoptosis and cell-cycle regulation. Combined MRX34 and sorafenib acted synergistically, yielding greater inhibition than either agent alone. Conclusions: MRX34 treatment resulted in increased miR-34a in tumor and decreased target gene expression that was dose-dependent and associated with tumor regression in multiple orthotopic murine models of liver cancer, with activity further enhanced in combination with sorafenib. MRX34 is currently being evaluated in a first-in-human trial of miRNA cancer therapy in patients with advanced malignancies, including HCC (NCT01829971).
Elevated Levels of 8-iso-Prostaglandin F2α in Pericardial Fluid of Patients With Heart Failure
Authors: ZiadMallat, IvanPhilip, MarylineLebret, DidierChatel, JacquesMaclouf, AlainTedgui
Journal: Circulation (1998)

Background—It has been suggested that oxidant stress may play a role in the pathophysiology of heart failure. However, no definitive information is available because most previous approaches used to measure oxidant stress are nonspecific, inaccurate, and unreliable. Methods and Results—To evaluate oxidant stress in the heart, we measured pericardial fluid levels of 8-iso-prostaglandin F2α (8-iso-PGF2α), a specific and quantitative marker of oxidant stress in vivo, in a series of 51 consecutive patients with ischemic and/or valvular heart disease referred for cardiac surgery. Pericardial levels of 8-iso-PGF2α were correlated with the functional severity of heart failure (NYHA classification) and with echocardiographic indices of ventricular dilatation measured by independent physicians. Pericardial levels of 8-iso-PGF2α were significantly increased in patients with symptomatic heart failure compared with asymptomatic patients and gradually increased with the functional severity of heart failure (P=.0003). ...
Abstract 5180: MicroRNA and triple negative breast cancer
Authors: BIN YI, Ruixia Ma, Yaguang Xi
Journal: Cancer Research (2018)

Abstract In 2017, a total of 252,710 new cases and 40,610 deaths from breast cancer in the United States were estimated by the American Cancer Society. Breast cancer is the most common malignancy and the second leading cause of death among American women. In this application, we will focus on triple negative breast cancer (TNBC), which is viewed by oncologists as a problematic and unpredictable sub-category of breast cancer because of higher rates of recurrence and poorer prognosis. TNBC accounts for up to 20% of all breast cancers and is highly prevalent in minority and young women. On average, 70% of women with metastatic TNBC die within 5 years, regardless of chemotherapy or other treatments. As such, there is an urgent medical need to develop more effective drugs to manage this deadly disease that raises a health disparity concern, especially in the State of Louisiana. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs for the treatment of pain, fever, and inflammation. Epidemiological studies have reported that the long term use of NSAIDs can prevent the occurrence multiple types of cancers, including breast cancer. However, their long term use for chemoprevention is not recommended because of toxicities associated with cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. Our results show that the NSAID, sulindac sulfide (SS) and two non-COX inhibitory derivatives, sulindac sulfide amide (SSA) and sulindac benzylamine (SBA), can significantly inhibit the growth of the major subtypes of TNBC cells (basal-like, mesenchymal, and luminal). In addition, the compounds significantly inhibit tumor cell invasion. While studying the mechanism, we found that four oncogenic miRNAs, miR-10b, miR-17, miR-21, and miR-9 can be downregulated by SS and derivatives, and they were reported to promote tumor metastasis exclusively. Therefore, we conclude that those oncogenic miRNAs are involved in anti-invasive activities of SS and derivatives in TNBC cells. Citation Format: BIN YI, Ruixia Ma, Yaguang Xi. MicroRNA and triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5180.
Abstract 2037: E-cadherin enhances immune control of metastatic melanoma
Authors: Bradley D. Shields, Brian Koss, Fade Mahmoud, Stephanie D. Byrum, Alan J. Tackett
Journal: Cancer Research (2018)

Abstract The advent of checkpoint blockade therapies has transformed the clinical management of metastatic melanoma. These monoclonal antibodies, targeted against CTLA-4 and PD-1, have shown durable and long-lasting responses in a subset of melanoma patients. However, response rates remain incomplete, even when using combination therapy (CTLA-4 plus PD-1). Identifying predictive or controlling features of responsiveness has been urgent goal in oncology research. Our group and others have previously shown responding tumors display high levels of E-cadherin, a cell-cell adhesion molecule which defines an epithelial-like phenotype. The varying clinical responses observed to checkpoint blockade in metastatic melanoma, paired with the knowledge that E-cadherin expression correlates with such responses, provides impetus to study the significance of E-cadherin in the context of checkpoint blockade. Here, we present a novel B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.E-cad). The parental B16F10 line does not express E-cadherin and is poorly immunogenic and notoriously resistant to treatment with immune checkpoint inhibitors. Thus, B16.E-cad and the vector control model epithelial-like (responsive) and mesenchymal-like (non-responsive) phenotypes respectively. We find, compared to vector control, B16.E-cad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo, despite similar proliferation rates in vitro. Analysis of immune cell infiltration (FACS) performed on tumors grown in C57/BL6 mice revealed no differences between vector, B16.Ecad and B16.SIY. Conversely, transplantation of B16.E-cad into Rag1-/-mice abrogated tumor growth delay indicating an immune-mediated tumor response. Additionally, B16.Ead tumors displayed greater responses to combination checkpoint inhibitor therapy. Further, imunohistochemistry for E-cadherin performed on patient pretreatment tumor biopsies revealed negative staining was predictive of a non-responsive status. These data indicate an epithelial-like phenotype in melanoma tumors facilitates tumor immunosurveillance and responsiveness to immune checkpoint blockade. Citation Format: Bradley D. Shields, Brian Koss, Fade Mahmoud, Stephanie D. Byrum, Alan J. Tackett. E-cadherin enhances immune control of metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2037.