tbuckley/cabot-search huggingface dataset:
Abstract 4501: Immunophenotypic identities of clinical samples have the potential to correlate with overall survival in cytogenetically normal AML patients
Authors: Pawel Gaj, Dominika Nowis, Stefano Volinia
Journal: Cancer Research (2016)

Abstract Tumor infiltrating lymphocytes (TILs) have been described to have great potential to modulate course of the disease. Capacity to eliminate cancer cells primarily depends on the interplay between tumor and its microenvironment. Despite the great interest which this topic gathered over last decades the role of immune cells interaction with cancer has hardly been studied in acute myeloid leukemia patients. Multitude of patient-specific factors, as well as a great repertoire of different kinds of tumor-infiltrating immune cells, potentially affecting disease progression should be the motivation to investigate implication of tumor immune cells interplay in possibly maximized cohorts of patients. Due to technical reasons the traditional microscopy-based techniques do not allow for the desired high-throughput approach. In the present study we demonstrate an inter-platform-compatible method which allowed us to predict the gene expression component involvement of 37 cell populations representing different stages of hematopoietic linage differentiation. The predictions were done for an extensive set of peripheral blood mononuclear cells (PBMC) and bone marrow aspirate material sampled from cytogenetically normal (CN) AML cases. Our results nicely confirmed poor survival prognosis observed for the patients demonstrating high contribution of the CD34+, CD38- hematopoietic stem cells in their bone marrow samples HR = 2.05, 95%CI = 1.22-3.43, p-value = 6.73E-03. We also show that a specific Mature NK cell_CD56+ CD16+ CD3- component found in gene expression signatures of bone marrow samples correlated independently with significantly worse survival in CN AML patients HR = 2.56, 95%CI = 1.49-4.42, p-value = 7.03E-04. Same analysis carried for the CN AML PBMC samples indicated independent positive effects for the predicted involvement of the Erythroid_CD34+ CD71+ GlyA- and Hematopoietic stem cell_CD133+ CD34dim cell populations in The Cancer Genome Atlas (TCGA) CN AML cohort. Acknowledgements The research was supported by a grant from European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION, a grant from the Ministry of Science and Higher Education of Poland [IP2012 048172 (DN)], and a grant from the National Science Centre Poland [2013/10/E/NZ5/00778 (DN)]. Citation Format: Pawel Gaj, Dominika Nowis, Stefano Volinia. Immunophenotypic identities of clinical samples have the potential to correlate with overall survival in cytogenetically normal AML patients. [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 4501.
Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis
Authors: Hussein N. Yassine, Qingru Feng, Ida Azizkhanian, Varun Rawat, Katherine Castor, Alfred N. Fonteh, Michael G. Harrington, Ling Zheng, Bruce R. Reed, Charles DeCarli, William J. Jagust, Helena C. Chui
Journal: JAMA Neurology (2016)

Higher dietary intake of the essential fatty acid docosahexaenoic (DHA) has been associated with better cognitive performance in several epidemiological studies. Animal and in vitro studies also indicate that DHA prevents amyloid deposition in the brain.To determine the association between serum DHA levels, cerebral amyloidosis, and the volumes of brain areas affected by Alzheimer disease.Cross-sectional analysis of serum DHA levels together with measures of amyloid deposition (Pittsburgh Compound B index), brain volumes, and neuropsychological testing scores from 61 participants in the Aging Brain Study. The study was conducted between June 2008 and May 2013, and the data were analyzed between October 2015 and April 2016. Linear models were adjusted for age, sex, years of education, and apolipoprotein E status.Serum DHA levels with cerebral amyloidosis measured using PIB PET.Samples were available from 61 Aging Brain Study participants (41 women and 20 men) who underwent amyloid PET imaging. The mean (SD) age of the participants was 77 (6) years and ranged from 67 to 88 years. Serum DHA levels (percentage of total fatty acids) were 23% lower in participants with cerebral amyloidosis than those without (0.97 vs 1.25, P = .007) and were inversely correlated with brain amyloid load (r = -0.32, P = .01) independent of age, sex, apolipoprotein E genotype, and years of education. Moreover, greater serum DHA levels were positively associated with brain volume in several subregions affected by AD, in particular the left subiculum (r = 0.38, P = .005) and the left entorhinal volumes (r = 0.51, P = .001). Serum DHA levels were also associated with nonverbal memory scores (r = 0.28, P = .03).In this study, serum DHA levels were associated with pathogenesis of cerebral amyloidosis and with preservation of entorhinal and hippocampal volumes. These findings suggest an important role for DHA metabolism in brain amyloid deposition during the preclinical or early symptomatic stages of Alzheimer disease.
Abstract 4579: Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased cell signaling and tumor cell intravasation
Authors: Imani N. Fennell, Kisha A. Scarlett, Christopher J. Coke
Journal: Cancer Research (2016)

Abstract G-protein-coupled receptor (GPCR) heterodimerization has emerged as a means by which new signaling entities can be created with respect to agonist binding. Preliminary data from our lab indicates that agonist-bound GPCR C-X-C Chemokine Receptor 4 (CXCR4) and agonist-bound cannabinoid receptor 2 (CB2R) interact at the cell membrane and that receptor interaction mitigates the effects of CXCL12-mediated CXCR4 signaling. RhoA, Rac1 and Cdc42 are small GTP-binding proteins of the Rho family that are activated downstream of CXCR4 signaling. The effects of RhoA, Rac1 and Cdc42 on the actin cytoskeleton have led to established roles for Rho proteins in cancer cell motility, metastasis and intravasation. Here we report the novel finding that CXCR4/CB2R heterodimerization decreases Rho signaling, resulting in decreased intravasation. To test the effect of receptor heterodimerization on RhoA, Rac1, and Cdc42 activation, PC3 cells were treated with the CXCR4 agonist SDF1α, the CB2R agonist AM1241 or with a combination of SDF1α and AM1241 for 1 minute. Cell lysates were collected and immunoprecipitation experiments were performed to detect RhoA, Rac1 and Cdc42. To test the effects of CXCR4/CB2R heterodimerization on intravsation, we performed a zymography assay for the detection of metalloproteinase-2 (MMP2) and metalloproteinase-9 (MMP9), which are commonly secreted by CXCR4 signaling. Immunopreciptation results indicated an increase in RhoA and Rac1 protein levels after 1 minute in PC3 cells compared to the untreated control. However, when treated with SDF1α and AM1241 for 1 minute, RhoA and Rac1 levels decreased compared to SDF1α independent treatment; there was no observable change in Cdc42 protein levels. The results from the zymography experiments demonstrated that co-treatment with SDF1α and AM1241, which induces CXCR4/CB2R heterodimerization, led to decreased MMP-2 and MMP-9 activity, as compared to the SDF1α-independent treatment. Preliminary results provide novel evidence that CXCR4 and CB2R heterodimerize at the cell membrane, which may result in decreased signaling through RhoA and Rac1, but not through Cdc42. Furthermore, CXCR4/CB2R heterodimerization results in decreased MMP activation, thus abrogating intravsation. Citation Format: Imani N. Fennell, Kisha A. Scarlett, Christopher J. Coke. Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased cell signaling and tumor cell intravasation. [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 4579.
<i>Notes from the Field</i>: Fatal Infection Associated with Equine Exposure — King County, Washington, 2016
Authors: Vance Kawakami, Krista Rietberg, Beth Lipton, Kaye Eckmann, Maryann Watkins, Hanna Oltean, Meagan Kay, Chantal Rothschild, Miwako Kobayashi, Chris Van Beneden, Jeff Duchin
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

On March 17, 2016, Public Health-Seattle & King County in Washington was notified of two persons who received a diagnosis of Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) infections. S. zooepidemicus is a zoonotic pathogen that rarely causes human illness and is usually associated with consuming unpasteurized dairy products or with direct horse contact (1). In horses, S. zooepidemicus is a commensal bacterium that can cause respiratory, wound, and uterine infections (2). The health department investigated to determine the magnitude of the outbreak, identify risk factors, and offer recommendations.
Abstract 4117: AMD070, a novel orally bioavailable CXCR4 inhibitor, inhibits the metastases of oral cancer via SDF-1/CXCR4 system
Authors: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Takahiro Wakui, Kyoko Kuribayashi, Maki Okubo, Masahiro Saito, Eri Masuyama, Hitoshi Kawamata
Journal: Cancer Research (2016)

Abstract We have demonstrated that the stromal cell-derived factor (SDF)-1/CXCR4 system is involved in metastatic processes in oral cancer. Moreover, we have also reported that blocking CXCR4 with AMD3100, a CXCR4 antagonist, may be a potent anti-metastatic therapy for CXCR4-related head and neck cancer. Recently, AMD070 has been described as a novel orally bioavailable inhibitor of CXCR4, being minimally invasive than AMD3100. In this study, we examined the effect of AMD070 on the SDF-1/CXCR4 dependent-metastases in oral cancer cells, B88-SDF-1, which express high levels of SDF-1 and CXCR4. We examined the effect of CXCR4-specific antagonists, AMD3100 and AMD070 on the cell growth, cell migration and cell invasion of B88-SDF-1 cells. Both antagonists did not affect the anchorage-dependent growth of B88-SDF-1 cells, but did inhibit the SDF-1/CXCR4 dependent-migration of the cells. Moreover, AMD070 significantly suppressed anchorage-independent growth and invasion of B88-SDF-1 cells. Next we examined the effect of AMD070 to distant metastasis in vivo. Daily administration of AMD070 per os significantly inhibited the metastasis of B88-SDF-1 cells to the lungs of nude mice. These results indicated that AMD070 might be a novel orally bioavailable inhibitor on the metastases of oral cancer by the SDF-1/CXCR4 system. Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Takahiro Wakui, Kyoko Kuribayashi, Maki Okubo, Masahiro Saito, Eri Masuyama, Hitoshi Kawamata. AMD070, a novel orally bioavailable CXCR4 inhibitor, inhibits the metastases of oral cancer via SDF-1/CXCR4 system. [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 4117.
Kinetic monitoring of EGFR T790M in urinary circulating tumor DNA to predict radiographic progression and response in patients with metastatic lung adenocarcinoma.
Authors: Hatim Husain, Karena Kosco, Cecile Rose T. Vibat, Vlada Melnikova, Mark G. Erlander, Ezra E. W. Cohen, Scott Michael Lippman, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2015)

8081 Background: Acquisition of the EGFR T790M resistance mutation is a hallmark of disease progression in patients with metastatic EGFR mutant lung adenocarcinoma treated with anti-EGFR inhibitors. Biopsies are challenging in relapsed patients and a non-invasive approach to detecting T790M is desired. We sought to monitor urinary circulating tumor (ct) DNA for the early acquisition of T790M and understand ctDNA kinetics in patients on anti-EGFR treatment. Methods: In a biomarker study of 100 patients with EGFR-mutated metastatic lung adenocarcinoma (39 patients enrolled), urine samples were obtained at different time points up to 8 months prior to radiographic progression on anti-EGFR tyrosine kinase inhibitors (TKIs) and at multiple time points post progression on next line therapy. Urinary ctDNA was extracted by a method that preferentially isolates short, fragmented ctDNA. Quantitative analysis of T790M was performed using PCR coupled with next generation sequencing (MiSeq), with standardized reporting of mutant allele copies per 105 genome equivalents. Results: Interim analysis was conducted in 22 patients. EGFR T790M mutation was detected in the urine of 15 out of 22 (68%) patients who received anti-EGFR treatment. Of 15 patients positive for T790M by urine, 10 patients had T790M mutation in tissue biopsy (CLIA test). Three patients, who were tissue T790M negative (n = 3) but had a very high clinical suspicion of T790M, had detectable T790M in both urine and plasma. EGFR T790M was detected in urine up to 3 months prior to the detection of radiographic progression on anti-EGFR TKIs. Examination of urine samples collected daily after initiation of anti-EGFR TKIs and second line therapy revealed early peaks in ctDNA one day after therapy which predicted CT radiographic response. Conclusions: We demonstrate for the first time that T790M can be successfully detected in urinary ctDNA months before progression on anti-EGFR TKIs. Urinary ctDNA testing identifies additional patients who are potentially eligible for anti-T790M treatment. Urine monitoring can enable dynamic assessment of response and progression from a completely non-invasive sample.
Investigation of non-V600 BRAF mutations commonly found in NSCLC for their sensitivity to dabrafenib or trametinib.
Authors: Amir Noeparast, Gil Verschelden, Ijeoma Umelo, Sylvia De Brakeleer, Lore Decoster, Erik Teugels, Jacques De Greve
Journal: Journal of Clinical Oncology (2015)

11091 Background: The most common BRAF mutations in non-small cell lung cancer (NSCLC) are non-V600 in contrast to melanoma. BRAF pathway inhibitors have not been systematically investigated in non-V600 mutations in vitro and in the clinic. We tested the effect of two clinically available BRAF pathway inhibitors (Trametinib and Dabrafenib) on a subset of clinically identified BRAF mutations in a cohort of lung cancers enriched for adenocarcinoma in patients with no or limited smoking history. Methods: NSCLC tumor samples (FFPE) were tested for the presence of EGFR, KRAS, NRAS, HRAS and BRAF mutations by DGGE or NGS-based methods. We generated 15 BRAF expression plasmids, harboring the mutations found in the given cohort and others described in the literature. BRAF mutants were subjected to an in vitro kinase assay. BRAF constructs were also expressed in HEK293T cells (with and without wt-CRAF) to study their impact on ERK signaling and determine the effect of inhibitors. Results: Among 229 NSCLC patients, 12 patients (5.2%) were found to harbor a BRAF mutation in their tumor: V600 (25%), G469A (16.7%), G469V (8.3%), D594N (25%), D594E (8.3%), G596C (8.3%) and G466V (8.3%). Mutations were characterized as activating or kinase-impaired (in-vitro kinase assay) . Kinase-impaired BRAF mutants could still activate the ERK pathway in a CRAF-dependent manner, more than wt-BRAF/wt-CRAF co-transfectant. A MEK inhibitor (Trametinib) and a selective BRAF-inhibitor (Dabrafenib) were tested at clinically relevant doses on HEK293T transfectants (either expressing BRAF mutant alone or together with CRAF). ERK signaling induced by activating mutations was reduced in response to both inhibitors separately. Trametinibinhibited the CRAF-dependent ERK signaling induced by impaired-kinase BRAF mutations. Dabrafenib activated the ERK pathway in cells expressing only CRAF as well as cells co-expressing a kinase-impaired BRAF mutation and CRAF. Conclusions: This study predicts sensitivity of activating non-V600 BRAF mutations in lung cancer to Trametinib or Dabrafenib. Targeting kinase impaired BRAF mutations which signal through CRAF using Dabrafenib will require the addition of Trametinib.
Abstract 3106: Elucidating molecular mechanisms linking microRNA-206 loss to tumor progression and metastasis
Authors: Kathleen D. Watt, Peter Truesdell, Andrew W. Craig
Journal: Cancer Research (2015)

Abstract Metastasis is the leading cause of cancer-related deaths, and this occurs when tumor cells invade basement membranes and blood vessels to colonize other tissues. Metastasis is facilitated by extracellular matrix (ECM)-degrading structures called invadopodia. Recently, several microRNAs (miRNAs) have been identified as tumor and metastasis suppressor genes. Loss of expression of miR-206 has been correlated with poor prognosis in gastric cancer, breast cancer, rhabdomyosarcoma and melanoma. A previous study by others has demonstrated that restoring miR-206 expression in human breast cancer cells was sufficient to block metastasis in tumor xenograft assays. However, the targets of miR-206 that cause metastasis in these cancer models have not been fully characterized. Here, we have tested the effects of miR-206 on invadopodia in metastatic cancer cells, and identified a novel target that may explain this effect. Transducer of Cdc42-mediated Actin assembly-1 (Toca-1) is an adaptor protein that promotes formation of invadopodia and metastasis in breast cancer models, and has a predicted miR-206 binding site within the 3′ UTR of Toca-1 transcripts. To test whether the high levels of Toca-1 expression that we have observed in metastatic cancer cell lines was due to loss of miR-206, we rescued miR-206 expression using transient, stable or inducible approaches in MDA-MB-231 breast cancer, A375 melanoma, and H1299 lung cancer cell lines. In each cell model, Toca-1 expression was reduced upon miR-206 expression at both the mRNA and protein levels, thus validating Toca-1 as a new target of miR-206. Further testing of the phenotypes induced by miR-206 rescue revealed dramatic defects in ECM degradation and cell invasion in breast cancer and melanoma cell models. In subcutaneous tumor xenograft assays, stable rescue of miR-206 in H1299 tumors led to defects in tumor growth compared to those expressing a scrambled control miRNA. In addition, miR-206 expression caused a dramatic reduction in the numbers of lung metastases. We are currently extending this to our melanoma models and inducible models to define changes in metastasis-related targets of miR-206 that are aberrantly expressed in metastatic cancers. In conclusion, our study demonstrates for the first time a link between miR-206 and suppression of invadopodia formation via Toca-1 silencing, which likely contributes to the metastasis suppressing activity of miR-206 in multiple cancer types. Citation Format: Kathleen D. Watt, Peter Truesdell, Andrew W. Craig. Elucidating molecular mechanisms linking microRNA-206 loss to tumor progression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3106. doi:10.1158/1538-7445.AM2015-3106
Abstract 839: Novel polypectomy system in a preclinical model of colon cancer
Authors: Furkan U. Ertem, Wan-Mohaiza Dashwood, Praveen Rajendran, Gottumukkala Raju, Asif Rashid, Roderick Dashwood
Journal: Cancer Research (2016)

Abstract Colonoscopy has been used for over a decade to monitor tumor progression in live animals. However, murine models typically have not involved routine resection of entire lesions, to parallel the clinical scenario in which polyps are observed and removed during a colonoscopy examination. A polyp resection (polypectomy) protocol was developed in the polyposis in rat colon (Pirc) model. Because a major cause of morbidity in such rodent models involves blockage of the colon, polypectomy can be used as a preventive strategy, helping to prolong the lifespan of the animal. Polypectomy in murine models opens the door to longitudinal prevention studies, and determining the molecular changes in resected tumors. A means of specifying the location of each lesion within the colon also was developed in order to track individual polyps in a temporal manner. The “PLC” classification system has three components: P, polyp number from the tail-end; L, location of the polyp from the tail-end; and C, clock face orientation of the polyp within the gut lumen. In summary, we developed a novel murine polypectomy protocol that closely parallels the human clinical scenario during a screening colonoscopy. The procedure employed the Pirc model, but it is directly applicable to longitudinal studies in other murine models of colon cancer. This work was supported by P01 grant CA090890 from the National Cancer Institute, by P30 grant ES023512 from the National Institute of Environmental Health Sciences, by the John S. Dunn Foundation, and by a Chancellor's Research Initiative from Texas A&amp;M University. Citation Format: Furkan U. Ertem, Wan-Mohaiza Dashwood, Praveen Rajendran, Gottumukkala Raju, Asif Rashid, Roderick Dashwood. Novel polypectomy system in a preclinical model of colon 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 839.
Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response
Authors: Giada Farinelli, Raisa Jofra Hernandez, Alice Rossi, Serena Ranucci, Francesca Sanvito, Maddalena Migliavacca, Chiara Brombin, Aleksandar Pramov, Clelia Di Serio, Chiara Bovolenta, Bernhard Gentner, Alessandra Bragonzi, Alessandro Aiuti
Journal: Molecular Therapy (2016)

Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.
The PREVEND risk model for new onset heart failure with preserved and reduced ejection fraction
Authors: F. P. J. Brouwers, Q. Cao, P. P. Van Geel, A. A. Voors, R. T. Gansevoort, R. A. De Boer, P. Van der Harst, D. J. Van Veldhuisen, W. H. Van Gilst, J. H. Hillege
Journal: European Journal of Heart Failure (2014)