tbuckley/cabot-search huggingface dataset:
Abstract LB-182: Differential modulation of the PD-1 pathway impacts the anti-tumor activity of CAR T cells
Authors: Regina J. Lin, Anne-Sophie Gautron, Laurent Poirot, Oi Kwan Wong, Barbra Sasu, Bijan Boldajipour
Journal: Cancer Research (2017)

Abstract Adoptive T cell therapy using ex vivo expanded tumor-infiltrating lymphocytes (TILs) or T cells engineered with chimeric antigen receptors (CAR T) has shown tremendous success in many hematological diseases, however treatments of solid tumors have been less successful so far. It is presumed that adoptive cell therapy is limited by the presence of immune-suppressive mechanisms within the solid tumor microenvironment. To enhance T cell activity against solid tumors, we seek to overcome these immune barriers and one approach is to do this by blocking checkpoints such as the PD-1 receptor. Using CAR T cells targeting the glioblastoma (GBM) tumor-specific antigen EGFRvIII, we investigated 3 approaches of inhibiting PD-1: (i) shRNA-mediated knockdown, (ii) TALEN®-mediated knockout, and (iii) antibody-mediated blockade. In contrast to the PD-1 antibody that augmented CAR T cell activity in vivo, the PD-1 shRNA impaired the anti-tumor activity of CAR T cells in vitro and in vivo. Detrimental effects of the PD-1 shRNA were associated with impaired survival of CAR T cells in vitro and in vivo. Interestingly, TALEN®-mediated PD-1 knockout generated CAR T cells with superior cytotoxic potency and prolonged functional persistence in vitro. Further characterization of PD-1 TALEN® CAR T cells, and how they compare in activity against the CAR T/anti-PD-1 combination in both subcutaneous and intracranial GBM models, is underway. These studies will not only elucidate the role of PD-1 in CAR T cell biology, but also inform CAR T cell combination therapy approaches for solid tumor indications. Citation Format: Regina J. Lin, Anne-Sophie Gautron, Laurent Poirot, Oi Kwan Wong, Barbra Sasu, Bijan Boldajipour. Differential modulation of the PD-1 pathway impacts the anti-tumor activity of CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2017-LB-182
HIV agenda must be prioritised to reduce deaths from AIDS in sub-Saharan Africa
Authors: Sophie Cousins
Journal: BMJ (2017)

Treatment failure and late HIV diagnosis are leading to an “unacceptably high” number of people across sub-Saharan Africa dying of AIDS related diseases, a leading medical charity has said.

A new report from Medecins Sans Frontieres (MSF) found that hospitals run and supported by the organisation in the Democratic Republic of Congo, Guinea, Kenya, and Malawi were seeing a 30-40% mortality rate among patients with HIV. 1 Almost one third of those deaths occurred within 48 hours of patients being admitted to hospital, and 78% of these patients had been taking antiretroviral drugs for an average of six years, …
Abstract 5493: The cistrome of estrogen receptor beta in colorectal cancer cells
Authors: Rajitha Indukuri, Jun Wang, Fahmi Mesmar, Cecilia Williams
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is the second leading cause of death in the United States and a truly preventive approach still remains to be developed. Men have the highest incidence rate for CRC and pre-menopausal women have a lower incidence of CRC, suggesting hormonal factors mediate protective roles. ERβ is the predominantly expressed estrogen receptor in the colonic epithelium and is lost during CRC progression. In colon cancer cell lines re-expression of ERβ has anti proliferative and anti-inflammatory properties, there is however little understanding of the mechanism whereby ERβ mediates these effects in colon cells. In order to elucidate the mechanism of ERβ in CRC, we re-expressed this receptor using lentivirus in four different CRC cell lines. We optimize chromatin-immunoprecipitation (ChIP) with an antibody thoroughly validated for this purpose and used IgG and input as well as cell lines without ERβ expression as controls. ChIP-seq was performed using Illumina library preparation and next generation sequencing. Alignment of sequence reads against the reference genome of version hg19 was done using Bowtie, and statistically significant peaks (FDR) were identified using MACS. Results were compared to RNA-seq analysis of the same cell lines. Key binding-sites and corresponding gene regulations were confirmed using qPCR. We present for the first time, the cistrome of ERβ in different CRC cell lines. We identify key binding motifs, including ERE and AP-1 sites. Together, our results uncover ERβ as an important determinant for attenuating cancer progression. Note: This abstract was not presented at the meeting. Citation Format: Rajitha Indukuri, Jun Wang, Fahmi Mesmar, Cecilia Williams. The cistrome of estrogen receptor beta in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2017-5493
Abstract 2256: Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer
Authors: Shingo Kawano, Kota Amemiya, Yuki Tsuchiya, Toshiaki Hagiwara, Hirokazu Matsuzawa, Yurika Makino, Shunsuke Motegi, Ryoichi Tsukamoto, Ryosuke Ichikawa, Kazumasa Kure, Kumpei Honjo, Hisashi Ro, Shingo Ito, Yu Okazawa, Rina Takahashi, Kosuke Mizukoshi, Masaya Kawai, Shinya Munakata, Koichiro Niwa, Shun Ishiyama, Kiichi Sugimoto, Hirohiko Kamiyama, Hiromitsu Komiyama, Makoto Takahashi, Yutaka Kojima, Michitoshi Goto, Atsushi Okuzawa, Yuichi Tomiki, Kazuhiro Sakamoto, Motohiro Kojima, Atsushi Ochiai
Journal: Cancer Research (2017)

Abstract Background: Generally, Semaphorins are secretary or transmembrane-bound molecules that act as axon guidance cues in the nervous system. Recent research showed increased expression of semaphorin 3C correlates with cancers that possess higher invasive and metastatic characteristics. For example, in breast cancer, inhibition of semaphorin 3C reduces adhesion and invasion. The aim of this study was to evaluate a possibility that semaphorin 3C might be a new prognostic marker in colorectal cancer. Material and methods: We used two cohorts. Cohort 1 was the 192 patients with colorectal cancer resected surgically between 2009 and 2010. We used GSE 14333 dataset as Cohort 2 which included 226 patients with the colorectal cancer. In each cohorts, we divided the patients in to the two groups i.e., high or low semaphorin 3C expression group using receiver operating characteristic (ROC) curve based on the information of the recurrence of colorectal cancer. Disease-free-survival (DFS) rates were calculated using Kaplan-Meier methods. Differences between curves were evaluated with the log-rank test. Results: In the cohort 1, the DFS in the patients with higher expression was worse than that in the patients with lower expression (P = 0.0467). Semaphorin 3C has two probes (203788_s_at and 203789_s_at) in GSE14333. In the cohort 2, using each two probe of semaphorin 3C, the DFS in the patients with higher expression was worse than that of those patients with lower expression (P = 0.0015 and P = 0.0003). Conclusions: This study suggested that Semaphorin 3C might be a new prognostic marker in colorectal cancer. Citation Format: Shingo Kawano, Kota Amemiya, Yuki Tsuchiya, Toshiaki Hagiwara, Hirokazu Matsuzawa, Yurika Makino, Shunsuke Motegi, Ryoichi Tsukamoto, Ryosuke Ichikawa, Kazumasa Kure, Kumpei Honjo, Hisashi Ro, Shingo Ito, Yu Okazawa, Rina Takahashi, Kosuke Mizukoshi, Masaya Kawai, Shinya Munakata, Koichiro Niwa, Shun Ishiyama, Kiichi Sugimoto, Hirohiko Kamiyama, Hiromitsu Komiyama, Makoto Takahashi, Yutaka Kojima, Michitoshi Goto, Atsushi Okuzawa, Yuichi Tomiki, Kazuhiro Sakamoto, Motohiro Kojima, Atsushi Ochiai. Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2256. doi:10.1158/1538-7445.AM2017-2256
Abstract SY25-04: Tumor and host factors regulating immunotherapy responsiveness
Authors: Thomas Frank Gajewski
Journal: Cancer Research (2017)

Abstract Checkpoint blockade immunotherapy is favored in patients having a T cell-inflamed tumor microenvironment at baseline. Therefore, absence of a T cell-inflamed phenotype represents a first approximation of immunotherapy resistance. Investigation of molecular features of tumor genomics, host genetics, and commensal microbiota that correlate with the degree of spontaneous T-cell infiltration has revealed multiple layers of pathways that impact on relative response versus resistance to immunotherapeutic interventions. The first tumor-intrinsic oncogene pathway demonstrated mechanistically to mediate T-cell exclusion from the tumor microenvironment and lack of checkpoint blockade efficacy is the Wnt/β-catenin pathway. Additional molecular aberrations correlated with deficient immune infiltration in various cancers include loss of function mutation or absence of PTEN, LKB1, or p53 and activation of FGFR3 or PPAR-γ. Mouse modeling has revealed that tumor cell-intrinsic β-catenin pathway activation also mediates downstream resistance to adoptive T-cell therapy, due to defective expression of key chemokines. In one patient case analyzed, transition from a β-catenin-negative to a β-catenin-positive phenotype has been associated with secondary resistance to immunotherapy. TCGA and other large genomic datasets have been an invaluable tool for identifying such molecular correlates, through availability of tumor RNAseq and exome sequencing data as well as germline SNP analysis. Host germline polymorphisms also have been identified that correlate with the degree of T-cell infiltration in the tumor, and mouse models are being utilized to investigate mechanisms. Specific commensal bacteria associated with the degree of T-cell infiltration also have been identified in animal models, and similar analyses are ongoing with human stool samples in patients undergoing checkpoint blockade therapy. A common feature of non-T cell-inflamed tumors is a relative lack of Batf3-dendritic cells and absence of a type I IFN gene signature. Thus, regulation at the level of innate immunity seems to be a key determining factor. Strategies aimed at boosting innate immune activation in the tumor microenvironment represent a major category of therapeutic intervention to convert non-T cell-inflamed tumors to T cell-inflamed, and STING agonists and probiotics are beginning to be investigated clinically. Citation Format: Thomas Frank Gajewski. Tumor and host factors regulating immunotherapy responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-04. doi:10.1158/1538-7445.AM2017-SY25-04
Abstract 1411: Differential mismatch repair-dependent damage responses in subpopulations of cells from human intestinal organoids
Authors: Bo Lin, Qingfen Yang, Abhijit Rath, Christopher D. Heinen
Journal: Cancer Research (2017)

Abstract Hereditary mutations in DNA mismatch repair (MMR) genes cause the cancer predisposition syndrome called Lynch syndrome. Patients predominantly develop colorectal cancer and some extracolonic cancers at a young age. The MMR pathway repairs mismatches created during DNA replication, but also can induce apoptosis and cell cycle arrest in response to certain DNA damaging agents as a protective mechanism to eliminate cells at risk of accumulating mutations. Our understanding of this MMR-directed DNA damage response has come primarily from studies in human cancer cell lines. We wished to examine the role of the MMR-dependent damage response in a model that may be more relevant to the human intestine. Therefore, we have created human intestinal organoids (HIOs) in vitro either by directing the differentiation of human embryonic stem cells (hESCs) or through culturing of adult intestinal tissue samples. We have used these HIOs to specifically study the MMR dependent damage response to DNA alkylation damage. We have found that whereas hESCs undergo rapid apoptosis in response to alkylation damage, the differentiated HIOs or those created from adult tissues undergo not only apoptosis, but also senescence and accelerated differentiation following damage. Using CRISPR-Cas9 gene editing in hESCs, we also created MMR-deficient HIOs that failed to respond to the drug indicating that these responses are MMR-dependent. We then determined that the cells undergoing apoptosis following DNA damage are most likely the intestinal stem cells suggesting that different cell types in the intestine have different MMR-dependent responses to damage. Together these results suggest that loss of MMR function in the intestinal crypts may provide a selective advantage particularly in an environment conducive with DNA damage that promotes tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Bo Lin, Qingfen Yang, Abhijit Rath, Christopher D. Heinen. Differential mismatch repair-dependent damage responses in subpopulations of cells from human intestinal organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1411. doi:10.1158/1538-7445.AM2017-1411
Abstract 494: Frequent <i>NRG1</i> genomic rearrangements in invasive mucinous adenocarcinoma from caucasian patients
Authors: Domenico Trombetta, Giulio Rossi, Angelo Sparaneo, Federico P. Fabrizio, Maria C. Manzorra, Evaristo Maiello, Vito M. Fazio, Paolo Graziano, Lucia A. Muscarella
Journal: Cancer Research (2017)

Abstract Invasive Mucinous Adenocarcinoma (IMA) accounts for 2-5% of lung adenocarcinomas and it is associated with an unfavorable clinical course, mainly due to lack of effective treatments. Current knowledge of the molecular alterations involved in IMAs is limited. Recently, the NRG1 genomic rearrangement was identified as a subtype-specific molecular feature of Asiatic IMA cohorts since it acts as a strong inductor of the aberrant tyrosine kinase activity of ErbB2/ErbB3 heterodimers through PI3K–AKT and MAPK cellular cascades. In light of these premises we explored the occurrence and frequency of NRG1 fusions in a cohort of 90 Formalin Fixed Paraffin Embedded (FFPE) lung adenocarcinoma from Caucasian patients (35 non-IMAs and 55 IMAs) by performing FISH analysis to study the NRG1 genomic region (β-III isoform, chr 8p12). In total, 16 out of 55 (29%) IMAs showed NRG1 rearrangements, whereas in non-mucinous lung adenocarcinoma group it was found with a frequency of 3% (1/35). The functional effect of the genomic rearrangement was confirmed by RT-PCR and sequencing in three cases with available RNA, where NRG1-CD74 fusion transcripts were identified. An aberrant expression of pErbB3 was also observed in these three NRG1 rearranged cases by performing immunohistochemistry analysis, thus confirming the ErbB3 cascade activation. Our results strongly confirm NRG1 rearrangements as potentially treatable oncogenic driver alterations associated with a definite lung adenocarcinoma subtype in Caucasian population and support a clear molecular rationale to novel therapeutic opportunity for these aggressive tumors. Note: This abstract was not presented at the meeting. Citation Format: Domenico Trombetta, Giulio Rossi, Angelo Sparaneo, Federico P. Fabrizio, Maria C. Manzorra, Evaristo Maiello, Vito M. Fazio, Paolo Graziano, Lucia A. Muscarella. Frequent NRG1 genomic rearrangements in invasive mucinous adenocarcinoma from caucasian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 494. doi:10.1158/1538-7445.AM2017-494
Abstract 1317: Simultaneous identification of candidate melanoma risk variants using massively parallel reporter assay
Authors: Jiyeon Choi, Tongwu Zhang, Michael Kovacs, Mai Xu, Nghi Lam, Leandro Colli, Kevin Brown
Journal: Cancer Research (2017)

Abstract Recent melanoma Genome-Wide Association Study (GWAS) has identified 20 common susceptibility loci via meta-analysis of ~15,000 cutaneous malignant melanoma cases. While GWAS is extremely powerful in identifying genomic regions contributing to melanoma risk, teasing out functional variants and unraveling molecular mechanisms by which the risk is conferred presents a tremendous challenge due to limited resolution of genetic structure and lack of high-throughput assay system. To simultaneously identify functional risk variants from multiple GWAS loci, we employed recently developed Massively-Parallel Reporter Assays (MPRA). Based on the hypothesis that many GWAS functional variants regulate gene expression through transcriptional mechanism, we systematically examined allele-specific transcriptional activities of genetically indistinguishable candidate variants. Out of ~2,800 melanoma-associated variants (r2&amp;gt;0.4, EUR) from 16 melanoma loci for which transcriptional mechanism could be applied, 835 variants were prioritized based on their relevance as melanocyte-/melanoma-specific cis-element represented by ENCODE annotation as open chromatin or putative promoter/enhancer histone marks in melanocytes and melanoma cell lines. Pooled oligoes of 145bp encompassing each variant with either melanoma risk or protective allele coupled with 10 different unique sequence tags were cloned into luciferase vectors and transfected to melanoma cell lines. Resulting expressed tag counts were subsequently determined using massively parallel sequencing. We were able to identify ~200 potentially functional variants displaying allelic transcriptional activity by combining transfections in a melanoma cell line and HEK293FT cell line. Top functional SNPs from melanoma GWAS loci were also shown as significant eQTL SNPs in human melanocytes including MX2 on chromosome 21. Overlaying MPRA functional SNPs with melanocyte eQTL SNPs further enabled isolation of a functional risk variant among several highly linked MX2 eQTL SNPs. The results from this analysis will greatly accelerate the identification of functional melanoma risk variants and further shed light on molecular mechanisms of genetic susceptibility of melanoma in population. Citation Format: Jiyeon Choi, Tongwu Zhang, Michael Kovacs, Mai Xu, Nghi Lam, Leandro Colli, Kevin Brown. Simultaneous identification of candidate melanoma risk variants using massively parallel reporter assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1317. doi:10.1158/1538-7445.AM2017-1317
Abstract 2754: A novel liquid biopsy method for development of aptamer libraries that bind blood plasma exosomes from breast cancer patients
Authors: Valeriy Domenyuk, Symon Levenberg, Adam Stark, Mark Miglarese, David Spetzler
Journal: Cancer Research (2017)

Abstract Improved technologies capable of characterizing system-wide changes associated with complex diseases will be required to be able to detect millions of proteins and their isoforms as well as multi-molecular complexes. We present a method for developing aptamer libraries using blood plasma exosomes that provides unprecedented system-wide coverage of native exosomal complexes. To train a naïve aptamer library toward cancer samples (positive selection), the library (~1013 biotinylated ssODN species) was incubated with plasma from individual cancer patients and aptamer-bound exosomes were isolated using polymer-based precipitation. Negative selection was performed by contacting the aptamer library with exosomes from donors without breast cancer and recovering unbound aptamers from the supernatant. In all, 12 libraries trained toward 12 individual breast cancer patients were used to probe additional samples. Exosome-bound aptamers were identified and quantified by Next Generation Sequencing (NGS) to build highly accurate signatures for cancer/healthy donor classification. Using these signatures, cancer patients’ binding profiles were easily distinguishable from controls. Interestingly, cancer-trained libraries did not distinguish any of the negative control samples from each other, indicating that the selection pressure for cancer was high and noise due to inherent inter-healthy donor heterogeneity was minimal. Full validation studies are ongoing. Aptamer libraries may ultimately be deployed as a minimally-invasive diagnostic adjunct in breast and other cancers. Citation Format: Valeriy Domenyuk, Symon Levenberg, Adam Stark, Mark Miglarese, David Spetzler. A novel liquid biopsy method for development of aptamer libraries that bind blood plasma exosomes from breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2754. doi:10.1158/1538-7445.AM2017-2754
Heritable components of the human fecal microbiome are associated with visceral fat
Authors: Caroline I. Le Roy, Michelle Beaumont, Matthew A. Jackson, Claire J. Steves, Timothy D. Spector, Jordana T. Bell
Journal: Gut Microbes (2017)

Obesity and its associated diseases are one of the major causes of death worldwide. The gut microbiota has been identified to have essential regulatory effects on human metabolism and obesity in particular. In a recent study we provided some insights into the link between the gut microbiota (GM) and adiposity, as well as host genetic modulation of these processes. Our results identify novel evidence of association between 6 adiposity phenotypes and faecal microbial operational taxonomic units (OTUs). Accumulation of visceral fat, a key risk factor for cardio-metabolic disease, has the strongest and most pervasive signature on the gut microbiota of the factors we examined. Furthermore, we observe that the adiposity-associated OTUs were classified as heritable and in some cases were also associated with host genetic variation at obesity-associated human candidate genes FHIT, TDRG1 and ELAVL4. This addendum confirms our previously published results in the TwinsUK cohort using a different approach to OTU clustering and multivariate analysis, and discusses further the importance of considering the GM as a complex ecosystem.