tbuckley/cabot-search huggingface dataset:
Abstract 4038: A functional genomics approach to the identification of genes involved in resistance to Oxaliplatin in colorectal cancer
Authors: Federica Invrea, Francesca Cavicchioli, Consalvo Petti, Rosalia Russo, Claudio Isella, Enzo Medico
Journal: Cancer Research (2018)

Abstract Currently, the first line therapy for metastatic colorectal cancer (CRC) is the FOLFOX regimen, which includes Oxaliplatin in combination with Fluorouracil and Leucovorin. Responses to FOLFOX range from overt regressions (35%) to full resistance (25%), and eventually all patients become resistant. Indeed, the molecular mechanisms of Oxaliplatin resistance remain mostly to be understood. To identify genes involved in sensitivity/resistance to Oxaliplatin, we designed an integrated approach including forward genetic screens and computational analyses. The pipeline includes: (i) stable transduction of CRC cells with pooled shRNA libraries; (ii) Oxaliplatin treatment for six weeks to select a drug-resistant subpopulation; (iii) identification of shRNA constructs enriched in the Oxaliplatin-resistant subpopulation by next-generation sequencing analysis. We focused the shRNA libraries targeting phosphatases and ubiquitin conjugation pathway genes. The first are involved in several biological processes, reversing the biochemical activity of kinases and typically acting as feedback loop regulators. The second direct proteins to degradation by the proteasome regulating homeostasis, cell cycle, and DNA repair pathways. HCT116 CRC cells, markedly sensitive to Oxaliplatin, were transduced in duplicate with both shRNA libraries. After Oxaliplatin treatment for six weeks, resistant populations emerged from the library-transduced cells, but not from control-transduced cells. To reveal shRNA constructs responsible of such phenotype, we extracted genomic DNA from transduced cells and, upon amplification of shRNA constructs by targeted PCR and next-generation sequencing, we compared the repertoire of shRNA sequences in HCT116 cells selected with Oxaliplatin with that of cells grown in standard medium. Screening hits were then prioritized for functional characterization, resulting in a phosphatase (CDC25C) and an ubiquitin ligase candidate (DCAF17). In conclusion, we successfully setup a functional genomic screening for acquired resistance to Oxaliplatin in CRC. Specific shRNA constructs from both the phosphatase and ubiquitin ligase libraries were enriched after Oxaliplatin treatment, highlighting candidate genes whose loss of function could potentially drive resistances to Oxaliplatin. Citation Format: Federica Invrea, Francesca Cavicchioli, Consalvo Petti, Rosalia Russo, Claudio Isella, Enzo Medico. A functional genomics approach to the identification of genes involved in resistance to Oxaliplatin in colorectal 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 4038.
Abstract 1068: LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals
Authors: Jae Won Chang, Bon Seok Koo
Journal: Cancer Research (2018)

Abstract Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, a protein of the extracellular matrix secreted by cultured human keratinocytes. While LAMB3 is involved in the invasive and metastatic abilities of several tumor types, including those found in the colon, pancreas, lung, cervix, stomach, and prostate, its mechanism of action in thyroid cancer has not been investigated previously. Our results show that LAMB3 is upregulated in papillary thyroid cancer, and that its suppression reduces cell migration/invasion via downregulation of epithelial–mesenchymal transition-associated proteins (N-cadherin, vimentin, slug) and inhibition of matrix metalloproteinase 9. LAMB3 suppression also significantly decreases Akt phosphorylation and inhibits the transcription of c-MET, reducing its activation. These results suggest that LAMB3 leads to tumor invasion via Akt activation induced by the HGF/c-MET axis in papillary thyroid cancer cells. Our findings reveal a novel mechanism of action for LAMB3 in papillary thyroid cancer cells. Citation Format: Jae Won Chang, Bon Seok Koo. LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals [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 1068.
Abstract 15357: Detection of Aoritc Wall Inflammation in Patients With Acute Aortic Intramural Hematoma by 18F-Fluorodeoxyglucose Positoron Emission Tomography (FDG-PET)
Authors: TakeshiKITAI, ShuichiroKaji, AkihitoOhnishi, TadaakiKoyama, MichioSenda, YutakaFurukawa
Journal: Circulation (2014)

Background: Elevated serological markers of inflammation were reported to be associated with adverse outcome in patients with acute aortic intramural hematoma (IMH). The combined anatomic and metabolic information of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has shown potential in the imaging of aortic wall instability and underlying inflammation in aortic disease. The present study aimed to investigate the clinical significance of FDG-PET in patients with IMH. Methods: A total of consecutive 46 patients with acute aortic syndrome were admitted within 24 hours from the symptom onset between September 2013 and May 2014. Patients who had uncontrolled systemic inflammation or surgical site infection were excluded. FDG-PET of the body trunk and CT angiography of the entire aorta was performed in acute phase. The maximal SUV values (SUVmax) were assessed within aortic wall in the entire descending thoracic aorta, and segmentally analyzed in each slice at proximal descending aorta (PD), mid ...
Increased Activity of Nuclear Factor-κB Participates in Cardiovascular Remodeling Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats
Authors: ShiroKitamoto, KensukeEgashira, ChuKataoka, MasamichiKoyanagi, MakotoKatoh, HiroakiShimokawa, RyuichiMorishita, YasufumiKaneda, KatsuoSueishi, AkiraTakeshita
Journal: Circulation (2000)

Background—Chronic inhibition of endothelial nitric oxide (NO) synthesis by the administration of Nω-nitro-l-arginine methyl ester (L-NAME) to rats induces early vascular inflammatory changes [monocyte infiltration into coronary vessels, nuclear factor-κB (NF-κB) activation, and monocyte chemoattractant protein-1 expression] as well as subsequent arteriosclerosis (medial thickening and perivascular fibrosis) and cardiac fibrosis. However, no direct evidence for the importance of NF-κB in this process is known. Methods and Results—We examined the effect of a cis element decoy strategy to address the functional importance of NF-κB in the pathogenesis of cardiovascular remodeling. We found here that in vivo transfection of cis element decoy oligodeoxynucleotides against NF-κB to hearts prevented the L-NAME–induced early inflammation and subsequent coronary vascular medial thickening. In contrast, NF-κB decoy oligodeoxynucleotide transfection did not decrease the development of fibrosis, the expression of tra...
Antenatal vitamin D exposure and childhood eczema, food allergy, asthma and allergic rhinitis at 2 and 5 years of age in the atopic disease‐specific Cork <scp>BASELINE</scp> Birth Cohort Study
Authors: Áine Hennessy, Jonathan O'B Hourihane, Lucio Malvisi, Alan D. Irvine, Louise C. Kenny, Deirdre M. Murray, Mairead E. Kiely
Journal: Allergy (2018)

Prospective studies of antenatal and infant vitamin D exposure and atopic disease from extensively characterised, disease-specific, maternal-infant cohorts with gold standard analysis of vitamin D status and clinically validated atopic outcomes are lacking. This study aimed to investigate associations between intrauterine vitamin D status and atopic outcomes in an extensively characterised, disease-specific, maternal-infant cohort.Circulating 25-hydroxyvitamin D (25(OH)D) was measured in maternal sera at 15 weeks of gestation (n = 1537) and umbilical cord blood (n = 1050) using a CDC-accredited LC-MS/MS platform, and the association with clinically validated atopic disease outcomes (eczema, food allergy, asthma, allergic rhinitis) at 2 and 5 years was explored using multivariable logistic regression.Persistent eczema in the first 2 years of life was present in 5% of infants. Food allergy at 2 years was confirmed in 4%. The prevalence of aeroallergen sensitisation at 2 years was 8%. Asthma at 5 years was reported in 15% and allergic rhinitis in 5% of 5-year-olds. There were no significant differences in the distributions of maternal 25(OH)D at 15 weeks of gestation (mean [SD] 58.4 [26.2] and 58.5 [26.1] nmol/L) and cord 25(OH)D concentrations (mean [SD] 35.2 [17.8] and 35.4 [18.3] nmol/L) between children with and without atopic disease. Neither maternal (aOR [95% CI]: 1.02 [0.97, 1.08], P = 0.450) nor cord 25(OH)D (aOR [95% CI]: 1.00 [0.91, 1.09], P = 0.991) were significant predictors of atopic disease outcomes in fully adjusted models.These data in a disease-specific cohort with prospectively collected, validated atopic outcomes do not support an association between antenatal exposure to vitamin D and atopic disease outcomes in childhood.
Abstract 5332: Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer
Authors: Atsushi Imai, Kiyoshi Misawa, Daiki Mochizuki, Hiroyuki Mineta, Takeharu Kanazawa
Journal: Cancer Research (2018)

Abstract Staging and pathological grading are useful, but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Accordingly, molecular biomarkers that predict the risk of recurrence are necessary to improve clinical outcomes. The ability to distinguish between low- and high-risk HNSCCs at an early stage may reduce follow-up costs. We hypothesized that the quantitative methylation specific PCR (Q-MSP) assay could be used to define patterns of DNA methylation that differentiate low- and high-risk HNSCCs. The methylation statuses of the promoters of 11 tumor-related genes (p16, RASSF1A, E-cadherin, H-cadherin, MGMT, DAPK, DCC, COL1A2, TAC1, SST, and GALR1) were analyzed in 133 HNSCC cases using quantitative methylation-specific PCR. Frequent methylation of p16 (44%), RASSF1A (18%), E-cadherin (53%), H-cadherin (35%), MGMT (35%), DAPK (53%), DCC (42%), COL1A2 (44%), TAC1 (61%), SST (64%), and GALR1 (44%) in HNSCC were detected. Disease-free survival was lower in patients with 6-11 methylated genes than in those with 0-5 methylated genes (log-rank test, P = 0.001). In a multivariate Cox proportional hazards analysis, the methylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with poor survival, with hazard ratios of 4.474 (95% CI, 1.241-16.124). In a joint analysis of these four genes, patients with 2-4 methylated genes had a significantly lower survival rate than those with 0-1 methylated genes in early-stage HNSCC. Importantly, the methylation of some genes was closely related to poor prognosis in early-stage HNSCC, providing strong evidence that these hypermethylated genes are valuable biomarkers for prognostic evaluation. In conclusion, the methylation profiles of E-cadherin, COL1A2, TAC1, and GALR1 were the most powerful combination for predicting early-stage HNSCC. This demonstrates that molecular stratification may predict cancer progression. These findings can benefit HNSCC screening and surveillance algorithms. Although our study was retrospective, was conducted at a single institution, and the number of patients was small, it serves as a platform to establish optimal therapeutic strategies for early-stage HNSCC. Citation Format: Atsushi Imai, Kiyoshi Misawa, Daiki Mochizuki, Hiroyuki Mineta, Takeharu Kanazawa. Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage 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 5332.
Coronary Artery Calcium in Acute Coronary Syndromes
Authors: AxelSchmermund, DietrichBaumgart, GünterGörge, RainerSeibel, DietrichGrönemeyer, JunboGe, MichaelHaude, JohnRumberger, RaimundErbel
Journal: Circulation (1997)

Background Quantification of coronary artery calcified plaques by electron-beam CT (EBCT) may predict cardiovascular events. However, whereas advanced coronary atherosclerotic plaques can be identified, mildly stenotic lipid-rich (soft) plaques may be difficult to detect. The value of EBCT in a subgroup of patients has therefore been questioned. To investigate this, we evaluated patients with acute coronary syndromes by EBCT and compared the results with coronary angiography and, in patients with an indeterminate angiogram, intracoronary ultrasound (ICUS). Methods and Results EBCT was performed in 118 consecutive patients (57±11 years of age) with previous myocardial infarction (n=101) or unstable angina (n=17). A standard protocol requiring a CT density >130 Hounsfield units in an area ≥1.03 mm2 was used for the definition of coronary artery calcium. We found that 110 patients had moderate to severe coronary artery disease by coronary angiography, and 8 had either mildly stenotic plaques at a single site...
Arrhythmogenic Marker for the Sudden Unexplained Death Syndrome in Thai Men
Authors: KoonlaweeNademanee, GumpanartVeerakul, SumaleeNimmannit, VipadaChaowakul, KiertijaiBhuripanyo, KhanchitLikittanasombat, KriangTunsanga, SurachaiKuasirikul, PridaMalasit, SudaratTansupasawadikul, PyatatTatsanavivat
Journal: Circulation (1997)

Background Between 1981 and 1988, the Centers for Disease Control and Prevention reported a very high incidence of sudden death among young male Southeast Asians who died unexpectedly during sleep. The pattern of death has long been prevalent in Southeast Asia. We carried out a study to identify the clinical markers for patients at high risk of developing sudden unexplained death syndrome (SUDS) and long-term outcomes. Methods and Results We studied 27 Thai men (mean age, 39.7±11 years) referred because they had cardiac arrest due to ventricular fibrillation, usually occurring at night while asleep (n=17), or were suspected to have had symptoms similar to the clinical presentation of SUDS (n=10). We performed cardiac testing, including EPS and cardiac catheterization. The patients were then followed at ≈3-month intervals; our primary end points were death, ventricular fibrillation, or cardiac arrest. A distinct ECG abnormality divided our patients who had no structural heart disease (except 3 patients wit...
Abstract 3454: HIV-1 envelope protein gp120 promotes glioma tumor growth through the Akt and MAP kinase pathways
Authors: Gabriel Valentin-Guillama, Yuriy Kucheryavykh, Lilia Kucheryavykh
Journal: Cancer Research (2018)

Abstract The median survival of glioblastoma (GBM) patients with HIV is significantly shorter compared to HIV-negative GBM patients, despite the fact that they receive the same treatments. This indicates that HIV infection is associated with more aggressive tumor behavior. Earlier we shown that gp120, a glycoprotein found in the HIV shell, stimulates up-regulation of glycolysis in glioma cells. The purpose of this study was to evaluate the underlying signaling mechanisms of gp120 dependent up-regulation of glycolysis in glioma cells. Using antibody array and western blot we have identified that U87 glioma cells treated with gp120 (200 ng/ml) for 5 consequent days showed increased activation of MAP kinase and Akt/mTOR pathways. Increase of pAkt(pS473), pGSK3b(pS9), pMKK3(S189), pmTOR(S2448), p38(T180/Y182), pJNK(T183) has been identified. This data coincides with previously obtained results showing that glioma cells treated with gp120 exhibit higher proliferation rates and increased cell survival compared to un-treated glioma cells. In summary, we conclude that gp120 triggers activation of regulatory kinases Akt and MAPK involved in cell growth, cell proliferation, cell survival, protein synthesis, transcription, glycolysis, and cell migration. Citation Format: Gabriel Valentin-Guillama, Yuriy Kucheryavykh, Lilia Kucheryavykh. HIV-1 envelope protein gp120 promotes glioma tumor growth through the Akt and MAP kinase pathways [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 3454.
Tribunal made error in allowing psychiatrist back on register, says appeal court
Authors: Clare Dyer
Journal: BMJ (2018)

A medical practitioners’ tribunal that let a struck-off psychiatrist back onto the UK medical register made “an error of principle” in the way it made the decision, three Court of Appeal judges have ruled unanimously.1

The tribunal had “applied the wrong test” when it restored Shekhar Chandra to the register, the judges held. It had relied almost exclusively on the issue of whether he had remediated his behaviour and failed properly to understand the central importance of the need to maintain public confidence and professional standards.

Chandra was struck off in 2008 for sexual misconduct with a patient and for dishonesty, …
Abstract 11591: Physiological CPR Quality Parameters and ROSC Indicators
Authors: Paul Aelen, Simone Ordelman, Pierre Woerlee, Gerrit-Jan Noordergraaf
Journal: Circulation (2015)

Introduction: Survival of cardiac arrest depends on CPR quality with blood flow as the main parameter. Blood flow is affected (among others) by compression depth. AHA guidelines advise the same depth range for all patients while their individual optimum may vary widely. An individual and time dependent optimum, guided by a non-invasive measure of blood flow may result in an increased survival chance. We investigated surrogate parameters that reflect invasive blood flow. Methods: VF was induced in seven anesthetized pigs of ± 30 kg. CPR was performed at 100 cpm with a proprietary automated CPR device. Compression depth was altered every 2 minutes (sequence: 4.0, 3.25, 4.0, 5.0, 6.0, 5.0 and 4.0 cm) to obtain a large range of blood flows. After 14 minutes of CPR defibrillation was performed. After a stable ROSC period the complete sequence was repeated. Correlation coefficients between net carotid blood flow and potential surrogate parameters were calculated for the compression period in order to see what parameters could be used to reflect CPR quality. The same analysis was done for a 6 min period around the last compression (see figure 1) to investigate what parameters could be used to detect ROSC. Results: Average correlation coefficients between carotid flow and surrogate parameters are shown in figure 1. Conclusion: DBP and CPP were the best CPR quality and ROSC indicators. Contrary to CPP, DBP has the potential to be measured non-invasively (e.g. with a cuff) which in the future might be used to steer CPR and detect ROSC. PPG signals (i.e. a pulse oximetry sensor) had a negative correlation with flow as PPG reflects blood volume inversely. The baseline channels showed some potential to be used as ROSC detector and as CPR surrogate, especially in the infrared channel. The amplitudes of the PPG were not of use to detect ROSC or to steer CPR. SBP, MAP, PP, ETCO2 and VCO2 have the potential to detect ROSC but are not of great use as a measure of CPR quality. For ETCO2 the low correlation is remarkable.
Abstract 3159: Rac1 and Cdc42 as drivers in ovarian cancer metastasis
Authors: Melanie Rivera, Dayna Dominguez, Christine Pauken, Elsa Romero, S. Ray Kenney, Yang Shi, Ji-Hyun Lee, Jennifer Gillette, Laurie G. Hudson, Angela Wandinger-Ness
Journal: Cancer Research (2018)

Abstract Five-year ovarian cancer patient survival has not improved for decades, largely due to disease recurrence. Therefore, drivers of relapse need to be identified. We first reported that Rac1 and Cdc42 GTPases are highly overexpressed in serous ovarian cancer using immunohistochemistry. To correlate GTPase expression with survival outcomes, we analyzed gene expression data in The Cancer Genome Atlas, revealing that ovarian cancer patients with the highest RAC1 RNA levels had significantly worse age-adjusted survival than those with low RAC1. Quantitative analyses of Rac1b, a constitutively active Rac1 splice variant, show dramatic overexpression in tumor epithelia relative to stroma and normal epithelia. Since high Rac1 and Cdc42 levels drive cancer cell adhesion, invasion and metastasis, we used multiple assays to assess the dependence of ovarian cancer cell behaviors on Rac1 and Cdc42. Using Matrigel invasion chambers, treatment of multiple ovarian cancer cell lines with specific Rac1 and Cdc42 inhibitors resulted in significantly decreased cellular invasion. Conversely, with overexpression of Rac1, ovarian cancer cells demonstrated increased invasion. Furthermore, IP injection of ovarian cancer cells overexpressing Rac1 resulted in increased adhesion, invasion and metastasis in the omentum and peritoneum in vivo. These data support Rac1 and Cdc42 as important drivers of invasive and metastatic ovarian cancer and as novel high-value therapeutic targets with potential impact in reducing disease metastasis. Citation Format: Melanie Rivera, Dayna Dominguez, Christine Pauken, Elsa Romero, S. Ray Kenney, Yang Shi, Ji-Hyun Lee, Jennifer Gillette, Laurie G. Hudson, Angela Wandinger-Ness. Rac1 and Cdc42 as drivers in ovarian cancer metastasis [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 3159.
Mitogen-Activated Protein Kinases Control Cardiac KChIP2 Gene Expression
Authors: YingJia, KoichiTakimoto
Journal: Circulation Research (2006)

Hypertrophied myocardium is associated with reductions in the transient outward K+ current (Ito) and expression of pore-forming Kv4.2/4.3 and auxiliary KChIP2 subunits. Here we show that KChIP2 mRNA and protein levels are dramatically decreased to 10% to 30% of control levels in the left ventricle of aorta-constricted rats in vivo and phenylephrine (PE)-treated myocytes in vitro. PE also markedly decreases Ito density. Inhibition of protein kinase Cs (PKCs) does not affect the PE-induced reduction in KChIP2 mRNA level, whereas activation of PKC with phorbol ester (phorbol myristate [PMA]) causes a marked reduction in KChIP2 mRNA level. Pharmacological inhibition of MEKs or overexpression of a dominant-negative MEK1 increases the basal KChIP2 mRNA expression and blocks the PMA-induced decrease in auxiliary subunit mRNA level. In addition, a constitutively active MEK1 decreases the basal KChIP2 mRNA level, and PMA causes no further reduction in auxiliary subunit mRNA level in active MEK1-expressing cells. F...