tbuckley/cabot-search huggingface dataset:
Abstract 2958: Quantitative and correlative analysis of variant UGT1A mRNA expression in human liver
Authors: Nathan R. Jones, Gang Chen, Philip Lazarus
Journal: Cancer Research (2010)

Abstract UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of various endogenous and xenobiotic compounds including several carcinogens and chemotherapeutic agents. UGTs are divided into two sub-families based on sequence homology. The nine UGT1A family members are encoded by a single locus on chromosome 2q37, where each family member has a unique exon 1 and shares exons 2-5. A recently identified exon 5b in the common region of the UGT1A gene cluster leads to the expression of 18 additional mRNA species from this locus. In vitro studies indicate that the proteins encoded by these variant mRNAs negatively modulate the activity of the wild type isoforms. It is hypothesized that inter-individual variation in the ratio of wild type to variant mRNA expression may affect glucuronidation capacity. The goal of this study was to quantitatively examine variant UGT1A mRNA expression in individual human liver specimens to better assess the importance of splicing variants in overall UGT1A activity. To differentiate between the 5’ (exon 1) and 3’ (exon 5) splice variants, a nested, quantitative PCR reaction was developed that allows both variants to be distinguished simultaneously. Results of the study indicate that there is a 406-, 278-, 58-, and 139-fold inter-individual variation in the expression ratio of wild-type to variant mRNA for UGTs 1A1, 1A4, 1A6, and 1A9, respectively, in the 10 human livers examined. UGT1A variant expression reached as high as 8.2-fold more than wild-type UGT1A1, 2.9-fold higher than wild-type UGT1A4, 0.13-fold lower than wild-type UGT1A6, and 0.46-fold lower than wild-type UGT1A9. Even though the expression ratio of wild-type to variant mRNA differs widely between different individuals, results indicate that the expression ratio is consistent for all UGTs examined within a single individual. The correlation between the expression ratio of UGTs 1A1 and 1A4 in different individuals is highly significant (R2 = 0.9661, p&amp;lt;0.0001). Similarly, the correlation between the expression ratio of UGT1A1 and UGT1A6, UGT1A1 and UGT1A9, UGT1A4 and UGT1A6, UGT1A4 and UGT1A9, and UGT1A6 and UGT1A9 are all significant (R2=0.5265, p=0.0269; R2=0.8994, p=0.0003; R2=0.5782, p=0.0174; R2=0.9610, p&amp;lt;0.0001; R2=0.582, p=0.0277, respectively). Together, these data suggest that UGT1A variant expression could significantly impact overall UGT1A activity and that there is a high correlation between wild-type : variant mRNA expression ratios across the entire UGT1A locus within individuals. Future studies will be conducted to determine whether a difference in the UGT1A expression ratio has an impact on glucuronidation capacity in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2958.
Abstract 220: TNFα activates NF-κB through RIP1 ubiquitination-dependent and independent pathways
Authors: Laiqun Zhang, Ken Blackwell, Lauren Workman, Hasem Habelhah
Journal: Cancer Research (2012)

Abstract TNFα-induced NF-κB activation has long been believed to depend on TRAF2/5- and cIAP1/2-mediated RIP1 ubiquitination. Recently, HOIP/HOIL-1-mediated linear ubiquitination of NEMO/IKKγ has emerged as a new player in TNFα-induced NF-κB activation. However, the mechanisms by which these proteins mediate NF-κB activation have become more complex than ever before due to an accumulation of conflicting results. Several independent studies even challenged the notion that these proteins ever play essential roles in NF-κB activation. Here, we report the identification of immediate and delayed phases of IKK activation in TNFα-treated cells. TNFα-induced immediate IKK activation requires ubiquitination of RIP1 catalyzed by cooperative actions of TRAF2, cIAP1/2, UbcH5 and Ubc13, and that in the absence of any one of these components; those remaining are only capable of mediating delayed IKK activation by recruiting the HOIP/HOIL-1 complex. In RIP1-deficient cells, TRAF2 undergoes increased auto-ubiquitination through K63-linkage, yet it is not capable of mediating immediate IKK activation. Notably, depletion of either HOIP in RIP1-deficient cells or both TRAF2 and cIAP1/2 in wild-type cells completely impairs IKK activation. In addition, deletion of the TRAF2 RING domain also severely reduces the immediate phase of IKK activation. These data suggest that two RING finger E3 ligases (TRAF2 and cIAP1) and two E2 enzymes (UbcH5 and Ubc13) cooperate to catalyze immediate RIP1 ubiquitination and IKK activation, and that, in the absence of RIP1, TRAF2 and cIAP1/2 recruit HOIP/HOIL-1 and mediate the delayed phase of IKK activation. TRAF5 has no substantial role in TNFα-induced NF-κB activation. Importantly, in embryonic hepatocytes, RIP1 is completely degraded, yet these cells are not sensitized to TNFα-triggered cell death because of delayed IKK activation. Thus, this study provides evidences for the existence of RIP1 ubiquitination-dependent and -independent pathways that mediate NF-κB activation, and thereby clarifies molecular details of this important signaling mechanism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 220. doi:1538-7445.AM2012-220
Abstract 526: Cancer immunoediting by the innate immune system in the absence of adaptive immunity
Authors: Jack Bui, Timothy O'Sullivan, Robert Saddawi-Konefka, William Vermi, Mark Smyth, Robert Schreiber
Journal: Cancer Research (2012)

Abstract Cancer immunoediting is the process whereby the immune system protects against cancer formation and sculpts the immunogenicity of developing tumors cells. Although the full process is known to depend on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. By comparing the incidence and immunogenicity of 3′methylcholanthrene (MCA)-induced sarcomas in syngeneic wild-type, RAG2-/-, and RAG2-/- x γc-/- mice, we show that the innate immune system can edit the immunogenicity of primary tumors. Specifically, RAG2-/-x γc-/- mice displayed the highest incidence of MCA sarcomas, followed by RAG2-/- mice, and WT mice have the lowest incidence at four separate doses of MCA. Moreover, when cell lines were generated from MCA sarcomas, the cell lines derived from MCA sarcomas growing in RAG2-/-x γc-/- mice had the highest immunogenicity, followed by cell lines from RAG2-/- mice, and cell lines from WT mice had the lowest immunogenicity. These results show that the innate immune system can edit tumors in the absence of adaptive immunity. To examine the cellular basis of editing by the innate immune system, we analyzed the innate cells that infiltrate tumors formed from transplanting highly immunogenic MCA sarcoma cell lines into RAG2-/- or RAG2-/-x γc-/- mice. We found that M1 macrophages were detected at high levels in immunogenic tumors in RAG2-/- but not RAG2-/- x γc-/- mice. The accumulation of M1 macrophages required IFNγ and was associated with effective tumor editing. In the absence of γc and IFNγ, M2 macrophages were abundant, and editing was impaired. Notably, M1 macrophages can be elicited by administration of CD40 agonistic antibodies, thereby restoring cancer editing activity in RAG2-/-x γc-/- mice. Our results suggest that crosstalk between natural killer cells and M1 macrophages, through IFNγ, can be elicited in highly immunogenic tumors, leading to cancer immunoediting. Our highly immunogenic cell lines will provide a system to dissect the cellular and molecular basis of cancer immunoediting by the innate immune system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 526. doi:1538-7445.AM2012-526
Endoscopic Necrosectomy With Self-Expandable Metal Stent (SEMS) Drainage: A Novel Approach in the Treatment of Walled-Off Pancreatic Necrosis (WOPN)
Authors: E Joo
Journal: Endoscopy (2011)

Purpose: Pancreatic necrosis is a feared complication of acute pancreatitis with high morbidity and mortality. Recent literature has suggested the advantages of a minimally-invasive approach.
Abstract B45: Embryogenesis meets tumorigenesis: Nodal/activin signaling drives self-renewal and invasiveness of pancreatic cancer stem cells
Authors: Enza Lonardo, Patrick C. Hermann, Maria-Theresa Mueller, Irene Miranda-Lorenzo, Christopher Heeschen
Journal: Cancer Research (2011)

Abstract Nodal and activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and/or Activin regulate self-renewal and invasiveness of pancreatic cancer stem cells. While their expression was hardly detectable in differentiated pancreatic cancer cells, cancer stem cells demonstrate a drastic upregulation for Nodal and, to a lesser extent, Activin while TGF-β remained unchanged. Pancreatic stellate cells as the putative microenvironment for cancer stem cells produce very high amounts of Activin, and, to a lesser extent, Nodal. Knockdown and pharmacological inhibition of their common receptor Alk4/7 both significantly, but reversibly reduced cancer stem cell self-renewal / invasiveness and cancer stem cells subsequently became sensitive to gemcitabine. Importantly, while orthotopically engrafted primary human cancer cell suspensions were highly responsive to Nodal/Activin inhibition plus gemcitabine, engrafted primary human pancreatic cancer tissue xenografts containing massive stroma did not slow down tumor progression. Intriguingly, the addition of a stroma-targeting sonic hedgehog pathway inhibitor resulted in enhanced delivery of the Nodal/Activin inhibitor and gemcitabine, respectively, and translated into long-term disease stabilization. Therefore, modulation of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a novel therapeutic strategy for targeted elimination of cancer stem cells in order to overcome their resistance towards gemcitabine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B45.
Risk factors for advanced lesions undetected at prior colonoscopy: not always poor preparation
Authors: A. Ferrández, M. Navarro, M. Díez, F. Sopena, P. Roncalés, M. Polo-Tomas, R. Sáinz, A. Lanas
Journal: Endoscopy (2010)

See also: Commentaire de travail de A. Ferréndez et al., pp. 1071Endoscopy 2010; 42(12): 1121-1121DOI: 10.1055/s-0032-1306715
An Imbalance between the Excretion of Thromboxane and Prostacyclin Metabolites in Pulmonary Hypertension
Authors: Brian W. Christman, Charles D. McPherson, John H. Newman, Gayle A. King, Gordon R. Bernard, Bertron M. Groves, James E. Loyd
Journal: New England Journal of Medicine (1992)

Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium.
Assets of oncologist who falsely diagnosed cancers to be divided among patients
Authors: Owen Dyer
Journal: BMJ (2016)

The liquidated assets of a Michigan oncologist who falsely diagnosed hundreds of patients with cancer and poisoned them with high dose chemotherapy so that he could bill for the drugs is to be put into a fund for his victims, 553 of whom have been identified so far.

But the case of Farid Fata, who prosecutors called “the most egregious fraudster in US history,” could reignite this summer as attorneys study a sealed file of new allegations that name other doctors and health providers as accomplices.

Fata, …
LEFT ATRIAL TO LEFT VENTRICULAR END SYSTOLIC VOLUME INDEX RATIO BY ECHOCARDIOGRAPHY CAN PREDICT ELEVATED LEFT ATRIAL PRESSURE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Amarbir Bhullar, Manminder Bhullar, Manmeet Singh, Kamil Muhyieddeen, Bhavik Khatri, Ryan Berg, Enrique Carbajal, Chandra Katikireddy
Journal: Journal of the American College of Cardiology (2016)
Somatostatin Receptor Imaging–Guided Pasireotide Therapy in Medullary Thyroid Cancer With Ectopic Adrenocorticotropin Production
Authors: Frederik A. Verburg, Martin Anlauf, Felix M. Mottaghy, Wolfram Karges
Journal: Clinical Nuclear Medicine (2014)

A 51-year-old man with a history of metastatic medullary thyroid cancer (MTC) presented with high adrenocorticotropin (ACTH) and urinary free cortisol levels. The diagnosis of ectopic ACTH production, a rare MTC complication, was established in this patient. PET/CT using the somatostatin analogue DOTA-(Tyr)-octreotate labeled with gallium (Ga-DOTATATE) was performed, showing positive radionuclide uptake in multiple MTC metastases. After this therapy with the novel somatostatin analogue, pasireotide was initiated after which urinary free cortisol and ACTH levels decreased. The present case thus illustrates a potential theranostic use of Ga-DOTATATE PET/CT in MTC.
SM-01 * APPLICATION OF BEVACIZUMAB TO POST-IRRADIATED CEREBRAL LESION: DIAGNOSIS, INTERVENTION AND OUTCOME
Authors: N. Fukui, Y. Arakawa, D. Murata, K. Fujimoto, S. Miyamoto
Journal: Neuro-Oncology (2014)

BACKGROUND: Taking results of AVAglio (Chinot et al., 2014), BRAIN study (Friedman et al., 2009) and JO22506 (Nagane et al., 2012), bevacizumab (BEV) had been approved for the treatment of newly diagnosed and recurrent malignant glioma. In addition, there are some trials using BEV for symptomatic cerebral radiation necrosis (RN, Levin et al., 2011) and other brain tumor (e.g. meningioma) patients. METHODS: We retrospectively analyzed 10 cases (median age: 59.5 [range 26-69]) of cerebral lesion occurred after irradiation. By the combination of diagnostic imaging (MRI and PET) and clinical course, they were diagnosed as RN. Primary irradiated lesions were as below: 5-case of metastatic brain tumor, 2-case of meningioma and 3-case of other primary head and neck tumor. These patients were administered six cycles of 5 mg/kg bevacizumab every two weeks. RESULTS: In 7 cases, planned 6-cycles of BEV had been finished. In 3 of these 7 cases, wound complication or (extracranial) hemorrhage was clinically treated. In another 3 cases, BEV were ceased: disease progression, fetal hemorrhagic complication and deterioration of performance status respectively. After the BEV treatment, 3 cases were diagnosed as tumor recurrence by surgical resection of treated lesions. DISCUSSION: Diagnosis of RN is so difficult; we must pay attention to possibility of tumor recurrence. On the other hand, BEV could improve clinically and radiologically cerebral edema induced by RN and tumor progression. We had better consider application of BEV to post-irradiated cerebral lesion, case by case.
Abstract 935: Genetic variants in chromosome 6p21.3 and risk of non-Hodgkin lymphoma
Authors: Sophia S. Wang, Idan Menashe, James R. Cerhan, Nathaniel Rothman, Richard K. Severson, Scott Davis, Stephen J. Chanock, Leslie Bernstein, Patricia Hartge, Lindsay Morton
Journal: Cancer Research (2010)

Abstract Background. Non-Hodgkin lymphoma (NHL) case-control studies consistently demonstrate the G-308A promoter polymorphism in the tumor necrosis factor gene on chromosome 6p21.3 to be associated with increased risk of the NHL subtype, diffuse large B-cell lymphoma (DLBCL). Initial results from a genome-wide association study have implicated a polymorphism located on 6p21.33 with increased risk of the follicular lymphoma subtype. In the present analysis, we evaluated 488 candidate gene regions (defined as 20kb 5’, 10kb 3’) and their relation to risk for NHL and the DLBCL and follicular lymphoma subtypes with a particular focus on genes within the 6p21 chromosomal region. Methods. We genotyped 6679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S.-based case-control study. Genotyping was conducted on a custom-designed Illumina Infinium assay at the NCI Core Genotyping Facility. We obtained a gene region-level summary of association by computing the minimum p-value (“minP test”). We used logistic regression to evaluate the association between single nucleotide polymorphism (SNP) genotypes and haplotypes with NHL (adjusted for sex, race and age). For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression. We evaluated tests for trend under the co-dominant model used a three-level ordinal variable for each SNP. Results. We identified 34 gene regions significantly associated with all NHL (p &amp;lt;0.05). The three most significant gene regions were all found on chromosome 6p21.3 (RING1/RXRB; AIF1/BAT2; BAT4, p=0.001). Within those gene regions, the most significant SNPs (p&amp;lt;0.0002) were rs2855429 and rs213213 (RING1/RXRB), rs2857597 and rs3130071 (AIF1/BAT2), and rs3115667 (BAT4). All five SNPs were statistically significantly associated with both DLBCL and follicular lymphoma. Additional gene regions on 6p21.3 associated with NHL include MSH5 (p=0.009), FAM46A (p=0.01) and TNXB/CREBL1 (p=0.04). Stratification by age and gender did not alter our results; consistent results were observed in analyses restricted to non-Hispanic Caucasians. Haplotype analyses yielded the same regions and SNPs of significance. Detailed analysis of the 6p21.3 region will be presented. Conclusions. Our results further implicate gene variants within the 6p21.3 chromosomal region in NHL etiology. Full characterization of the 6p21.3 region and identification of functional variants within this region are warranted for understanding lymphomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 935.
FRI0299 Heart rate recovery predicts outcomes in patients with pulmonary arterial hypertension associated with connective tissue diseases
Authors: O. A. Minai, Q. Nguyen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> We have previously reported that heart rate recovery (HRR) after a six-minute walk test (6MWT) is a free and easily measured biomarker that can accurately predict clinical worsening in patients with idiopathic pulmonary arterial hypertension. It is unknown if HRR can predict clinical outcomes in patients with connective tissue diseases. <h3>Objectives</h3> We aimed to determine whether abnormal heart rate recovery at one minute of rest (HRR1) after the 6MWT(HRR1 &lt; 16 beats per minute) predicts survival and hospitalization in patients with pulmonary hypertension associated with connective tissue diseases (CTD-PAH). <h3>Methods</h3> Patients with pulmonary hypertension and a diagnosis of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), or mixed connective tissue disease (MCTD) who underwent the 6MW test between August 1, 2009 and October 30, 2011 were included in the analysis. Patients on beta-blocker therapy at the time of the 6MW test were excluded. <h3>Results</h3> 66 patients with CTD-PAH completed the 6MW test. Compared to patients with HRR1 &gt; 16, patients with HRR1 &lt; 16 were older (58 + 15 years vs. 52 + 16 years; <i>p</i> = 0.001), less likely to be female (75% vs. 97%; <i>p</i> = 0.017), and had worse WHO FC (<i>p</i> = 0.003). Patients with HRR1 &lt; 16 and HRR1 &gt; 16 did not differ significantly in baseline pulmonary function test variables (% predicted FVC, FEV1, and DLCO). Patients with abnormal HRR1 had lower 6MW distance (272.3 + 94.0 meters vs. 367.7 + 103.7 meters; <i>p</i> &lt; 0.001). Patients with abnormal HRR1 had higher incidence of mortality (44% vs. 13%; <i>p</i> = 0.006) and PH-related hospitalizations (49% vs. 13%; <i>p</i> = 0.002). Compared to 6MW distance, HRR1 was a better predictor of PH-related hospitalizations (C-statistic for HRR1 = 0.735 vs. C-statistic for 6MW distance = 0.607). <h3>Conclusions</h3> In patients with PH associated with CTD, abnormal HRR1 (defined as HRR1 &lt; 16) after the 6MW test is a strong predictor of survival and hospitalization. HRR1 after the 6MW test is a non-invasive, low cost, and easily obtained measurement that can aid in predicting clinical outcome in patients with PH associated with CTD. <b>References:</b> Minai OA, Gudavalli R, Mumadi S, Liu X, McCarthy K, Dweik RA. Heart rate recovery predicts clinical worsening in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;185:400-408 <b>Disclosure of Interest</b>: None Declared
Abstract 3471: Antibody-directed neutralization of fibrinolytic receptor annexin II inhibits human breast cancer growth in a xenograft model
Authors: Meena Sharma, Marc Blackman, Mahesh C. Sharma
Journal: Cancer Research (2011)

Abstract The fibrinolytic pathway has long been known to be associated with breast cancer. Plasmin is the major end product of fibrinolytic pathway and is critical for normal physiological functions. The mechanism(s) by which plasmin is generated in breast cancer is not yet fully understood. Previously we identified ANX II, a fibrinolytic receptor, in human breast cancer samples and observed a strong positive correlation with advanced stage of cancer. We further demonstrated that the tissue plasminogen activator (tPA) binds to ANX II in invasive breast cancer MDA-MB231 cells which at least in part responsible for plasmin generation. We hypothesized that ANX II-dependent plasmin generation in breast cancer is necessary to activate the switch for neoangiogenesis thereby promoting aggressive cancer phenotype. Our immunohistochemical studies of human breast cancer tissues demonstrate strong positive correlation between annexin II expression and neoangiogenesis. These data not only indicate a link between ANX II and neoangiogenesis but also suggest that ANX II may be a potential target to slow or inhibit breast cancer growth by inhibiting neoangiogenesis. In this report we show that administration of anti-ANX II antibody potently inhibits the growth of human breast cancer in a xenograft model. Inhibition of tumor growth was due to inhibition of neoangiogenic activity within the tumor. In vitro studies demonstrated that anti-ANX II antibody inhibited angiogenesis on three dimensional matrigel cultures. The inhibition of in vitro angiogenesis was due to endothelial cell (EC) apoptosis. Taken together, these data suggest that selective disruption of fibrinolytic activity of ANX II may be a novel strategy for inhibition of neoangiogenesis in human breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3471. doi:10.1158/1538-7445.AM2011-3471