tbuckley/cabot-search huggingface dataset:
Clinical Experience with Dipaxin and with the Combined Use of Prothrombopenic Agents
Authors: Ricardokatz, Héctorducci, Wernerroeschmann, Lucíatoriello
Journal: Circulation (1954)

The experience with a new prothrombopenic agent, Dipaxin, is presented. With a 30 mg. dose a prothrombin complex concentration under 30 per cent is reached in 41 hours or less. When associated with 1500 mg. of Tromexan the latent period is reduced to 24 hours. The prothrombopenic action of Dipaxin is readily counteracted with vitamin K1 administered either orally or intravenously.
Phase II study of a novel neoadjuvant chemotherapy (NAC) for breast cancer (BC).
Authors: Miguel E. Albino, Fernando Cabanillas, Orestes Antonio Pavia, Margarita Bruno, Miguel M. Echenique, Victor Carlo, Luisa Vanessa Marcial
Journal: Journal of Clinical Oncology (2012)

1060 Background: The goal of this NAC study was to improve the pathologic response of pts with localized BC. Methods: 51 pts with localized BC &gt;1 cm were treated with this novel regimen consisting first of docetaxel 75 mg/m 2 , epirubicin 80 mg/m 2 , and cyclophosphamide 500 mg/m 2 (TEC) and PEG Filgrastim for 4 cycles. Pretreament PET scan was done and repeated after course 1. Following the 4 th course, ER+/HER2- patients received 4 additional TEC cycles if they achieved CR by MRI, or were switched to a non cross-resistant regimen (vinorelbine, bevacizumab, capecitabine) if they had &lt; CR. HER2+ pts were given docetaxel + trastuzumab for 4 additional cycles, or were switched to a different regimen if &lt; PR. MD Anderson residual cancer burden (MDARCB) score was used to measure pathologic response and correlation with several prognostic factors was studied. Results: Median age = 53; 27 were postmenopausal; 42 had invasive ductal carcinoma, 5 invasive lobular; 12 triple negative, 11 HER2+, and 28 ER+ or PR+/HER2-. MDARCB was significantly better in HER-2+ and triple negative tumors (table). ER+ or PR+/Her2- pts had the least favorable MDARCB with none achieving 0 and only 21% attaining MDARCB=1. 59% of pts with &gt; 5% SUV drop attained MDARCB score 0-1 vs 13% with ≤ 5% drop. %Ki-67 correlated well with MDARCB (table). Ki-67 correlated well with receptor status: 85% of Triple Neg or Her2+ pts had Ki-67 &gt;17 vs only 29% of ER+ or PR+/Her2-. Conclusions: a) This novel NAC regimen leads to markedly favorable MDARCB scores in triple negative and Her-2+ cases. b) Several factors may be useful in predicting response to chemotherapy, including receptor status, Ki-67, and PET scan response after 1 st chemotherapy course. c) Ki-67 proliferative rate is closely correlated with receptor status. d) Early PET could be used to predict MDARCB. The challenge now is to improve response in ER+ or PR+/Her2- pts. [Table: see text]
Abstract 3072: MiRNA-2861 behaves as LCSC biomarker and regulates the HDAC5-ERK signal pathway
Authors: Yimin Zhu, Mengya Zhao, Lin Li
Journal: Cancer Research (2018)

Abstract Cancer stem cells (CSCs) are responsible for cancer initiating, recurrence and drug-resistance. Discovery of novel biomarkers for CSCs is helpful for early diagnosis and prognosis. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSCs differentiation model was established through introducing serum into the medium of H460 spheres. MiR-2861 expression was significant higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861.The role of HDAC5 in the regulation of LCSCs differentiation was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSCs differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy. Citation Format: Yimin Zhu, Mengya Zhao, Lin Li. MiRNA-2861 behaves as LCSC biomarker and regulates the HDAC5-ERK signal pathway [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 3072.
Tachycardia-Induced Change of Atrial Refractory Period in Humans
Authors: Wen-ChungYu, Shih-AnnChen, Shih-HuangLee, Ching-TaiTai, An-NingFeng, Benjamin Ing-TiauKuo, Yu-AnDing, Mau-SongChang
Journal: Circulation (1998)

Background—Atrial fibrillation (AF) has been shown to shorten the atrial effective refractory period (ERP) and make the atrium more vulnerable to AF. This study investigated the effect of atrial rate and antiarrhythmic drugs on ERP shortening induced by tachycardia. Methods and Results—Seventy adult patients without structural heart disease were included. For the first part of the study, right atrial ERP was measured with a drive cycle length of 500 ms before and after 10 minutes of rapid atrial pacing using five pacing cycle lengths (450, 400, 350, 300, and 250 ms) in 10 patients. For the second part of the study, the remaining 60 patients were included to study the effects of antiarrhythmic drugs on changes in atrial ERP induced by AF. Atrial ERP was measured with a drive cycle of 500 ms before and after an episode of pacing-induced AF. After the patients were randomized to receive one of six antiarrhythmic drugs (procainamide, propafenone, propranolol, dl-sotalol, amiodarone, and verapamil), atrial ERP...
Abstract 5505: GAN gene exon 8 SNP is related to gigaxonin expression and increased expression of e-cadherin in head and neck cancer
Authors: Albert Ko, Natarajan Venkatesan, Jenna Chatoff, Marco Morselli, Gregory Fishbein, Pascale Bomont, Matteo Pellegrini, Marilene Wang, Eri Srivatsan
Journal: Cancer Research (2018)

Abstract Gigaxonin is the protein product of Giant Axonal Neuropathy (GAN) gene and is involved in the processing of intermediate filaments of neural cells and vimentin fibers in fibroblasts. We have shown earlier that gigaxonin is associated with p16 in NFkB ubiquitination of cisplatin sensitive tumor cells. Our studies have shown that there is a direct relationship between the presence of exon 8 SNP (C&amp;gt;T) and expression of giagxonin in cancer cell lines. We have also seen an inverse relationship between exon 8 SNP and tumor recurrence and metastasis. RNA-seq studies of cancer cell lines and primary tumors have shown a direct relationship in the expression of gigaxonin to the expression of e-cadherin and inverse relationship to the expression of Vimentin and Zeb1. Immunohistochemical (IHC) studies of primary head and neck cancers have confirmed the inverse relationship between e-cadherin and vimentin. We hypothesize therefore that gigaxonin is involved in the ubiquitination of vimentin and cancer stem cell markers such as zeb1 resulting in the chemo sensitization of human tumor cells. Citation Format: Albert Ko, Natarajan Venkatesan, Jenna Chatoff, Marco Morselli, Gregory Fishbein, Pascale Bomont, Matteo Pellegrini, Marilene Wang, Eri Srivatsan. GAN gene exon 8 SNP is related to gigaxonin expression and increased expression of e-cadherin in head and neck 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 5505.
Abstract 16653: Clinical Outcome and Short-term Follow up After Surgical Unroofing of a Myocardial Bridge in Patients With Angina and No Obstructive Coronary Artery Disease
Authors: Vedant S Pargaonkar, Ingela Schnittger, Jennifer A Tremmel, Ian Rogers, Shigemitsu Tanaka, Ryotaro Yamada, Takumi Kimura, Michael Fischbein, R Scott Mitchell, Jack Boyd
Journal: Circulation (2015)

Introduction: Although a myocardial bridge (MB) is a common, generally benign anatomic variant, a small subset of patients experience severe anginal symptoms related to their MB, resulting in significant physical limitations and a poor quality of life. Surgical unroofing (supra-arterial myotomy) is a treatment option when medical management fails, but little is known regarding the clinical outcomes of patients who undergo surgical unroofing. Methods: A total of 34 patients (10 men, 24 women) with severe angina and a hemodynamically significant MB underwent surgical unroofing. All patients had failed medical management and had undergone extensive testing prior to surgery, including exercise echocardiography, coronary computerized tomography angiography, invasive coronary angiography, intravascular ultrasound (a MB was defined as an echolucent half-moon sign and/or ≥10% systolic compression), and hemodynamic testing using an intracoronary pressure and Doppler flow wire at rest and during dobutamine stress to calculate a diastolic fractional flow reserve (dFFR) (the ratio of diastolic intracoronary pressure divided by aortic pressure), as well as the peak Doppler flow velocity. An abnormal dFFR was defined as ≤0.76 during dobutamine stress. A Seattle angina questionnaire (SAQ) was administered to evaluate symptoms and quality of life before and after surgery. Results: The mean age was 45.1 ± 15.7 years and median follow-up was 6.6 (2 - 13) months after surgery. There were no major complications during the pre, intra, or post-operative period of the surgery. Following surgery, patients reported a significant improvement in all five dimensions of the SAQ (figure). Conclusions: In carefully selected patients with severe angina secondary to a hemodynamically significant MB who have failed medical management, surgical unroofing appears to be a safe and effective option for improving physical limitations, anginal symptoms, and overall quality of life.
Abstract 5886: Translational reprogramming of breast cancer and its role in tamoxifen resistance
Authors: Sofia Bakogianni, Phillip Geter, Amanda Ernlund, Rezina Arju, Abhilash Gadi, Robert J. Schneider
Journal: Cancer Research (2018)

Abstract Breast cancer is the most commonly diagnosed malignancy among women in the U.S. and the second leading cause of cancer-related deaths in women. The estrogen receptor-positive (ER+) breast cancer subtype comprises the majority (70-80%) of breast cancer cases and the majority of late recurrences. Anti-estrogen therapy with tamoxifen remains a cornerstone of adjuvant therapy for ER+ breast cancers in the premenopausal setting, but resistance is inevitable for a third of patients, leading to metastatic disease, which is responsible for the majority of breast cancer deaths. Our work demonstrates that tamoxifen resistance in ER+ breast cancer involves selective mRNA translation mediated by hyperactivation of mTOR and MNK1, two kinases that play major roles in mRNA translation. The hyperactivation of mTOR and MNK1 converges on eukaryotic translation initiation factor 4E (eIF4E) to increase its availability and mRNA selectivity. Using tamoxifen-sensitive and -resistant ER+ cells, we conducted genome-wide transcriptomic and translatomic analyses +/- silencing of eIF4E. We identified key genes responsible for tamoxifen resistance, whose mRNAs are selectively translationally upregulated with increased levels of eIF4E. RUNX2 is a key mRNA that is selectively translationally upregulated, which we show provides resistance by opposing estrogenic signaling and possibly phenotypically reprogramming the cell. Silencing of RUNX2 strongly resensitizes the cells to tamoxifen. We also show that RUNX2 impairs cellular proliferation and cell survival of previously drug-resistant cells in the presence of tamoxifen. Silencing of key translationally upregulated mRNAs, such as RUNX2, can partially restore endocrine therapy sensitivity. Using a tamoxifen-resistant ER+ PDX model, and patient-derived sensitive and resistant tumor tissues (no recurrence or recurrence within 5 years), we validated the hyperactivation of mTOR and MNK1, the overexpression of eIF4E, and selective mRNA translation in tamoxifen resistance. We hypothesize that selection for increased expression of RUNX2 and other selectively translated mRNAs promotes a more “basal-like,” estrogen-independent phenotype. We aim to determine how tamoxifen resistance translationally reprograms breast cancer cells to a different breast cancer phenotype (e.g., cancer stem cell-like, basal-like, luminal with disrupted ER signaling). Citation Format: Sofia Bakogianni, Phillip Geter, Amanda Ernlund, Rezina Arju, Abhilash Gadi, Robert J. Schneider. Translational reprogramming of breast cancer and its role in tamoxifen resistance [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 5886.
Akt Mediates the Cross-Talk Between β-Adrenergic and Insulin Receptors in Neonatal Cardiomyocytes
Authors: CarmineMorisco, GerolamaCondorelli, ValentinaTrimarco, AlessandroBellis, ChiaraMarrone, GianluigiCondorelli, JunichiSadoshima, BrunoTrimarco
Journal: Circulation Research (2005)

Upregulation of the sympathetic nervous system plays a key role in the pathogenesis of insulin resistance. Although the heart is a target organ of insulin, few studies have examined the mechanisms by which β-adrenergic stimulation affects insulin sensitivity in cardiac muscle. In this study, we explored the molecular mechanisms involved in the regulation of the cross-talk between β adrenergic and insulin receptors in neonatal rat cardiomyocytes and in transgenic mice with cardiac overexpression of a constitutively active mutant of Akt (E40K Tg). The results of this study show that β-adrenergic receptor stimulation has a biphasic effect on insulin-stimulated glucose uptake. Short-term stimulation induces an additive effect on insulin-induced glucose uptake, and this effect is mediated by phosphorylation of Akt in threonine 308 through PKA/Ca2+-dependent and PI3K-independent pathway, whereas insulin-evoked threonine phosphorylation of Akt is exclusively PI3K-dependent. On the other hand, long-term stimulati...
Interpretation of Transpulmonary Pressure Measurements in a Patient with Acute Life-Threatening Pulmonary Edema
Authors: Gaetano Florio, Simone Redaelli, Kenneth Shelton, Maddalena Teggia Droghi, Roberta Santiago, Francesco Marrazzo, Robert Kacmarek, Lorenzo Berra
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Increased Cardiac Adrenergic Drive Precedes Generalized Sympathetic Activation in Human Heart Failure
Authors: BengtRundqvist, MikaelElam, YrsaBergmann-Sverrisdottir, GraemeEisenhofer, PeterFriberg
Journal: Circulation (1997)

Background Previous studies with radiotracer methods have indicated increases in cardiac norepinephrine (NE) and renal NE spillover in patients with severe congestive heart failure (CHF). However, data on the regional sympathetic profile in early stages of CHF are limited. In this study, sympathetic function in the heart, kidneys, and skeletal muscle was evaluated in patients with mild-to-moderate CHF and compared with that in patients with severe CHF and healthy subjects. Methods and Results Total body and regional NE spillover from the heart and kidney was assessed with isotope dilution with steady state infusions of [3H]NE. Sympathetic nerve traffic to the skeletal muscle vascular bed (MSA) was recorded intraneurally. Cardiac NE spillover in patients with mild-to-moderate CHF (n=21) was increased threefold versus that in healthy subjects (n=12, P<.05), whereas total body and renal NE spillover and MSA did not differ from those in healthy subjects. In the severe CHF group (n=12), cardiac NE spillover wa...
TRAIL Promotes the Survival and Proliferation of Primary Human Vascular Endothelial Cells by Activating the Akt and ERK Pathways
Authors: PaolaSecchiero, AriannaGonelli, EdvigeCarnevale, DanielaMilani, AssuntaPandolfi, DavideZella, GiorgioZauli
Journal: Circulation (2003)

Background— TRAIL protein is expressed in the medial smooth cell layer of aorta and pulmonary artery, whereas endothelial cells express all TRAIL receptors (TRAIL-Rs). Methods and Results— The role of TRAIL/TRAIL-Rs in vascular biology was investigated in primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells, which showed comparable surface expression of death (TRAIL-R1 and -R2) and decoy (TRAIL-R3 and -R4) TRAIL-Rs. TRAIL activated the protein kinase Akt in HUVECs, as assessed by Western blot for phospho-Akt. Moreover, experiments performed with a pharmacological inhibitor of the phosphatidylinositol 3-kinase/Akt pathway (LY294002) or a dominant-negative Akt (K179M) demonstrated that TRAIL significantly protected HUVECs from apoptosis induced by trophic withdrawal via Akt and that inhibition of Akt sensitized HUVECs to TRAIL-induced caspase-dependent apoptosis. TRAIL also stimulated the ERK1/2 but not the p38 or the JNK pathways and induced a significant increase in endothe...
Abstract 5816: Inhibition of Hsp90 sensitizes pancreatic cancer in vitro and in vivo to chemo-radiotherapy
Authors: Ganji Purnachandra Nagaraju, Bassel F. El-Rayes
Journal: Cancer Research (2018)

Abstract Purpose: Important signaling pathways contributing to proliferation, development, metastasis and resistance to chemo-radiotherapy in pancreatic adenocarcinoma (PDAC) includes the PI3K/AKT/HIF-1α/STAT-3 pathway. The molecular chaperone heat shock protein 90 (HSP90) controls the activity, stability, turnover, and trafficking of many molecules involved in these major signaling pathways. Functional inhibition of HSP90 may inhibit these pathways simultaneously. We evaluated the efficacy of HSP90 functional inhibitor ganetespib in combination with chemo-radiotherapy against PDAC in vitro and in vivo. Methods and Materials: Cell proliferation (Br-dU), colony formation (clonogenic assay), migration (spheroid), and Western blot analyses were carried out in HPAC and PANC-1 PDAC cell lines to determine the effect of ganetespib alone or in combination with 5-FU+ 2Gy XRT. Tumor regression study of PDAC with ganetespib alone and in combination with chemo-radiation was analyzed in xenograft mouse models. Results: At the clinically achievable dose of 50 nM, ganetespib inhibited PDAC cells proliferation (p&amp;lt;0.001), potentiated 5-FU chemotherapy and 2Gy of ionizing radiation (p&amp;lt;0.001), and decreased the levels of survival molecules such as PI3K, p-AKT, and p-ERK in vitro. Additionally, ganetespib indeed potentiates the effects of chemo-radiation in both cell lines: significant decrease in colony formation as well as decrease in migration. Combinations of ganetespib and chemo-radiation therapy demonstrated synergistic ability in human xenograft mouse models (p&amp;lt;0.001). Conclusion: Ganetespib potentiates the effects of chemo-radiation in preclinical studies. Evaluating HSP90 inhibitors in PDAC patients is a rational approach in assessing the fatal PDAC. Citation Format: Ganji Purnachandra Nagaraju, Bassel F. El-Rayes. Inhibition of Hsp90 sensitizes pancreatic cancer in vitro and in vivo to chemo-radiotherapy [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 5816.
Abstract 38: Mitophagy deficiency promotes osteolytic bone metastasis in breast cancer
Authors: Rong Deng, Hai-Liang Zhang, Rui-Zhao Cai, Jun Tang, Xiao-Feng Zhu
Journal: Cancer Research (2018)

Abstract Introduction: Metastasis of breast cancer to the bone is a common complication and occurs in 65-80% of late-stage patients. Specifically, the development of osteolytic bone lesions increases patient morbidity and mortality with debilitating skeletal complications. Mitophagy is a selective form of autophagy that removes damaged or excessive mitochondria in response to various metabolic stresses. However, the role of mitophagy in development of cancer remains largely unclear. The Janus-faced role of mitophagy during tumorigenesis leads to a novel challenge when targeting it for cancer therapies. This study focuses on the role of mitophagy deficiency in breast cancer osteolytic bone metastasis, and explores the potential of rescuing mitophagy deficiency as possible therapeutic targets for metastatic disease. Methods: Specific single-guide RNAs (sgRNAs) were used to deplete ULK1 expression in breast cancer cell lines. Mitophagy was monitored by detecting Tom20 and Hsp60. In addition, mitochondrial DNA (mtDNA) was used to further confirm the reduction of mitochondrial mass. For bone metastasis studies, luciferase-tagged tumor cells were injected into the left cardiac ventricle of anesthetized female nude mice. Metastatic progression was monitored by bioluminescence imaging (BLI). Micro-CT imaging was used to detect bone volume, cortical wall thickness, trabecular thickness and number in mice of tibia. TRAP assay was used to detect osteoclast differentiation assays. Results: We found that the core Atg protein ULK1 was not only expressed at low level in breast cancer, but also required for hypoxia-induced mitophagy. ULK1-related mitophagy deficiency promoted the formation of metastatic osteolytic lesions in experimental bone metastasis mouse model with MDA-MB-231 cells. TRAP staining revealed that mature osteoclasts significantly increased in RAW264.7 cells treated with CM from ULK1-knockout breast cancer cells. In addition, MEK inhibitor trametinib was sufficient to upregulate the expression of ULK1 and reduced the release of cytokines, which is key to osteoclast differentiation via triggering mitophagy, thereby effectively blocking breast cancer osteolytic bone metastasis. Conclusion: In conclusion, we demonstrate the functional importance of mitophagy defect in breast cancer for promoting osteolytic bone metastasis. We also provide strong preclinical evidence for using MEK-ERK pathway inhibitors to disrupt ERK kinase-involved ULK1 degradation and induce mitophagy as a breast cancer bone metastasis therapy. Citation Format: Rong Deng, Hai-Liang Zhang, Rui-Zhao Cai, Jun Tang, Xiao-Feng Zhu. Mitophagy deficiency promotes osteolytic bone metastasis in 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 38.
Abstract P127: Ayurveda Improves Arterial Stiffness and Cardiometabolic Risk in Coronary Patients: A Prospective Pilot Study
Authors: RobertDuBroff, VasantLad, CristinaMurray-Krezan
Journal: Circulation (2014)

Introduction: Ayurveda is the ancient East Indian holistic approach to health that includes yoga, meditation, breathing exercises, medicinal herbs, and other practices. Although it has been practiced for nearly 5000 years there is little objective data regarding its efficacy in coronary disease. Hypothesis: Can the addition of Ayurveda to usual care improve markers and risk factors of cardiovascular disease? Methods: Twenty-six volunteers with a history of prior myocardial infarction, coronary bypass surgery, or coronary angioplasty/stent were recruited from the University of New Mexico cardiology clinics. Each patient underwent consultation with a single Ayurvedic specialist and received personalized instruction in daily yoga, meditation, breathing, medicinal herbs, and a caloric unrestricted Ayurvedic diet. Standardized measurements of arterial stiffness (pulse wave velocity) and cardiometabolic risk factors were obtained at baseline and after 90 days of therapy. Results: Nineteen patients, mean age 71....
Drug reaction with eosinophilia and systemic symptoms syndrome induced by combination of vemurafenib and cobimetinib in melanoma: A series of 11 cases
Authors: Barbara Brégeon, Claire Bernier, Nicolas Josselin, Lucie Peuvrel, Marie Le Moigne, Mélanie Saint-Jean, Gaëlle Quéreux
Journal: Journal of the American Academy of Dermatology (2018)