tbuckley/cabot-search huggingface dataset:
Abstract 1858: Theranostic nanoparticles for detection and treatment of pancreatic cancer
Authors: Phillip Chuong, Neal Bhutiani, Lacey R. McNally
Journal: Cancer Research (2017)

Abstract Background: Despite continued efforts to improve early detection and treatment of pancreatic adenocarcinoma, the disease still carries a poor prognosis. The combination of multispectral optoacoustic tomography (MSOT) and theranostic nanoparticles offers a possible solution by providing tumor targeting using fluorescent dyes and treatment through drug delivery. We describe a 40 nm colloidal mesoporous silica nanoparticle (CMS) with vermiform pores and a chitosan coating and tagged with the V7 peptide to provide pH-specific dual targeting to deliver a contrast agent in a tumor-specific fashion. Methods: CMSs were synthesized using a modified Stober method, coated with chitosan, and conjugated with a V7 peptide, resulting in a dual acidic pH targeting system. Particle characterization was performed using transmission electron microscopy (TEM), UV-vis spectrophotometry, Zeta potential, and dynamic light scattering . To determine acidic pH specificity of V7-CMS, Panc1 and S2VP10 cell lines were incubated in cell culture medium at either pH 7.4 or 6.6 followed by treatment with V7-CMS. Particle uptake was determined using near infrared (NIR) fluorescence and tissue phantoms. Finally, for in vivo testing, the same CMSNs were injected into mice bearing S2VP10 pancreatic tumors. MSOT imaging was performed 8 hours after CMS injection. Results: TEM images demonstrated successful synthesis of approximately 40 nm V7-CMSs with vermiform pores. On NIR imaging, V7-CMS demonstrated acidic pH specificity in both S2VP10 and Panc 1 cells at pH 6.6, with particle localization and signal intensity 8-fold and 5-fold higher, respectively, than that observed at pH 7.4. In tissue phantoms, increased pH specificity was also observed in both S2VP10 and Panc 1 cells at pH 6.6. Particle location and signal intensity on MSOT was 20-fold and 4-fold higher, respectively, than that observed at pH 7.4. In the murine orthotopic S2VP10 pancreatic tumor model, MSOT imaging 8 hours after IV CMS injection demonstrated V7-CMS accumulation specifically within pancreatic tumors. Conclusion: The acidic pH specific dual targeting system using chitosan-coated and pHLIP V7-tagged CMSs results in tumor specificity. Preferential binding and dye release was increased as much as 20-fold at pH 6.6 as compared to pH 7.4 in tissue phantoms. MSOT was able to detect tumor specific accumulation of V7-CMS in vivo. These small, pH specific particles hold significant promise for effectively identifying pancreatic tumors with high sensitivity and specificity and for targeted drug delivery. Note: This abstract was not presented at the meeting. Citation Format: Phillip Chuong, Neal Bhutiani, Lacey R. McNally. Theranostic nanoparticles for detection and treatment of pancreatic 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 1858. doi:10.1158/1538-7445.AM2017-1858
Abstract 411:In vivopooled shRNA library identifies KPNB1 as a new drug target for epithelial ovarian cancer
Authors: Michiko Kodama, Takahiro Kodama, Kosuke Yoshihara, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal Copeland, Nancy Jenkins
Journal: Cancer Research (2017)

Abstract Objective Epithelial ovarian cancer (EOC) is a most lethal cancer in gynecology, of which cure rate is 30%. To seek its new therapeutic targets, we performed in vivo loss of function screen. Method Human EOC cell line, SKOV3, was transduced with pooled druggable shRNA library containing 42450 shRNAs targeting 7490 genes. Transduced cells were intraperitoneally injected into 12 female nude mice and monitored for PC tumor formation. Genomic DNA of 12 biggest PC tumors were sequenced to identify shRNAs depleted in these tumors. Results Ten potential drug targets were identified, including 2 known oncogenes, ERBB2 and RAF1. Second highest ranked gene, KPNB1, is known as a nuclear transporter. KPNB1 inhibition significantly decreased and overexpression increased in vitro cell proliferation in multiple EOC cell lines. KPNB1 inhibition caused multi-phase cell cycle delay at both of G1/S and G2/M transition via elevation of p21 and p27 and induced apoptosis. KPNB1 inhibition significantly decreased in vivo tumor formation through the same mechanism as in vitro, because more cleaved PARP and less Ki67 positive cells were found in KPNB1 knockdown tumors via immunochemical staining. We found a positive correlation between KPNB1 mRNA levels and poor survival of EOC patients, suggesting the oncogenic role of KPNB1 in human EOC. Comprehensive mass spectrometric study identified that KPNB1 positively regulated several members of anaphase promoting complex/cyclosome. Lastly, we found that ivermectin, a well-known anti-parasitic drug, exerted an anti-proliferative effect on EOC cell lines via KPNB1 inhibition, and its combination with paclitaxel synergistically suppressed cell proliferation in vitro and inhibited tumor formation in vivo. Conclusion In vivo pooled shRNA library screen identified KPNB1 as a new drug target for EOC. Ivermectin can be a new therapeutics for EOC especially combined with paclitaxel. Citation Format: Michiko Kodama, Takahiro Kodama, Kosuke Yoshihara, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal Copeland, Nancy Jenkins. In vivo pooled shRNA library identifies KPNB1 as a new drug target for epithelial ovarian 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 411. doi:10.1158/1538-7445.AM2017-411
Abstract LB-243: Precision medicine: Lung biomarkers
Authors: Curtis C. Harris
Journal: Cancer Research (2017)

Abstract More than half of all new lung cancer diagnoses are made in patients with locally advanced or metastatic disease, at which point therapeutic options are scarce. It is anticipated, however, that the widespread use of Low-Dose Computed Tomography (LDCT) screening, will lead to a greater proportion of lung cancers being diagnosed at an early, operable, stage. Still, the overall rate of recurrence for surgically treated Stage I lung cancer patients is up to 30% within 5 years of diagnosis. Thus, the identification and clinical application of biomarkers of early stage lung cancer are a pressing medical need. The integrative analysis of "omic," clinical and epidemiological data for single patients is a core principle of precision medicine. Through rigorous bioinformatics and statistical analyses we have identified biomarkers of early-stage lung cancer based on DNA methylation, expression of mRNA and miRNA, inflammatory cytokines, and urinary metabolites. Beyond a more comprehensive understanding of the molecular taxonomy of lung cancer, these biomarkers can have very practical implications in the context of unmet clinical needs of early stage lung cancer patients: First, current guidelines for LDCT screening broadly include individuals based on age and history of heavy smoking. Tumor-derived circulating biomarkers in the blood and urine associated with lung cancer risk could narrow and prioritize individuals for LDCT screening. Second, a high number of nodules are identified by LDCT, of which fewer than 5% are finally diagnosed as lung cancer. Biomarkers may help discriminate malignant nodules from benign or indolent lesions. Third, the expected rise in the numbers of lung cancer patients diagnosed at an early stage will necessitate new treatment options. Circulating, urinary and tissue-based biomarkers that molecularly categorize Stage I patients after tumor resection can help identify high-risk patients who may benefit from adjuvant chemotherapy or innovative immunotherapy regimens. References 1. Vargas, A.J. and C.C. Harris, Biomarker development in the precision medicine era: lung cancer as a case study. Nat Rev Cancer, 2016. 16(8): p. 525-37. 2. Robles, A.I. and C.C. Harris, Integration of multiple "OMIC" biomarkers: A precision medicine strategy for lung cancer. Lung Cancer, 14 June 2016: p. [Epub ahead of print]. 3. Robles, A.I., et al., An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers. J Thorac Oncol, 2015. 10(7): p. 1037-48. Citation Format: Curtis C. Harris. Precision medicine: Lung biomarkers [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-243. doi:10.1158/1538-7445.AM2017-LB-243
Abstract 3334: The FGFR4-388Arg variant exerts pro-tumorogenic effects in lung cancer by inducing an EMT phenotype
Authors: Álvaro Quintanal-Villalonga, Rocío Suárez, Laura Ojeda-Márquez, Santiago Ponce-Aix, Amancio Carnero, Luis Paz-Ares, Irene Ferrer, Sonia Molina-Pinelo
Journal: Cancer Research (2017)

Abstract The FGFR4-388Arg allele, where an arginine substitutes a glycine in the 388 codon of the FGFR4 gene, has been associated to poorer patient outcome in different tumor types. In lung cancer, the variant has been related to shorter overall survival in adenocarcinoma (ADC) patients, while no relationship with squamous cell carcinoma prognosis (SCC) has been reported. Mechanistically, the FGFR4-388Arg variant has been related to increased MAPK pathway activation and to EMT in prostate cancer in vitro models. Furthermore, the variant has been associated with higher STAT3 signaling in murine models of breast and lung cancer. However, so far the molecular biology for this FGFR4 variant in lung cancer patients has not been addressed. We overexpressed the FGFR4-388Gly and FGFR4-388Arg variants in lung cancer cell lines from different histologic backgrounds and performed tumorogenicity surrogate assays and downstream signaling activation assessment. In the generated stable cell lines, we also determined the expression of EMT markers. Furthermore, we determined the FGFR4 variant and the FGFR4 and N-cadherin mRNA expression in a cohort of NSCLC patients (N=65) and correlated these data to patient outcome. We reported that FGFR4-388Arg increases tumorogenicity in lung cancer cell lines. Mechanistically, these functional effects seem to be mediated by MAPK and STAT3 overactivation and by the induction of an EMT phenotype, which includes N-cadherin increased expression. In fact, this induction of N-cadherin protein expression by the FGFR4-388Arg variant seems to be responsible for the pro-oncogenic effects reported. In NSCLC patient tumor samples, the FGFR4-388Arg variant correlates with higher N-cadherin expression and with poorer survival. In conclusion, the FGFR4-388Arg variant is a potential prognostic biomarker in NSCLC, including ADC and SCC patients. This variant increases tumorogenesis through the activation of MAPK and STAT3 signaling pathways and through the promotion of an EMT phenotype. Citation Format: Álvaro Quintanal-Villalonga, Rocío Suárez, Laura Ojeda-Márquez, Santiago Ponce-Aix, Amancio Carnero, Luis Paz-Ares, Irene Ferrer, Sonia Molina-Pinelo. The FGFR4-388Arg variant exerts pro-tumorogenic effects in lung cancer by inducing an EMT phenotype [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 3334. doi:10.1158/1538-7445.AM2017-3334
Abstract 397: Whole genome copy number variation analysis using a SNP-focused targeted sequencing panel for tumor analysis
Authors: Jiashi Wang, Kristina Giorda, Zhongwu Lai, Daniel Stetson, Mirna Jarosz
Journal: Cancer Research (2017)

Abstract Accurate genome-wide copy number variation (CNV) analysis is critical for disease and cancer research. Current approaches for CNV analysis include fluorescence in situ hybridization (FISH), array comparative genomic hybridization (array CGH), and SNP arrays. Unfortunately, these methods are not sensitive enough for real world cancer samples because of tumor ploidy, purity and heterogeneity. NGS-based targeted sequencing is increasingly being used for CNV analysis due to throughput, coverage, cost, and sample input requirements. For CNV analysis, detection power is improved by combining both read depth and SNP allele frequency analysis, particularly for copy-neutral events such as loss of heterozygosity. A custom xGen Lockdown CNV backbone panel was developed for broad, uniform genome coverage and to enrich for population-based SNPs. We demonstrate use of the panel as an addition to the xGen Exome Research Panel and a custom cancer focused panel. Downstream analysis incorporates both read depth and observed minor allele frequencies to determine CNVs with enhanced sensitivity. To increase the resolution for large-scale alterations of chromosome 7, a hot-spot for disease-associated CNVs, probe density was increased 6 fold. A known standard, NA12878, was used to validate the panel’s ability to detect heterozygous SNPs with high confidence. In addition, mixtures of cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were tested with varying levels of background copy-neutral genomic DNA. The sensitivity and specificity of the panel to detect CNV and LOH events with was assessed using deep exome and Affymetrix SNP array data. The ability to detect copy number alterations with high resolution and accuracy would be a valuable resource for disease and cancer research. Citation Format: Jiashi Wang, Kristina Giorda, Zhongwu Lai, Daniel Stetson, Mirna Jarosz. Whole genome copy number variation analysis using a SNP-focused targeted sequencing panel for tumor analysis [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 397. doi:10.1158/1538-7445.AM2017-397
An uncommon right iliac fossa mass in an older woman
Authors: Thomas H Newman, Eline A Caine, Kathryn Lynes, Joseph Sebastian
Journal: BMJ (2017)

A 74 year old woman was referred to the general surgery clinic after she found a lump in her lower abdomen, which she had noticed 4-5 weeks previously. She also reported a feeling of not completely emptying her bowels, and reduced frequency of bowel opening. She had noticed no blood or mucus in the toilet bowl, and had not had abdominal pain, lower urinary tract symptoms, or vaginal discharge. She had lost two stone (12.7 kg) in weight over a few months, but she attributed this to a recent diagnosis of diabetes mellitus. Her surgical history was a total abdominal hysterectomy and bilateral salpingo-oophorectomy in 1996 for menorrhagia. On examination, she had a large non-tender soft swelling in the right iliac fossa but no evidence of inguinal, femoral, or pfannenstiel incisional hernia. Blood tests were unremarkable, and a colonoscopy identified only mild diverticular disease. A computed tomography (CT) scan of her abdomen and pelvis was taken (fig 1⇓).



Fig 1  Sagittal slice of a computed tomogram …
Abstract 994: Diagnosing leukemia structural variations via a novel genome mapping approach
Authors: Christopher Pool, Jie Xu, Darrin Bann, David Goldenberg, Arati Sharma, David Claxton, Feng Yue, James Broach
Journal: Cancer Research (2017)

Abstract Identification of structural variants (SVs) is critical to the prognosis of AML. SVs are not readily identified by next generation sequencing methods and are currently diagnosed by cytogenetics, an intrinsically low resolution tool. We have adapted a new method for determining large SVs as a clinical tool for evaluating AML and other cancer genomes. The Bionano Irys images in microfluidic nanochannels large (&amp;gt;150 Kb) segments of genomic DNA that have been bar coded by site specific nicking and local incorporation of fluorescent label. The complement of individual molecules can be assembled through matching bar codes to create a de novo map of the genome from which, by matching to a reference genome, identifies and catalogs structural variants at resolution of ca. 1 Kb. With this technology, we characterized structural variants signatures in breast cancer, renal clear cell carcinoma, and CML cell lines. Structural variants were then validated via PCR/Sanger sequencing, fluorescent in situ hybridization and whole genome sequencing. We identified a thorough compendium of consistent false positive rearrangements identified by this technology, most of which reflect errors in the reference human genome assembly. We then applied this methodology to ten AML patient samples, seven from archived blood samples and three directly obtained from newly diagnosed patients. Karyotyping on one archived sample identified a t(6:9) translocation in the majority of cells. We identified that rearrangement at a much higher resolution than cytogenetics, which allowed us to map the breakpoint via PCR/Sanger sequencing to nucleotide resolution and confirm a fusion of NUP214 to DEK, a known oncogene. We also discovered the reciprocal t(9:6) translocation, which had not been identified by cytogenetics. In the six other cases from archived samples, we have confirmed the translocation identified by cytogenetic karyotyping and in several cases found additional rearrangements. Moreover, in the first pediatric case, which we completed within five days of obtaining the sample, we have identified four distinct translocations, all of which have been associated previously with AML. Overall, this is technology has the ability to quickly and accurately identify SVs in cancer cell lines and AML patient samples with higher resolution than cytogenetics, demonstrating its clinical usefulness in the diagnosis and subsequent treatment of leukemia. Citation Format: Christopher Pool, Jie Xu, Darrin Bann, David Goldenberg, Arati Sharma, David Claxton, Feng Yue, James Broach. Diagnosing leukemia structural variations via a novel genome mapping approach [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 994. doi:10.1158/1538-7445.AM2017-994
Abstract 468: Evaluation of microRNA inhibition in medulloblastoma
Authors: Alexander Vavra, Sydney Stoops, Jonathan White
Journal: Cancer Research (2017)

Abstract Medulloblastoma is the most common pediatric malignant brain tumor. The current treatment plan consists of a combination of surgery, radiation, and chemotherapy which results in an 80% five year survival rate. However, the survival rate does not take into account the developmental delays and learning disabilities inherited as a result of the aggressive treatment plan on a developing brain. As such the development of new treatment options is needed. While many protein targets are currently being explored for therapeutic intervention, the role of non-coding RNAs is of increasing interest. Specifically microRNA profiling in medulloblastoma has been performed by others to highlight expression profiles which can be mapped to the disease state and also to potentially identify associated protein targets. Moreover, it is particularly intriguing that microRNAs themselves may be directly targeted as therapeutic points of intervention. With this in mind, our lab is currently investigating methods for directly targeting microRNAs in medulloblastoma and we have recently validated several upregulated miRNAs for further investigation. Specifically, we evaluated the expression profile eighteen selected miRNAs in DAOY and D341 cell lines. Our results indicate that four miRNAs (miR-196a, miR-183, miR-96, and miR-182) are statistically overexpressed in both cell lines. Results of these findings and our initial efforts to target these selected miRNAs will be described. Citation Format: Alexander Vavra, Sydney Stoops, Jonathan White. Evaluation of microRNA inhibition in medulloblastoma [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 468. doi:10.1158/1538-7445.AM2017-468
Abstract 3826: Clinical validation of a serum protein panel (FLNA, FLNB and KRT19) for diagnosis and prognosis of prostate cancer
Authors: Shobha Ravipaty, Wenfang Wu, Aditee Dalvi, Nikunj Tanna, Joe Andreazi, Tracey Friss, Allison Klotz, Chenchen Liao, Jeonifer Garren, Sally Schofield, Eleftherios P. Diamandis, Eric A. Klein, Albert Dobi, Shiv Srivastava, Poornima Tekumalla, Michael A. Kiebish, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain, Viatcheslav Akmaev
Journal: Cancer Research (2017)

Abstract Background: Prostate cancer (PrCa) is a leading cause of cancer deaths in males in the US. Current tests of prostate-specific antigen (PSA) screening and the diagnostic prostate biopsy are often inconclusive. Many patients with a PSA positive blood test often undergo invasive repeat biopsy procedures. Additionally, there is a need for diagnostic tests that differentiate between low and high-risk cancers. This study reports on the development of a novel serum protein panel of three PrCa biomarkers, Filamin A, Filamin B and Keratin-19 (FLNA, FLNB and KRT19) using multivariate models for disease screening and prognosis. Methods: ELISA and IPMRM (LC-MS/MS) based assays were developed and analytically validated by quantitative measurements of the biomarkers in serum. Retrospectively collected and clinically annotated serum samples with PSA values and Gleason scores (GS) were analyzed from 503 subjects who underwent prostate biopsy, and showed no evidence of cancer with or without indication of prostatic hyperplasia, or had a definitive pathology diagnosis of prostatic adenocarcinoma. Probit linear regression models were used to combine the analytes into score functions to address the following clinical questions: does the biomarker test augment PSA for population screening? Can aggressive disease be differentiated from lower risk disease, and can the panel discriminate between benign prostate hyperplasia (BPH) and PrCa? Results: Table 1: Berg PrCa Panel AUC summary for the four clinical indications. Conclusion: As shown in Table 1, modelling of the data demonstrated that the new PrCa biomarkers and PSA in combination were better than PSA alone in identifying PrCa, improved the prediction of high and low risk disease, and improved prediction of BPH versus PrCa. Citation Format: Shobha Ravipaty, Wenfang Wu, Aditee Dalvi, Nikunj Tanna, Joe Andreazi, Tracey Friss, Allison Klotz, Chenchen Liao, Jeonifer Garren, Sally Schofield, Eleftherios P. Diamandis, Eric A. Klein, Albert Dobi, Shiv Srivastava, Poornima Tekumalla, Michael A. Kiebish, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain, Viatcheslav Akmaev. Clinical validation of a serum protein panel (FLNA, FLNB and KRT19) for diagnosis and prognosis of prostate 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 3826. doi:10.1158/1538-7445.AM2017-3826