tbuckley/cabot-search huggingface dataset:
Abstract 2464: Disrupting the epigenetic modifier HMGA2 in DIPG and GBM inhibits tumor invasion, growth and tumorigenicity
Authors: Harpreet Kaur, Marianne Hütt-Cabezas, Isabella Taylor, Melanie Weingart, Fausto Rodriguez, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2016)

Abstract Diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM) are lethal, incurable brain tumors with poor prognosis. Identifying and targeting novel molecular markers regulating tumor invasion and growth can lead to development of better therapies. HMGA2, a minor-groove DNA-binding protein, is a transcriptional modulator in normal and cancer stem cells. We hypothesized that HMGA2 contributes to pediatric high grade glioma invasion and tumorigenicity through its ability to alter the transcription of large numbers of genes. We found increased expression of HMGA2 in a subset of GBM and DIPG tumors by western blotting and immunohistochemistry. We confirmed this result in multiple patient-derived tumor cell lines, including 3 DIPG neurosphere cell lines. Lentiviral short hairpin RNA (shRNA)-mediated reduction of HMGA2 in GBM cells significantly reduced invasion in transwell assay and colony formation in soft agar assay (shHMGA2 vs. shControl, P&amp;lt;0.01). Similarly, shRNA mediated suppression of HMGA2 in DIPG cell lines reduced proliferation as measured by BrdU incorporation, reduced invasion by transwell assay and increased apoptosis by cleaved caspase-3 (CC-3) immunofluorescence (shHMGA2 vs. shControl, P&amp;lt;0.01). Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug Netropsin significantly inhibited growth (BrdU assay) and increased apoptosis (CC-3 immunofluorescence) of DIPG cell lines (P&amp;lt;0.01). Mice bearing orthotopic GBM xenograft cell lines transduced with HMGA2 shRNA lived longer (median survival = 108 days) compared to control shRNA (67.5 days, P&amp;lt;0.0001 by log-rank analysis). Our results suggest an oncogenic role of HMGA2 in promoting DIPG and GBM invasion and growth, identifying HMGA2 as a potential therapeutic target in these devastating tumors. Netropsin or other minor groove binding agents may be effective therapeutics for pediatric high-grade gliomas. Citation Format: Harpreet Kaur, Marianne Hütt-Cabezas, Isabella Taylor, Melanie Weingart, Fausto Rodriguez, Charles G. Eberhart, Eric H. Raabe. Disrupting the epigenetic modifier HMGA2 in DIPG and GBM inhibits tumor invasion, growth and tumorigenicity. [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 2464.
Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome
Authors: Jonathan M. Pitt, Marie Vétizou, Nadine Waldschmitt, Guido Kroemer, Mathias Chamaillard, Ivo Gomperts Boneca, Laurence Zitvogel
Journal: Cancer Research (2016)

Abstract The equilibrium linking the intestinal microbiota, the intestinal epithelium, and the host immune system establishes host health and homeostasis, with perturbations of this balance resulting in chronic inflammatory and autoimmune immunopathologies. The mutualistic symbiosis between gut microbiota and host immunity raises the possibility that dysbiosis of the intestinal content also influences the outcome of cancer immunotherapy. Here, we present our recent findings that specific gut-resident bacteria determine the immunotherapeutic responses associated with CTLA-4 checkpoint blockade. This new evidence hints that interindividual differences in the microbiome may account for the significant heterogeneity in therapeutic and immunopathologic responses to immune checkpoint therapies. We discuss how this new understanding could improve the therapeutic coverage of immune checkpoint inhibitors, and potentially limit their immune-mediated toxicity, through the use of adjunctive “oncomicrobiotics” that indirectly promote beneficial immune responses through optimizing the gut microbiome. Cancer Res; 76(16); 4602–7. ©2016 AACR.
Abstract 166: Optimizing the detection of subclonal somatic variants with VarDict
Authors: Zhongwu Lai, Brad Chapman, Miika Ahdesmäki, Oliver Hofmann, Justin Johnson, Jonathan Dry
Journal: Cancer Research (2016)

Abstract Detection of somatic variants in tumor tissues is far from a solved problem. Heterogenous tumor materials complicate variant assessment in low frequency subclonal populations, which can play an important role in the development of drug resistance. Loss of heterozygosity, copy number variation and other ploidy changes can further change the expected distribution of variant metrics. We demonstrate improvements in the specificity and sensitivity of variant calling algorithms by optimising linear combinations of widely used filtering criteria such as allelic frequency, depth and p-value distributions. We specifically improve SNP and indels from the freely available VarDict caller (https://github.com/AstraZeneca-NGS/VarDictJava) and show that these optimisations can be generalised across a wide range of allelic frequencies. We validate our findings against synthetic and in vitro standards such as the ICGC-TCGA DREAM challenge truth set. Our proposed filtering strategy is widely applicable to other variant callers, and the updated filters for VarDict dramatically improve sensitivity and precision on low frequency variants which are crucial for our ability to reconstruct likely tumor populations from short read sequencing data and to study tumor evolution. Citation Format: Zhongwu Lai, Brad Chapman, Miika Ahdesmäki, Oliver Hofmann, Justin Johnson, Jonathan Dry. Optimizing the detection of subclonal somatic variants with VarDict. [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 166.
Abstract 4126: An anti-CD4 antibody protects mice from anti-PD-1/PDL-1 antibody-induced fatal anaphylaxis and shows potent anti-metastatic activity in the 4T1 spontaneous metastasis model
Authors: Satoru Ito, Shoji Yokochi, Yoshiro Ishiwata, Satoshi Ueha, Francis Shand, Kouji Matsushima
Journal: Cancer Research (2016)

Abstract [Introduction] We previously reported that an α-CD4 depleting monoclonal antibody (mAb) has very potent anti-tumor effects in several murine tumor models, particularly when combined with α-PD-1/L1 mAbs (Cancer Immunol. Res. 3: 631-640; 2015). Here we examined the effect of this α-CD4 mAb on 4T1 murine mammary tumors, which undergo spontaneous metastasis from an orthotopically transplanted site to the lung. [Methods] 4T1 tumor cells (1 × 105) were injected into the mammary fat pad of female BALB/c mice and primary tumor volume was measured every 2-3 days. Spontaneous lung metastasis was quantitated by removing the lungs, fixing them in Bouin's fixative, and counting the number of metastatic nodules on the surface of lung. [Results] Administration of α-CD4 mAb (clone GK1.5; days 5 and 9 after tumor inoculation) significantly inhibited 4T1 lung metastasis (n = 10) without affecting primary tumor size. α-PD-1 and α-PD-L1 mAbs had minimal effects on primary tumor growth and metastasis. However, administration of α-PD-1 or α-PD-L1 mAbs triggered an IgG1-mediated fatal anaphylactic reaction upon the third or fourth administration. Interestingly, the anaphylactic reaction was completely prevented by co-administration of the α-CD4 mAb. [Discussion] Based on these results, α-CD4 mAb may be useful for preventing metastasis associated with advanced cancer. In addition, α-CD4 mAb appeared to be protective against the IgG-mediated anaphylactic reaction and autoimmune-like side effects that are associated with α-PD-1/α-PD-L antibody administration-induced enhanced B-cell immunity. Increased myelopoiesis due to high G-CSF production by 4T1 cells may have contributed to the anaphylactic reaction. Citation Format: Satoru Ito, Shoji Yokochi, Yoshiro Ishiwata, Satoshi Ueha, Francis Shand, Kouji Matsushima. An anti-CD4 antibody protects mice from anti-PD-1/PDL-1 antibody-induced fatal anaphylaxis and shows potent anti-metastatic activity in the 4T1 spontaneous metastasis model. [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 4126.
Abstract 473: A tumor and immune related miRNA signature predicts progression-free survival of melanoma patients treated with ipilimumab
Authors: Ahmad Tarhini, Priyanka Vallabhaneni, Theofanis Floros, William A. LaFramboise, Panayiotis V. Benos, Lucas Santana dos Santos.
Journal: Cancer Research (2016)

Abstract Background Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (Tarhini et al, PLOS One 2014). MicroRNA (miRNA) expression profiles of tumors of treated patients were investigated for their therapeutic predictive value. Methods Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks x2 doses) bracketing surgery. Tumor specimens were obtained at baseline and following ipilimumab at definitive surgery (week 6-8). MiRNA expression profiling was performed on the tumor biopsies of 30 patients using Affymetrix miRNA array (v.4). Significance Analysis of Microarrays (SAM) was performed to test the association of each differentially expressed miRNA molecule with outcome. Targets of the selected miRNAs were obtained from miRTarBase (http://mirtarbase.mbc.nctu.edu.tw). Functional annotation analysis of the list of miRNA target genes were performed using DAVID (https://david.ncifcrf.gov). The FDR method was used to adjust for multiple testing in SAM and the functional analysis. Results An expression profile consisting of a 4-miRNA signature was associated with improved progression free survival. The signature consisted of miR-34c (previously reported to suppress cancer growth and invasion), miR-711 (reported as a prognostic marker in cutaneous T-cell lymphomas and to target and suppress Heat Shock Protein 70 highly expressed in melanoma), miR-641 (activates MAPK by targeting NF1 and cooperates with its host gene AKT2 in human cancer) and miR-22 (reported to function as a tumour suppressor). Functional annotation analysis of target genes for the 4-miRNA signature was statistically significantly enriched for various cancer-related pathways including regulation of cell proliferation (GO:0042147), regulation of apoptosis (GO:0042981), MAPK signaling pathway (hsa04010) and positive regulation of T cell activation (GO:0050870). Conclusions MiRNA expression profiling identified a 4-miRNA signature that is significantly associated with PFS in advanced melanoma patients treated with neoadjuvant ipilimumab. Preliminary results show that targets of these 4 miRNAs are biologically relevant and important. These findings warrant further investigation in relation to ipilimumab and other immunotherapeutics. Citation Format: Ahmad Tarhini, Priyanka Vallabhaneni, Theofanis Floros, William A. LaFramboise, Panayiotis V. Benos, Lucas Santana dos Santos. A tumor and immune related miRNA signature predicts progression-free survival of melanoma patients treated with ipilimumab. [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 473.
Abstract LB-358: Plasma HGF level is associated with obesity, increased risk and reduced survival of pancreatic cancer
Authors: Dong Yan, Ping Chang, Donghui Li
Journal: Cancer Research (2016)

Abstract Background: Obesity is one of the modifiable risk factors for the development and progression of pancreatic cancer. However, the mechanisms of obesity-related pancreatic cancer has not been well defined. In our previous analysis of the genome-wide association data, we identified a significant interaction of obesity with cytokine signaling pathway. Methods: In the current study, we selected several genes from this pathway that code for secreted or membrane proteins and measured the protein levels in plasma samples of 100 pancreatic patients and 100 healthy controls drawn from a case-control study conducted at MD Anderson. Cases and controls were frequency matched by age, sex, race and body mass index (BMI). Plasma levels of HGF (hepatocyte growth factor), MIP-1β (microphage infiltration factor 1-beta), FasL (Fas ligand) and PLA2 (phospholipase A2) were measured using the Luminex and ELISA methods. The protein levels were analyzed in relation to cancer risk and patient survival using analysis of variance, non-parametric test, Kaplan Meier plot, log-rank test, and Cox proportional hazard regression models. Results: A significantly higher level of HGF and MIP-1β and lower level of FasL was observed in cancer patients than in controls, with the mean values of 365.7 vs. 146.2 pg/ml, P&amp;lt; 0.001; 216.5 vs.122.3 pg/ml, P = 0.002, 23.1 versus 29.4 pg/ml, P&amp;lt;0.001, respectively. Individuals with a high HGF or low FasL level had, respectively, 4.6-fold (95% confidence interval [CI] = 2.4-9.1, P&amp;lt;0.001) and 2.9-fold (95% CI = 1.55-5.38, P = 0.001) increased risk of pancreatic cancer with adjustment for other known risk factors. Furthermore, a significant association of HGF level with BMI was observed in cases (R2 = 0.269, P = 0.005). The HGF level (mean ± SE pg/ml) was significantly higher in obese (682±204) than that in overweight (268±40) or normal weight patients (313±71), P = 0.01 and 0.005, respectively. Patients with higher levels of HGF had a significantly reduced overall survival than those with lower levels (9.3 vs. 13.3 months, P = 0.006). Cox proportional hazard regression analysis demonstrated that a higher level of HGF was an independent prognostic factor (Hazard Ratio = 2.61, 95% CI = 1.22-5.64, P = 0.01) after adjusting for BMI, disease stage and other clinical factors. Conclusion: A higher plasma level of HGF was related to obesity and overall survival in pancreatic adenocarcinoma, which may serve as a potential diagnostic and prognostic marker for pancreatic cancer. Citation Format: Dong Yan, Ping Chang, Donghui Li. Plasma HGF level is associated with obesity, increased risk and reduced survival of pancreatic 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 LB-358.
Consensus conference: Therapeutic endoscopy and bleeding ulcers
Journal: JAMA (1989)

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Preventing Diabetes: Early Versus Late Preventive Interventions
Authors: Jaakko Tuomilehto, Peter E.H. Schwarz
Journal: Diabetes Care (2016)

There are a number of arguments in support of early measures for the prevention of type 2 diabetes (T2D), as well as for concepts and strategies at later intervention stages. Diabetes prevention is achievable when implemented in a sustainable manner. Sustainability within a T2D prevention program is more important than the actual point in time or disease process at which prevention activities may start. The quality of intervention, as well as its intensity, should vary with the degree of the identified T2D risk. Nevertheless, preventive interventions should start as early as possible in order to allow a wide variety of relatively low- and moderate-intensity programs. The later the disease risk is identified, the more intensive the intervention should be. Public health interventions for diabetes prevention represent an optimal model for early intervention. Late interventions will be targeted at people who already have significant pathophysiological derangements that can be considered steps leading to the development of T2D. These derangements may be difficult to reverse, but the worsening of dysglycemia may be halted, and thus the clinical onset of T2D can be delayed.
Abstract 207: Regulation of mitochondrial biogenesis in primary human clear cell renal cell carcinoma cells
Authors: Helén Å. Nilsson, Martin E. Johansson
Journal: Cancer Research (2016)

Abstract Clear cell renal cell carcinoma, ccRCC, is the most prevalent type of kidney cancer. In over 90% of ccRCCs the tumor suppressor protein von Hippel Lindau is inactivated, leading to a pseudohypoxic phenotype with vast effects on angiogenesis as well as energy metabolism. In accordance with the Warburg effect, aerobic glycolysis increases, while mitochondrial oxidative phosphorylation is decreased. We have previously published data showing that also the number and activity of mitochondria is strikingly reduced in primary human ccRCC cells compared to normal kidney epithelial cells. This was not seen in any of the established RCC cell lines included in the study. We are now continuing these studies by investigating the regulation of mitochondrial biogenesis in primary human ccRCC cells, and how the number and activity of mitochondria influences the tumorigenic properties of these cells. RNA has been isolated from ccRCC tissue areas identified as mitochondria high or low. The expression profile in these samples will be analyzed by RNA sequencing. Human primary ccRCC cells obtained from patient nephrectomies are kept in culture and the regulation of mitochondrial biogenesis in these cells is investigated. How the mitochondrial content affects tumorigenic properties such as proliferation, migration and resistance to apoptosis is also investigated. Preliminary data indicate that primary ccRCC cells have an absent or severly limited capability to increase the number of mitochondria on metabolic demand, and that the regulation of mitogenesis is defective. These results point towards a malfunctioning energy sensing and mitochondrial biogenesis in ccRCC cells that might be part of the explanation to the very low mitochondrial content in these cells. Citation Format: Helén Å. Nilsson, Martin E. Johansson. Regulation of mitochondrial biogenesis in primary human clear cell renal cell carcinoma cells. [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 207.
PWE-046 The development of human esophageal pain hypersensitivity is associated with anxiety and sympathetic nervous system activation: Abstract PWE-046 Figure 1
Authors: C A Botha, C H Knowels, Q Aziz
Journal: Gut (2012)

<h3>Introduction</h3> Experimental acid infusion in the distal oesophagus leads to secondary hyperalgesia in the proximal oesophagus in most healthy subjects but 30% remain resistant. The factors that mediate differences in sensitisation to acid are unclear and their study may help to understand risk factors for esophageal hypersensitivity in gastro-esophageal reflux disease. We aimed to determine the psycho-physiological factors which predict the development of esophageal pain hypersensitivity (EPH) to acid infusion in healthy subjects. <h3>Methods</h3> 52 healthy volunteers (mean age 29 yrs, range 19–49 yrs; 33 male) underwent psychological profiling for, anxiety, depression and personality type. Baseline pain thresholds (PT) to proximal esophageal electrical stimulation were measured before hydrochloric acid infusion (0.15 M) in the distal oesophagus for 30 min. This was followed by esophageal pain threshold measurements using visual analogue scales to electrical stimulation in the proximal, unexposed oesophagus at 30, 60 and 90 min. Parasympathetic (Cardiac Vagal Tone—CVT) and Sympathetic Nervous System (RR interval) responses were monitored throughout the study. Volunteers were classified as sensitisers if the proximal PT fell ≥6 mA after esophageal acidification. <h3>Results</h3> Four subjects dropped out, 35 subjects (73%) sensitised to acid, and 13 subjects (27%) did not sensitise. There was no difference in the age, sex or in personality domains between sensitisers and non-sensitisers (p&gt;0.05). Spielberg trait anxiety comparison indicated a trend, p=0.08 for sensitisers to be more anxious than non-sensitisers. At baseline there was no difference in CVT and RR interval between the two groups. During acid infusion the key difference in autonomic nerves system response was that in the sensitisers the RR interval was shorter in sensitisers than non-sensitisers (sensitisers: Δ1.7 SE±48.9 vs non-sensitisers: Δ66.1 SE±25.65. ΔRR interval difference 64.4 ms (SE ±37.3) p=0.002). Trait anxiety demonstrated a negative correlation with the RR interval r=−0.35 (p=0.04). <h3>Conclusion</h3> There was a trend for sensitisers to be more anxious and at baseline there were no differences in the PNS and SNS parameters between the two groups. During acid infusion, the sensitisers had a lower RR interval than non-sensitisers suggesting a higher heart rate and therefore SNS tone. Trait anxiety showed a negative correlation with the RR interval suggesting those with higher anxiety had higher heart rate. Our results suggest that higher anxiety and SNS activation has a pro nociceptive effect on the development of post-acid infusion esophageal sensitisation. This may explain why individuals with anxiety or stress at the time of visceral injury or inflammation are more likely to go onto develop EPH. <h3>Competing interests</h3> None declared.