tbuckley/cabot-search huggingface dataset:
Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes
Authors: David Nanchen, Baris Gencer, Olivier Muller, Reto Auer, Soheila Aghlmandi, Dik Heg, Roland Klingenberg, Lorenz Räber, David Carballo, Sebastian Carballo, Christian M. Matter, Thomas F. Lüscher, Stephan Windecker, François Mach, Nicolas Rodondi
Journal: Circulation (2016)

Patients with heterozygous familial hypercholesterolemia (FH) and coronary heart disease have high mortality rates. However, in an era of high-dose statin prescription after acute coronary syndrome (ACS), the risk of recurrent coronary and cardiovascular events associated with FH might be mitigated. We compared coronary event rates between patients with and without FH after ACS.We studied 4534 patients with ACS enrolled in a multicenter, prospective cohort study in Switzerland between 2009 and 2013 who were individually screened for FH on the basis of clinical criteria according to 3 definitions: the American Heart Association definition, the Simon Broome definition, and the Dutch Lipid Clinic definition. We used Cox proportional models to assess the 1-year risk of first recurrent coronary events defined as coronary death or myocardial infarction and adjusted for age, sex, body mass index, smoking, hypertension, diabetes mellitus, existing cardiovascular disease, high-dose statin at discharge, attendance at cardiac rehabilitation, and the GRACE (Global Registry of Acute Coronary Events) risk score for severity of ACS.At the 1-year follow-up, 153 patients (3.4%) had died, including 104 (2.3%) of fatal myocardial infarction. A further 113 patients (2.5%) experienced nonfatal myocardial infarction. The prevalence of FH was 2.5% with the American Heart Association definition, 5.5% with the Simon Broome definition, and 1.6% with the Dutch Lipid Clinic definition. Compared with patients without FH, the risk of coronary event recurrence after ACS was similar in patients with FH in unadjusted analyses, although patients with FH were >10 years younger. However, after multivariable adjustment including age, the risk was greater in patients with FH than without, with an adjusted hazard ratio of 2.46 (95% confidence interval, 1.07-5.65; P=0.034) for the American Heart Association definition, 2.73 (95% confidence interval, 1.46-5.11; P=0.002) for the Simon Broome definition, and 3.53 (95% confidence interval, 1.26-9.94; P=0.017) for the Dutch Lipid Clinic definition. Depending on which clinical definition of FH was used, between 94.5% and 99.1% of patients with FH were discharged on statins and between 74.0% and 82.3% on high-dose statins.Patients with FH and ACS have a >2-fold adjusted risk of coronary event recurrence within the first year after discharge than patients without FH despite the widespread use of high-intensity statins.
Abstract 201: Tribble 3 as integrator of metabolic stresses during lung cancer progression
Authors: Abeer Almiman, Jamila Adom, Yande Guo, Jiuhui Wang, Daotai Nie
Journal: Cancer Research (2016)

Abstract Introduction: Tribbles pseudokinase 3 (TRIB3) has been identified as a stress related gene. Recent studies reported the increased expression of TRIB3 in cancers and its correlation with the poor prognosis in cancer patients. However, other studies suggest TRIB3 as a tumor suppressor due to its inhibitory activities toward PI3K/Akt and Mek-Erk signaling. In the present study, we aim to investigate the expression of TRIB3 in lung cancer cells and whether it plays a role in lung cancer progression and responses toward chemotherapy. Methods: TRIB3 expression was determined by RT-PCR and Western blot. A lentiviral vector was used to overexpress TRIB3 in lung cancer cells. Small hairpin RNA constructs targeting TRIB3 were used to deplete TRIB3 expression. A CRISPR-CAS9 construct with guiding sequence matching to TRIB3 gene was used to knock out its expression. Cell proliferation, survival, and migration were determined using standard techniques. Results: Through in silico analyses, we found that high level of TRIB3 RNA was associated with poor survival of lung cancer patients. In lung cancer cells (NCI-H358), TRIB3 expression was markedly stimulated during metabolic stresses or ER stresses. Overexpression of TRIB3 in cells led to decreased cell proliferation and increased arrest at G0/G1 phase, even when the cells were not under overt metabolic stresses. RT-qPCR analyses of cell cycle proteins revealed an upregulation of p27, a CDK inhibitor, in cells overexpressing TRIB3. Overexpression of TRIB3 reduced Akt phosphorylation at threonine 308. Depletion or knockout of TRIB3 led to increased cell growth but cells became more sensitive to stressors, leading to increased apoptotic cell death. Conclusion: Our study reveals complex roles of TRIB3 in lung cancer progression. Induced by metabolic stresses, TRIB3 can block cell cycle progression through p27 in adaptive responses. Further studies are needed to determine whether and how TRIB3 functions as a metabolic gatekeeper during lung cancer progression. Citation Format: Abeer Almiman, Jamila Adom, Yande Guo, Jiuhui Wang, Daotai Nie. Tribble 3 as integrator of metabolic stresses during lung cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 201.
Abstract 764: LOX and LOXL2 inhibition as a treatment for ovarian cancer
Authors: Angela Cho, Amanda L. Hudson, Samuel Yuen, Nham Tran, Viive M. Howell, Emily K. Colvin
Journal: Cancer Research (2016)

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women. Despite advances in our understanding of the molecular biology of EOC, patient survival has not significantly improved in decades and new treatments are needed. There is increased interest in therapeutic targeting of the tumor microenvironment (TME). The lysyl oxidase (LOX) family of enzymes are involved in extracellular matrix remodelling through crosslinking of collagen and elastin. They have been shown to play an important role in the TME of other cancers and are regulated by hypoxia, however little is known about their role in EOC. Therefore we aimed to investigate the role of LOX and LOXL2 in EOC using in vitro models. Tumor epithelial (n = 2) and matched cancer-associated fibroblast cell lines (n = 2) derived from an SV40-induced mouse model of EOC were generated. MTT assays were performed on all cell lines to assess the effect of LOX and LOXL2 inhibition on cell viability. The effect of LOX and LOXL2 inhibition on cancer cell migration and invasion towards cancer-associated fibroblast conditioned media was also investigated using transwell assays. RNA and protein were isolated and analysed from cells cultured in normoxic and hypoxic conditions to assess whether LOX and LOXL2 gene and protein expression is regulated by hypoxia. Inhibition of LOX and LOXL2 did not affect cell viability. LOX and LOXL2 inhibition significantly reduced the migration and invasion of EOC cells towards cancer-associated fibroblast conditioned media in vitro (p&amp;lt;0.05). Gene expression analysis comparing Lox and Loxl2 expression in all cell lines demonstrated a significant increase in Lox and Loxl2 expression in cells cultured in hypoxia (p&amp;lt;0.05). Similarly, cellular and secreted LOX and LOXL2 protein expression was increased in cells cultured in hypoxic conditions, supporting hypoxia as a regulator of LOX and LOXL2 expression. This study demonstrates a role for LOX and LOXL2 in promoting migration and invasion of EOC cells in vitro. The upregulation of LOX and LOXL2 in hypoxia suggests a role in facilitating tumor growth and progression within hypoxic tumors. These results provide support for the utility of LOX and LOXL2 inhibition as promising and novel therapeutic strategies in EOC. Citation Format: Angela Cho, Amanda L. Hudson, Samuel Yuen, Nham Tran, Viive M. Howell, Emily K. Colvin. LOX and LOXL2 inhibition as a treatment for ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 764.
Abstract 3566: Glycosylation of the TNFR1 death receptor controls cell fate
Authors: Andrew Holdbrooks, Matthew J. Schultz, Zhongyu Liu, Daniel Bullard, Susan L. Bellis
Journal: Cancer Research (2016)

Abstract Activation of the TNFR1 death receptor by TNFα can induce cell survival or cell death signaling, however, the mechanisms regulating this TNFR1 signaling switch are poorly understood. TNFα-induced apoptosis is reported to require higher-order clustering and internalization of activated TNFR1, whereas surface retention of the activated receptor has been shown to promote survival signaling mediated by NFκB and MAPKs. Studies from our group have identified a novel glycosylation-dependent mechanism that controls this signaling switch. Specifically, we have found that TNFR1 localization and activity are regulated by the addition of a distinct sugar, an α2-6 linked sialic acid, by the enzyme ST6Gal-I, a Golgi sialyltransferase whose expression is upregulated in many cancer types. The sialylation effect on TNFR1 was examined in epithelial and monocytic cancer cell lines with forced overexpression or knockdown of ST6Gal-I, as well as in primary monocytes obtained from mice with ST6Gal-I knock-in or knockout. Data from these models indicate that α2-6 sialylation of TNFR1 blocks TNFα-induced apoptosis, and the suggested mechanism underlying this inhibition of apoptosis is the sialylation-driven inhibition of TNFR1 oligomerization and internalization, as observed through immunoblotting, immunocytochemistry and flow cytometry. Considering sialylated TNFR1 is retained on the plasma membrane following activation, we hypothesize that ST6Gal-I functions to not only block TNFR1-mediated cell death but also divert the cell's activity to favor survival. Supporting this hypothesis, cells with elevated levels of ST6Gal-I exhibit heightened expression and activation of many pro-survival factors, such as NFκB, MAPKs and AKT, in addition to decreased activation of caspase-3. Since levels of ST6Gal-I are elevated in multiple tumor cell populations, our group proposes that ST6Gal-I protects tumor cells against TNFα-induced apoptosis within the inflammatory tumor microenvironment. As preliminary support for this concept, peritoneal ascites fluid was collected from ovarian cancer (OC) patients, and the acellular, cytokine-rich fraction was incubated with OC cell lines with or without forced ST6Gal-I expression. Expression of ST6Gal-I conferred strong protection against cell death induced by soluble ascites. Based on these collective findings, we postulate that sialylation of TNFR1 by ST6Gal-I diverts the cellular response to TNFα from apoptosis to survival, providing a mechanism by which tumor cells can evade immune cell killing. Citation Format: Andrew Holdbrooks, Matthew J. Schultz, Zhongyu Liu, Daniel Bullard, Susan L. Bellis. Glycosylation of the TNFR1 death receptor controls cell fate. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3566.
C-11-METHIONINE PET AND RADIOTHERAPY DOSE DISTRIBUTION IN THE DIFFERENTIATION OF RADIONECROSIS AND TUMOUR PROGRESSION AFTER RADIOSURGERY OF BRAIN METASTASES
Authors: M. A. A. M. Heesters, H. L. van der Weide, Rene Bolt, R. H. Enting, Andor Glaudemans, H. P. Bijl, van Marc Dijk, Johannes Langendijk
Journal: Neuro-Oncology (2012)
Abstract 3681: Nischarin disruption promotes breast tumor development in mouse models
Authors: Shengli Dong, Suresh K. Alahari
Journal: Cancer Research (2016)

Abstract Nischarin is a novel tumor suppressor that was first discovered and characterized in our laboratory. The accumulating evidence suggests that Nischarin is a critical regulator of cell migration and breast tumor growth, metastasis and invasion. However, little is known about the exact function of Nischarin in in vivo physiological conditions, probably due to lack of any transgenic Nischarin animals. We recently generated Nischarin knockout mouse. This Nischarin knockout mouse has a dramatic unusual phenotype of mammary development and overall growth defect. Nischarin knockout mice do not spontaneously develop breast tumors. To determine the importance of Nischarin in regulation of breast cancer development, we bred Nischarin knockout virgin mice with PyMT (polyoma middle T antigen) and Neu background mice and the progeny produced tumors exclusively in the mammary gland. We found Nischarin knockout virgins with PyMT accelerated breast cancer onset and progression, which further suggests Nischarin inhibits tumor growth. Mammary epithelial cells (MECs) are surrounded by basement membrane, which mainly consists of extracellular matrix. We noted that the basement membrane of Nischarin knockout virgins contain much more collagen and fibronectin than those of wild type virgins. In addition, we observed that Nischarin disruption significantly changed extracellular acidification rates (ECAR) in mouse primary breast tumour cells. We suspected that this changed acidic microenvironment might facilitate breast tumor progression. Recent studies indicated that clinical anti-diabetic drug Metformin, an AMPK activator, inhibits breast cancer cell growth. Our data show that Het-PyMT and Null-PyMT primary cells were much more sensitive for metformin treatment. Thus we examined the importance of AMPK signaling in our mouse models. Interestingly, both tumor tissues and primary cells derived from Null-PyMT breast tumors had lower AMPK activity. Together, our data strongly support that Nischarin disruption promotes breast tumor development and AMPK signaling is important for Nischarin-mediated suppression of breast tumor. Citation Format: Shengli Dong, Suresh K. Alahari. Nischarin disruption promotes breast tumor development in mouse models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3681.
Biologic risk model development for recurrent and second primary tumors (SPTs) in patients (pts) with early stage non-small cell lung cancer (ES NSCLC).
Authors: K. A. Gold, E. S. Kim, J. Lee, C. Behrens, L. Solis, D. Liu, P. Yuan, B. D. Casey, I. I. Wistuba, W. K. Hong
Journal: Journal of Clinical Oncology (2010)

e17503 Background: Pts with ES NSCLC are at significant risk for recurrence or SPTs. Identifying higher risk pts is key to personalizing therapy. Goals of the Vanguard trial are to assess smoking-related disease-free survival and to develop a risk model, utilizing a large cohort of archived ES NSCLC specimens, to predict the risk of recurrence or SPTs in this high risk group. Methods: Pts on the phase II prospective Vanguard study had definitively treated ES NSCLC or head and neck cancer and were current/former smokers. Pts had bronchoscopies with biopsies at 6 predefined sites at enrollment, 12, 24, and 36 months (mos). Serum was collected every 6 mos for 3 yrs. ES NSCLC pt specimens identified in our tumor bank were used to explore promising biomarkers; pathological and clinical data was collected for all pts. Results: 54 pts (46 eligible) were enrolled in the Vanguard trial between 12/04 and 2/09. Median age 61 yrs (42-81); 26 (57%) were male. 42 pts had NSCLC; stage I 32 (76%), II 8 (19%), IIIA 2 (5%). 9 pts (21%) have recurred and 3 pts (7%) have SPTs so far. 37 pts (80%) have completed bronchoscopy at 12 mo, 21 pts (46%) at 24 mos, 10 pts (22%) at 36 mos. 27 pts remain on study. Analyses are planned on biopsy specimens to characterize molecular changes in bronchial epithelium over time. Tumor specimens from 521 pts with ES NSCLC from 2002-2005 were also collected with outcome data. Tissue microarrays have been constructed from archived tumor specimens and numerous biomarkers were tested, including members of IGF, EGF, and apoptotic pathways. On multivariate analyses, several markers correlate with overall survival, including pAMPK (p=0.002), MCM6 (p=0.014), and CXCR2 (p=0.003). Conclusions: This is a unique pt cohort with prospectively collected bronchial specimens over a 3 yr follow-up period. Also, we have assembled a large matched population of over 500 archived ES NSCLC specimens. Molecular testing performed in archived specimens will be validated in the Vanguard pts, which will allow for analysis of progressive molecular changes in bronchial epithelium over time. With these results, we will establish a risk model for development of recurrence or SPTs in ES NSCLC pts. (DoD W81XWH-04-1-0142) No significant financial relationships to disclose.
Patient eligibility and trial design for the salvage therapy of advanced urothelial carcinoma (UC) based on the impact of prognostic factors.
Authors: Guru Sonpavde, Joaquim Bellmunt, Jonathan E. Rosenberg, Dean F. Bajorin, Ashley Marie Regazzi, Toni K. Choueiri, Angela Q. Qu, Guenter Niegisch, Peter Albers, Andrea Necchi, Giuseppe di Lorenzo, Ronan Fougeray, Yu-Ning Wong, Srikala S. Sridhar, Yoo-Joung Ko, Matthew I. Milowsky, Matt D. Galsky, Gregory Russell Pond
Journal: Journal of Clinical Oncology (2014)

4514 Background: The prognostic impact of number of lines of prior chemotherapy, prior perioperative chemotherapy, prior platinum agent and site of primary tumor in salvage trials for advanced UC is unknown. This knowledge can inform trial design, stratification and eligibility criteria. Methods: Ten phase II trials of salvage therapy for advanced UC were pooled for data on the number of prior lines, prior perioperative chemotherapy, prior platinum (cisplatin, carboplatin) and site of primary (bladder vs. other) in addition to TFPC (time from prior chemotherapy), Hb (hemoglobin), PS (performance status), and LM (liver metastasis) status. Cox proportional hazards regression was used to evaluate the association of variables with overall survival (OS). Trial was included as a stratification factor. Results: The trials evaluated vinflunine (N=151), docetaxel +/- vandetanib (N=148), paclitaxel-gemcitabine (N=98), sunitinib (N=77), volasertib (N=50), nab-paclitaxel (N=48), everolimus (N=45), pazopanib (N=43), cetuximab +/-paclitaxel (N=39) and paclitaxel-cyclophosphamide (N=32). Of 731pts, 711 were evaluable for prior number of lines and perioperative chemotherapy, 663 for prior platinum and 512 for site of primary. The number of prior lines of therapy were 1 in 559 (78.6%), 2 in 111 (15.6%), and ≥3 in 41 (5.8%) pts. Prior perioperative chemotherapy was given to 277 (39.1%) and chemotherapy for metastatic disease to 454 (64.1%) pts. Prior platinum was cisplatin in 501 (75.6%), carboplatin in 216 (32.6%) and both in 57 (8.6%). Bladder was the primary site in 388 (75.8%). On univariate analyses, shorter TFPC, low Hb, low PS, LM, prior carboplatin and non-administration of prior perioperative chemotherapy were associated with worse OS (p<0.05 for all). On multivariate analyses, TFPC, Hb, PS and LM were significantly associated with OS, but none of the other factors were independently significant. Conclusions: These data imply that randomized trials in previously treated pts with advanced UC should stratify for TFPC, Hb, PS and LM status and may allow prior perioperative chemotherapy and not limit eligibility to only one prior therapy.
Risk for Incident Atrial Fibrillation in Patients Who Receive Antihypertensive Drugs
Authors: Beat A. Schaer, Cornelia Schneider, Susan S. Jick, David Conen, Stefan Osswald, Christoph R. Meier
Journal: Annals of Internal Medicine (2010)

Different antihypertensive drug classes may alter risk for atrial fibrillation. Schaer and associates identified hypertensive patients with new atrial fibrillation and matched each to a hypertensiv...
MicroRNA Mir-155 and Myb Proto-Oncogene Family Members Cooperate in Pathogenesis of Chronic Lymphocytic Leukemia.
Authors: Tomas Stopka, Karin Vargova, Pavel Burda, Juraj Kokavec, Nikola Curik, Adela Berkova, Marek Trneny, Arthur Skoultchi, Jiri Zavadil
Journal: Blood (2009)
Abstract 1630: Dysregulation of Hippo pathway in metastatic prostate cancer
Authors: Jen-Ming Huang, Gina C-Y Chu, Hyung L. Kim, Haiyen E. Zhau, Leland W.K. Chung.
Journal: Cancer Research (2016)

Abstract Background: Prostate cancer (PCa) is prevalently diagnosed and more than 80% of late stage PCa patients develop bone metastases. We hypothesized that the selective lodging of the PCa cells in the bone can be contributed by increased RANK-mediated cell signaling network. Cancer cell-derived RANKL orchestrates a complex bone-remodeling program facilitating PCa bone colonization through the activation of specific transcription factors (TFs) promoting PCa-bone microenvironment interaction through increased epithelial to mesenchymal transition (EMT), cell growth, and osteomimicry. Overexpression of RNAKL in indolent LNCaP cells drives cancer bone and soft tissue metastases. Methods and Results: Microarray gene expression was performed to compare RANKL- and Neo-vector- transfected LNCaP cells, LNCaPRANKL and LNCaPneo, respectively. qRT-PCR and western blot were performed to confirm the expression of RANKL-targeted genes in these cells. We found the new extracellular diffusible signal mediated by RANKL, regulating Hippo pathway in the aggressive PCa cells. Recombinant RANKL-treated indolent PCa cells, LNCaP and LAPC4, were shown to gain increased aggressiveness. The RANKL-treated indolent PCa cells exhibited down-regulation of Hippo pathway core kinases (Mst1/2 and Lats1/2) but up-regulation of YAP/TAZ expressions. By deleting downstream effectors of Hippo pathway, YAP/TAZ, interrupted the aggressive PCa cells to migrate, proliferate and invade and reversed their EMT phenotype. Inhibitions of YAP/TAZ in aggressive PCa cells via genetic knockdown approach resulted in E-cadherin increase and Vimentin decrease. With the identification of crosstalk between Hippo and TGF-β, or Wnt pathways, this opened up a new network and targeting opportunity for PCa bone metastasis. The metastatic PCa cells with YAP/TAZ deletions were illustrated for sensitization to other therapeutic agents such as TGF-β inhibitors. These results prompted us to study the mechanism, validate the functional significance, and devise potential targeting strategies of Hippo pathway in PCa bone metastasis. Conclusions: Our results showed that dysregulated Hippo pathway in the aggressive PCa cells. With deletions of YAP/TAZ, PCa metastatic abilities were inhibited. Our findings might explain why PCa cells prefer bone as primary metastatic sites. In addition, targeting YAP/TAZ could be a potential therapy for PCa bone metastasis. Citation Format: Jen-Ming Huang, Gina C-Y Chu, Hyung L. Kim, Haiyen E. Zhau, Leland W.K. Chung. Dysregulation of Hippo pathway in metastatic prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1630.