tbuckley/cabot-search huggingface dataset:
Association of Preoperative Antiviral Treatment With Incidences of Microvascular Invasion and Early Tumor Recurrence in Hepatitis B Virus–Related Hepatocellular Carcinoma
Authors: Zheng Li, Zhengqing Lei, Yong Xia, Jun Li, Kui Wang, Han Zhang, Xuying Wan, Tian Yang, Weiping Zhou, Mengchao Wu, Timothy M. Pawlik, Wan Yee Lau, Feng Shen
Journal: JAMA Surgery (2018)

A reduced incidence of microvascular invasion (MVI) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) may be associated with a decreased risk of early tumor recurrence and better survival after partial hepatectomy.To examine the association of preoperative antiviral treatment (AVT) with the incidences of MVI and posthepatectomy early tumor recurrence in HBV-related HCC.Data on a cohort of 2362 patients who underwent R0 resection for HBV-related HCC between January 2008 and April 2010 at the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China, were reviewed. The median (interquartile range) postoperative follow-up was 44.8 (22.8-59.3) months. Data were analyzed from June 2016 to October 2017.Preoperative AVT and partial hepatectomy.Overall survival and time to recurrence after surgery were calculated and compared using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Independent risk factors of MVI presence were assessed by logistic regression analysis.Among 2362 included patients, 1999 (84.6%) were men, and the median (interquartile range) age was 50.6 (43.1-57.3) years. A total of 2036 patients (86.2%) did not receive any preoperative AVT, while 326 (13.8%) received ongoing AVT more than 90 days before surgery. In the non-AVT group, compared with a preoperative HBV DNA level of less than 2000 IU/mL, a preoperative HBV DNA level of 2000 IU/mL or greater was associated with an increased risk of MVI (odds ratio [OR], 1.399; 95% CI, 1.151-1.701). Compared with the non-AVT group, patients receiving AVT had a lower incidence of MVI (38.7% [126 of 326] vs 48.6% [989 of 2036]; P = .001) and reduced risk of MVI (OR, 0.758; 95% CI, 0.575-0.998). A complete response to AVT was an independent protective factor of MVI (OR, 0.690; 95% CI, 0.500-0.952). Accordingly, preoperative AVT was associated with decreased 6-month, 1-year, and 2-year recurrences vs non-AVT (14.2%, 24.6%, and 38.5%, respectively, vs 23.4%, 37.1%, and 52.3%; P < .001); AVT was protective of early tumor recurrence (hazard ratio, 0.732; 95% CI, 0.605-0.886). In addition, patients in the non-AVT group were more likely to have multiple intrahepatic recurrences (49.1% [549 of 1119] vs 36.2% [54 of 149]; P = .003) and recurrences involving multiple hepatic segments compared with patients receiving AVT.A high preoperative HBV DNA level was an independent risk factor of MVI. Antiviral treatment administered more than 90 days before surgery was associated with reduced incidences of MVI and early tumor recurrence after partial hepatectomy for HBV-related HCC.
Abstract 4291: Oncogenic ALK regulates cell cycle progression via CDK1: Implications for therapy
Authors: Kathleen A. Scorsone, Sonal Gahlawat, Siddhartha Tyagi, Mayra C. Orellana, Thomas F. Westbrook, Ronald J. Bernardi
Journal: Cancer Research (2018)

Abstract Pharmacologic inhibition of oncogenic ALK can yield clinical responses in a variety of cancer types, including non-small cell lung cancer, anaplastic large-cell lymphoma, and neuroblastoma; however, de novo and acquired resistance remain major problems. As is seen with inhibition of other oncogenic receptor tyrosine kinases, ALK inhibition primarily induces G1 cell cycle arrest. However, we and others have also observed a role for receptor tyrosine kinases in regulating G2/M progression. For instance, oncogenic HER2 has been shown to directly phosphorylate tyrosine 15 of CDK1, the mitosis promoting factor. This tyrosine is also the well-known substrate of WEE1 and serves to inactivate CDK1 kinase activity as a critical component of the G2-M checkpoint. In the current study, we aimed to determine if oncogenic ALK functions in a similar capacity. We used recombinant proteins to demonstrate that ALK is also capable of directly phosphorylating tyrosine 15 of CDK1. Further, combined inhibition of ALK and WEE1 with crizotinib and AZD-1775 leads to greater reduction in pY15-CDK1 than either agent alone in ALK-amplified neuroblastoma cells. These findings suggest a model where oncogenic ALK and WEE1 provide redundant regulation of the G2-M checkpoint, which may be critical in cancer cells that have lost some of the usual complement of checkpoint controls, such as p53. Consequently, either ALK or WEE1 activity would be sufficient to maintain appropriate cell cycle regulation, while dual blockade would allow mitosis to proceed unchecked. In agreement with these predictions, we performed live cell imaging and observed that combined inhibition of ALK and WEE1 leads to aberrant mitotic progression and mitotic catastrophe. Further, this combination yields greater anti-proliferative activity than either agent alone in ALK-driven models. Thus, this therapeutic strategy holds great promise for ALK-driven cancers. Citation Format: Kathleen A. Scorsone, Sonal Gahlawat, Siddhartha Tyagi, Mayra C. Orellana, Thomas F. Westbrook, Ronald J. Bernardi. Oncogenic ALK regulates cell cycle progression via CDK1: Implications for therapy [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 4291.
Abstract 2021: The CXCL12/CXCR4 axis drives epithelial-mesenchymal transition in renal cell carcinoma
Authors: Alisa Zhilin-Roth, Jill A. Macoska
Journal: Cancer Research (2018)

Abstract Introduction. Renal cell carcinoma (RCC) is the one of the most common cancers diagnosed in adult men with more than 40000 new cases annually. Recurrence or metastasis of the disease occurs in more than 30% of patients and death from disease occurs in most of these patients due to limited therapeutic options. Clearly, a better understanding of factors contributing to RCC metastasis might improve therapeutic development and patient outcomes. One of the steps required for tumor cell progression from localized disease to metastatic disease is the acquisition of invasive abilities through epithelial to mesenchymal transition (EMT). EMT promotes loss of epithelial markers by downregulation of E-cadherin, gain of mesenchymal markers like Vimentin, and N-cadherin, and cytoskeletal rearrangement that enables cells to leave the primary site and intravasate into the blood or lymphatic systems and thereby colonize distant sites. Metastasis and colonization are highly directed mechanisms in which cancer cells migrate toward specific preferred organs that express specific protein receptors. One of these receptors is CXCR4, which is upregulated in advanced cancer including RCC and is correlated with poor survival. In this study we explored the hypothesis that CXCR4/CXCL12 signaling promotes migratory ability by inducing EMT in vitro in the RCC cell lines Caki-2 and 786-0. Methods. To pursue these studies we utilized in vitro mammalian cell culture, cell proliferation (WST) assays, cell migration (scratch) assays, and protein analysis methods including immunoblot and immunofluorescence. Results. These studies showed that RCC cell lines express CXCR4 that is activated by CXCL12 to induce cellular proliferation and promote a wound healing migratory response dependent on EMT cytoskeletal rearrangement by Rho GTPases. Moreover, CXCR4/CXCL12 induces down-regulation of E-cadherin, up-regulation of vimentin, N-cadherin and the upregulation of EMT transcription factors SLUG/SNAIL, consistent with EMT signaling activation. Lastly, CXCR4/CXCL12 activation promotes phosphorylation of AKT and ERK, suggesting that these signaling pathways are coupled to CXCR4/CXCL12-mediated RCC progression. Conclusions. Our findings suggest that CXCR4/CXCL12 activation in RCC has a pivotal role in EMT induction by the acquisition of a migratory and invasive phenotype. Understanding the underlying signaling pathways employed by the CXCL12/CXCR4 axis may shed new light on the migration/ invasion mechanisms that allow RCC cells to spread to distant organs and assist with the design and testing of new therapeutic strategies to treat advanced metastatic RCC. Citation Format: Alisa Zhilin-Roth, Jill A. Macoska. The CXCL12/CXCR4 axis drives epithelial-mesenchymal transition in renal cell carcinoma [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 2021.
Potential Therapeutic Targets for Cardiac Fibrosis
Authors: AndrewLeask
Journal: Circulation Research (2010)

Abstract: Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, “activated” fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the α-smooth muscle actin (α-SMA)–expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)β, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFβ, endothelin-1, Ang II, CCN2, and PDGF and to fibroblas...
Abstract 4328: hTERT protein expression, hTERT methylation and HPV infection in uterine cervical cancer
Authors: Pablo Moreno-Acosta, Mónica Molano, Nicolas Morales, Alfredo Romero-Rojas, Oscar Gamboa, Jinneth Acosta, Raynner Alvarez, Nicolas Magné, Nubia Muñoz
Journal: Cancer Research (2018)

Abstract The analysis of expression of the hTERT protein, the methylation status of the hTERT gene as the type of HPV infection, will contribute to deepen the role played by HPV infection in the expression and methylation of hTERT. The study included a group of one hundred fifty-five samples of women with squamous cell carcinomas of the uterine cervix in stage FIGO IIB-IIIB treated at the National Cancer Institute in Bogotá, Colombia. The expression of the hTERT protein was detected by immunohistochemistry both at the nuclear level and at the cytoplasmic level. In 79.7% of the cases, the protein was expressed at the nuclear level and 78% at the cytoplasmic level. HPV16, the most frequent viral type found, was detected by means of a GP5+/GP6+ mediated PCR- RLB in 84.4% and in 82.2% of the cases that expressed hTERT at the nuclear level and at the cytoplasmic level, respectively; with respect to HPV species, both at the nuclear level and at the cytoplasmic level, the species most frequently found was the alpha 9 species (HPVs 16, 31, 35, 52.58) followed by alpha 7 (HPVs 18, 45.59) and alpha 6 (HPVs 56, 66). In the multiple correspondence analyzes, a close relationship was observed between the cytoplasmic expression as nuclear of hTERT and the alpha species 9. A distant relationship was also observed between the expression of the protein and methylation, as well as between the non-methylation and the alpha 7 family of HPV; likewise, a distant relationship was observed between the non-methylation of hTERT and the alpha 9 species. The analyzes carried out show a possible relationship between the expression of the hTERT protein and the alpha 9 HPV species. Citation Format: Pablo Moreno-Acosta, Mónica Molano, Nicolas Morales, Alfredo Romero-Rojas, Oscar Gamboa, Jinneth Acosta, Raynner Alvarez, Nicolas Magné, Nubia Muñoz. hTERT protein expression, hTERT methylation and HPV infection in uterine cervical 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 4328.
Abstract 15975: Transmembrane Transport of Nitric Oxide in Endothelial Cells
Authors: Shiow-Shih Tang, Azad Raiesdana, Joseph Loscalzo
Journal: Circulation (2010)

Nitric oxide (NO) is a key endothelial cell (EC) signaling molecule that exerts its actions both within the EC and within heterologous target cells. Most investigators have assumed that NO traverse...
Interactions Between Ca2+ and H+ and Functional Consequences in Vascular Smooth Muscle
Authors: ClareAustin, SusanWray
Journal: Circulation Research (2000)

Abstract—Ca2+ and H+ ions can profoundly alter vascular tone. In many physiological and pathological processes, changes in the concentration of both ions occur. Thus, to understand the processes and mechanisms that modify force, it is necessary to understand what changes occur in these ions and, importantly, how they interact with each other. In this minireview, we highlight the quantitatively important mechanisms involved in the contractile responses of vascular tissues to pH change and discuss the cellular and molecular reasons underlying these responses.
Gene Transfer of Stromal Cell–Derived Factor-1α Enhances Ischemic Vasculogenesis and Angiogenesis via Vascular Endothelial Growth Factor/Endothelial Nitric Oxide Synthase–Related Pathway
Authors: Ken-ichiHiasa, MinakoIshibashi, KishoOhtani, ShujiroInoue, QingweiZhao, ShiroKitamoto, MasatakaSata, ToshihiroIchiki, AkiraTakeshita, KensukeEgashira
Journal: Circulation (2004)

Background— Stromal cell–derived factor-1α (SDF-1α) is implicated as a chemokine for endothelial progenitor cells (EPCs). We therefore hypothesized that SDF-1α gene transfer would induce therapeutic neovascularization in vivo by functioning as a chemokine of EPC. Methods and Results— To examine SDF-1α–induced mobilization of EPC, we used bone marrow–transplanted mice whose blood cells ubiquitously express β-galactosidase (LacZ). We produced unilateral hindlimb ischemia in the mice and transfected them with plasmid DNA encoding SDF-1α or empty plasmids into the ischemic muscles. SDF-1α gene transfer mobilized EPCs into the peripheral blood, augmented recovery of blood perfusion to the ischemic limb, and increased capillary density associated with partial incorporation of LacZ-positive cells into the capillaries of the ischemic limb, suggesting that SDF-1α induced vasculogenesis and angiogenesis. SDF-1α gene transfer did not affect ischemia-induced expression of vascular endothelial growth factor (VEGF) but...
Opioid Peptide Gene Expression Primes Cardiogenesis in Embryonal Pluripotent Stem Cells
Authors: CarloVentura, MargheritaMaioli
Journal: Circulation Research (2000)

Abstract—Zinc finger–containing transcription factor GATA-4 and homeodomain Nkx-2.5 govern crucial developmental fates and have been found to promote cardiogenesis in embryonic cells exposed to the differentiating agent DMSO. Nevertheless, intracellular activators of these transcription factors are largely unknown. In this study, pluripotent P19 cells expressed the prodynorphin gene, an opioid gene encoding for the dynorphin family of opioid peptides. P19 cells were also able to synthesize and secrete dynorphin B, a biologically active end product of the prodynorphin gene. DMSO-primed GATA-4 and Nkx-2.5 gene expression was preceded by a marked increase in prodynorphin gene expression and dynorphin B synthesis and secretion. The DMSO effect occurred at the transcriptional level. In the absence of DMSO, dynorphin B triggered GATA-4 and Nkx-2.5 gene expression and led to the appearance of both α-myosin heavy chain and myosin light chain-2V transcripts, two markers of cardiac differentiation. Moreover, dynorp...
Abstract 17837: The Correlation Between Complex Fractionated Atrial Electrogram and High Sensitivity-C Reactive Protein
Authors: DaisukeIshigaki, TakanoriArimoto, TadateruIwayama, NaoakiHashimoto, YuKumagai, SatoshiNishiyama, HirokiTakahashi, TetsuroShishido, TakuyaMiyamoto, JojiNitobe, HiroshiAoyama, TetsuWatanabe, IsaoKubota
Journal: Circulation (2014)

Introduction: Although complex fractionated atrial electrogram (CFAE) is purported to represent critical site for atrial fibrillation (AF) perpetuation, the mechanism and the significance of CFAE in the genesis of AF remain poorly understood. We investigated relationship between CFAE area and serum level of high-sensitivity C-reactive protein (hs-CRP). Hypothesis: CFAE area is correlated with serum level of hs-CRP in patients with AF. Methods: Consecutive 25 patients (20 men, 5 women, mean age 57±10 years) with drug resistant AF underwent first ganglionated plexi (GP) ablation were enrolled. Immediately before radiofrequency energy applications, blood sampling was obtained from systemic circulation. Three dimensional electroanatomical mapping of CFAE during AF was performed at least 100 points in the whole left atrium (LA). CFAE mapping was performed twice in all patients before and after GP ablation if AF was sustained. Results: CFAE area was estimated in all patients before GP ablation and in 17 patient...
Abstract 3432: Evolving genomes of breast cancer aromatase inhibitor resistance models
Authors: Reiner Hoppe, Siarhei Kandabarau, Ping Fan, V Craig Jordan, Hiltrud B. Brauch
Journal: Cancer Research (2018)

Abstract Acquired endocrine resistance is a severe barrier in the anti-hormonal treatment of breast cancer and is responsible for its failure in about half of the treated patients. In vitro models of long-term estrogen deprived breast cancer cells serve as laboratory tools to explore new therapeutic strategies. The models MCF-7:5C and MCF-7:2A mimic clinical AI resistance but regress with E2 due to the reconfiguration of survival signaling known as E2-inducible apoptosis (5C rapid, 2A delayed reaction). Alterations of stress related pathways including the accumulation of endoplasmic reticulum stress, oxidative stress, and inflammatory stress that occur prior to E2-induced apoptosis (Ariazi et al. 2011; Fan et al. 2013, 2015; Sweeney et al. 2014) and specific miRNA expression profiles (Hoppe et al Oncotarget 2016) have been linked with these resistance and E2-inducible apoptosis phenotypes. Little is known on their underlying genetic variability. Here we compare the mutational profiles of 5C and 2A clones with those of the estradiol stimulated growth sensitive MCF-7:WS8 and standard MCF-7 (ATCC) cells. Whole genome libraries were sequenced on the Illumina HiSeq platform (2x150bp reads). Alignments were manually inspected (bcftools mpileup) to avoid false negative variant calling in poorly (&amp;lt;20x) covered regions. Loci with at least 10x coverage and absence of any variant reads were classified as wildtype. The coding genome positions defined as mutant or wildtype in all four cell types served as a basis to select candidate mutations for the verification of MCF-7 variants via comparison to the COSMIC database (http://cancer.sanger.ac.uk/cosmic) and identification of novel mutations by variant calling (GATK HaplotypeCaller). Putative protein effects of variants were predicted by the SnpEff tool. We verified 421 point mutations in MCF-7 (COSMIC) of which 203 mutations were lost in our models, with additional specific losses of 4, 4, and 18 mutations in WS8, 2A and 5C, respectively. In 5C cells new mutations affected 261 genes with 31 high impact mutations based on splice site alterations in 7 genes (i.e. CERS2, SEMA3A, TDRD7, ATP5H) and gain of stop codons in 24 genes (i.e. CACNA1S, NOTCH4, SUN1, JPH3, SERPINB2). Similarly, in 2A cells there were 12 high impact mutations among 122 affected genes (e.g. ARHGEF5, ARHGAP35, ARAP2). We will report on the integrative genomic analysis including larger structural variants (short indels and CNVs) towards the evolution of these models for a comprehensive understanding of the biology of E2-inducible apoptosis. Citation Format: Reiner Hoppe, Siarhei Kandabarau, Ping Fan, V Craig Jordan, Hiltrud B. Brauch. Evolving genomes of breast cancer aromatase inhibitor resistance models [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 3432.
Abstract 5818: Globally optimizing therapeutic combinations against bortezomib-resistant multiple myeloma using a quantitative parabolic optimization platform
Authors: Masturah Rashid, Tan Boon Toh, Lissa Hooi, Aleidy Silva, Yanzhou Zhang, Neerja Karnani, Sudhakar Jha, Chih-Ming Ho, Wee Joo Chng, Dean Ho, Edward Kai-Hua Chow
Journal: Cancer Research (2018)

Abstract Multiple myeloma is an incurable hematological malignancy that relies on drug combinations as first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these drug combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure. Thus, there remains a need to identify improved drug combinations that may serve as later lines of treatment for improved treatment against bortezomib-resistant multiple myeloma. We have developed the quantitative parabolic optimization platform (QPOP) to optimize drug combinations against bortezomib-resistant multiple myeloma. By mapping phenotypic output data to parabolic response surfaces, QPOP is able to deterministically optimize drug combinations as well as drug dosages. By continuously optimizing in multiple systems of interest, from in vitro to in vivo, drug combinations can be globally optimized for greater efficacy in increasingly complex biological systems. While QPOP does not rely on molecular mechanism modeling or prediction, identified optimal drug combinations can reverse DNA hypermethylation and silencing of tumor suppressors that occurs following acquired bortezomib-resistance in multiple myeloma. Furthermore, this drug combination is broadly effective across a range of primary multiple myeloma patient samples. Beyond bortezomib-resistant multiple myeloma, global optimization of drug combinations by QPOP can serve to improve drug combination design across a range of other cancers and diseases through a continuous optimization process across the entire drug development pipeline. Citation Format: Masturah Rashid, Tan Boon Toh, Lissa Hooi, Aleidy Silva, Yanzhou Zhang, Neerja Karnani, Sudhakar Jha, Chih-Ming Ho, Wee Joo Chng, Dean Ho, Edward Kai-Hua Chow. Globally optimizing therapeutic combinations against bortezomib-resistant multiple myeloma using a quantitative parabolic optimization platform [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 5818.
Abstract 83: β1 Vs β2 Adrenergic Signaling Differentially Regulates Mitochondrial Dynamics Through Alterations In Calcineurin And Drp1
Authors: MichaelCoronado, GiovanniFajardo, MingmingZhao, DongquingHu, AleksandrStotland, SushmaReddy, RobertaGottlieb, DanielBernstein
Journal: Circulation Research (2014)

Signal transduction through β1 and β2-adrenergic receptors (ARs) is considered a primary mechanism for regulating cardiovascular function and remodeling. Upon β-AR activation (i.e., physical activity, cardiac pathology) inotropy and chonotropy increase and mitochondria must quickly meet increased energy demand. This suggests that βARs and mitochondria are coupled mechanistically to rapidly respond to the functional and energetic needs of the heart. To investigate the role of β1 vs. β2-AR signaling on mitochondrial dynamics, we compared β1-/- and β2-/- to WT controls. β2-/- had increased mitochondrial fragmentation (increased number and decreased size) by electron microscopy vs. both WT and β1-/-. β2-/- showed altered regulation of mitochondrial fission: increased Drp1 translocation to the mitochondria vs. WT, whereas β1-/- had lower Drp1 translocation. These data suggest differential regulation of fission by βAR signaling, β1 activating and β2 suppressing fission. Since Ca2+-dependent calcineurin is known...