tbuckley/cabot-search huggingface dataset:
Abstract 1440: Germline loss-of-function alleles in Finnish colorectal cancer patients
Authors: Tomas Tanskanen, Ulrika Hänninen, Tatiana Cajuso, Johanna Kondelin, Riku Katainen, Jiri Hamberg, Niko Välimäki, Esa Pitkänen, Kimmo Palin, Lauri A. Aaltonen
Journal: Cancer Research (2017)

Abstract Colorectal cancer, a major cause of cancer deaths worldwide, is often preventable by screening and surveillance, especially in patients at increased risk; however, its heritability is incompletely understood, and studies in isolated populations such as Finland may be valuable for gene discovery. We analyzed whole-genome or whole-exome sequencing data in 322 Finnish colorectal cancer cases of unknown etiology and 928 population-matched controls. To enrich for susceptibility alleles, cases were selected on the basis of early-onset colorectal cancer (age at diagnosis &amp;lt;50 years; 50/322, 16%), synchronous or metachronous colorectal cancer (30/322, 9.3%), familial colorectal cancer (134/322, 42%), personal history of noncolorectal cancer (93/322, 29%), or family history of at least two noncolorectal cancers (124/322, 39%). To increase the prior probability of pathogenicity of variants, the study was restricted to rare and low-frequency protein-coding loss-of-function variants (nonsense, frameshift, and essential splice site variants; allele frequency &amp;lt;3%). Single-variant and gene-level associations were tested, and genes with loss-of-function variants exclusively in cases were pinpointed. An independent set comprising 1,257 cases and 2,638 controls were genotyped using SNP arrays, and genotype imputation provided additional data on 225 (8.5%) of the 2,654 initially discovered loss-of-function variants. Principal component analysis was applied to correct for population structure. In association analyses, with a statistical power of at least 80% for a range of moderate-to-high effect sizes and low allele frequencies (e.g., odds ratio of 3 and allele frequency of 0.5%) at p &amp;lt;0.15, a total of 35 candidate colorectal cancer predisposition genes were identified, although none of them reached exome-wide significance. There were 21 genes with rare loss-of-function alleles in at least two cases but none of the sequenced controls. Whole-genome sequencing data from paired normal and tumor tissues were available in 243 cases, and potential second hits (wild-type allele losses or somatic point mutations) were found in 15 genes. These results may, through further analysis and replication, contribute to our knowledge of the genetic architecture and pathobiology of colorectal cancer susceptibility. Citation Format: Tomas Tanskanen, Ulrika Hänninen, Tatiana Cajuso, Johanna Kondelin, Riku Katainen, Jiri Hamberg, Niko Välimäki, Esa Pitkänen, Kimmo Palin, Lauri A. Aaltonen. Germline loss-of-function alleles in Finnish colorectal 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 1440. doi:10.1158/1538-7445.AM2017-1440
Abstract 4055: Enhancing anti-PD-1 immune blockade in melanoma through selective inhibition of histone deacetylase 6
Authors: Tessa Knox, Eva Sahakian, Jayakumar Nair, Jennifer Kim, Debarati Banik, Melissa Hadley, John Powers, Fengdong Cheng, Sida Shen, Javier Pinilla, Jeffrey Weber, Alan Kozikowski, Eduardo Sotomayor, Alejandro Villagra
Journal: Cancer Research (2017)

Abstract Histone deacetylases (HDACs), were originally described in a limited context as histone modifiers. New evidence has demonstrated that HDACs are also involved in a diverse range of cellular processes that are not restricted to the chromatin environment, such as the regulation of the cell cycle/apoptosis and, more recently, a modulator of immune response. However, much remains unknown about the mechanism of action of HDACs and their roles in the immune-biology of cancer. The non-specific nature of pan-HDAC inhibitors results in a narrow therapeutic window of use, limiting the dose and duration due to toxicity. Our group has focused in one specific HDAC, HDAC6, and shown that both the genetic abrogation and pharmacological inhibition of this HDAC modulates the expression of a variety of immune-regulatory proteins in the tumor microenvironment, including PD-L1, PD-L2, MHC class I, B7-H4 and TRAIL-R1. In particular, we have previously demonstrated that both pharmacological inhibition and/or genetic abrogation of HDAC6 plays a critical role in the immune check point blockade by down-regulating the expression of PD-L1 and other check-point modulators such as PD-L2, B7-H4, etc. Moreover, we have also observed that in vivo inhibition of HDAC6 reduces tumor growth in B16 and SM1 murine melanoma models within syngeneic immunocompetent hosts. Additionally, we have found that the combination of low doses of the HDAC6i Nexturastat A and checkpoint immune blockade, including anti-PD-1 and anti-CTLA4, results in an important improvement in anti-tumor immune responses as evidenced by the reduction of tumor growth when compared to treatment with individual stand-alone agents. In these studies we also evidenced an increased production of IFNγ and IL-2 in the stand-alone check-point inhibitor treatments, which leads to an upregulation of PD-L1 and PD-L2. Similar levels of IFNγ and IL-2 were found in the combination groups. However, the expression level of PD-L1 and PD-L2 were comparable to the non-treated group. Taking all together, we have found that HDAC6i could be used as a potential adjuvant in ongoing therapeutic options involving immune check-point blockade. Citation Format: Tessa Knox, Eva Sahakian, Jayakumar Nair, Jennifer Kim, Debarati Banik, Melissa Hadley, John Powers, Fengdong Cheng, Sida Shen, Javier Pinilla, Jeffrey Weber, Alan Kozikowski, Eduardo Sotomayor, Alejandro Villagra. Enhancing anti-PD-1 immune blockade in melanoma through selective inhibition of histone deacetylase 6 [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 4055. doi:10.1158/1538-7445.AM2017-4055
Factors Contributing to the Efficacy-Effectiveness Gap in the Case of Orphan Drugs for Metabolic Diseases
Authors: Y. Schuller, C. E. M. Hollak, C. C. Gispen-de Wied, V. Stoyanova-Beninska, M. Biegstraaten
Journal: Drugs (2017)

Authorization of orphan medicinal products (OMPs) is often based on studies with several methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it. We included all OMPs for rare metabolic diseases authorized in the EU up to 1 January 2016. Efficacy data were obtained from European Public Assessment Reports, relative effectiveness data from the Dutch National Healthcare Institute website, and real-world effectiveness data from literature and interviews with experts and patients. Efficacy and effectiveness were scored as ‘no effect’, ‘unclear’ or ‘good’ based upon a prespecified scoring system. We identified 31 authorized OMPs, of which 21 had post-marketing studies available, thus making it possible to score real-world effectiveness. Eight of 21 (38%) OMPs had a ‘good’ real-world effectiveness. The use of a clinical or validated surrogate primary endpoint and a representative study population seemed to be related to good effectiveness in the real world, as were type of marketing authorization, study population and disease prevalence. This study revealed that less than half of the authorized OMPs are effective in the real world. Since the type of primary endpoint used in the pivotal study seems to be associated with good real-world effectiveness, it is important to agree upon study endpoints through early dialogues among relevant stakeholders.
Abstract 4925: Microbiome-TP53 gene interaction in human lung cancer
Authors: Leigh Greathouse, James White, Valery Bliskovsky, Ashley Vargas, Eric Polley, Elise Bowman, Mohammed Khan, Ana Robles, Brid Ryan, Amiran Dzutsev, Giorgio Trinchieri, Marbin Pineda, Sven Bilke, Paul Meltzer, Marina Walther-Antonio, Garth Ehrlich, Joshua Mell, Joshua Earl, Sergey Balashov, Archana Bhat, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie Segre, Curtis Harris
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier function and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke create a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) or cancer cases (n=143), we conducted 16S rRNA gene sequencing (MiSeq), with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort. We demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue, indicating a shift in the overall microbial community in lung cancer patients as compared to those without cancer. Lung cancer cases were classified by the relative abundance of two taxa, Variovorax and Streptococcus, with an increase in Variovorax abundance in tumors as compared to non-tumor adjacent paired lung tissue (FDR corrected P=0.013). The species of Variovorax was identified histologically, and also by two additional 16S rRNA strategies (Resphera Insight analysis and PacBio sequencing). A group of taxa were associated with squamous cell carcinoma (SCC), of which Acidovorax were enriched in smokers (P =0.0013). Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD). Therefore, we observed a microbiome-gene and a microbiome-exposure interaction in SCC lung cancer tissue. Together, these results open the door for future biomarker research that could be used to improve screening and direct mechanistic studies of lung cancer therapy. Citation Format: Leigh Greathouse, James White, Valery Bliskovsky, Ashley Vargas, Eric Polley, Elise Bowman, Mohammed Khan, Ana Robles, Brid Ryan, Amiran Dzutsev, Giorgio Trinchieri, Marbin Pineda, Sven Bilke, Paul Meltzer, Marina Walther-Antonio, Garth Ehrlich, Joshua Mell, Joshua Earl, Sergey Balashov, Archana Bhat, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie Segre, Curtis Harris. Microbiome-TP53 gene interaction in human lung 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 4925. doi:10.1158/1538-7445.AM2017-4925
SIRFLOX study: Novel approach to define depth of response (DpR) within a volumetric model in patients with metastatic colorectal cancer (mCRC).
Authors: Volker Heinemann, Guy A. Van Hazel, Navesh K. Sharma, Michael P. N. Findlay, Jens Ricke, Marc Peeters, Val Gebski, Shola Adeyemi, Mark Van Buskirk, Peter Gibbs
Journal: Journal of Clinical Oncology (2016)

3542 Background: DpR has recently been proposed as a measure of efficacy that predicts the long-term treatment outcome for mCRC. DpR is a continuous measure that defines the nadir of tumor response, typically by the sum of the longest diameters of all target lesions compared to baseline. A novel volumetric model was applied to the independent blinded reader RECIST data from SIRFLOX, a multicenter RCT of 530 patients with non-resectable, liver-only or liver-dominant mCRC that compared first-line FOLFOX (± bev) plus Y-90 resin microspheres [SIRT] to FOLFOX (± bev) alone [Control]. Methods: Spherical tumor volume was estimated from the longest unidimensional length for ≤ 5 target hepatic lesions (RECIST 1.0) in the SIRFLOX ITT population. Finite mixture modelling was used to assess baseline tumor distribution and identify the optimal cut-point for subpopulations within which any potential predictors of DpR could be described. Results: There was a 7% greater decrease in median liver tumor volume in SIRT vs. Control (-75% vs. -68%; P = 0.036). Deepest response (median time to nadir) occurred 60 days later in SIRT than Control (266 vs. 206 days; P < 0.001). A larger treatment effect and longer time to nadir were observed in patients with > 12% hepatic tumor burden (median DpR -90% in SIRT vs. -77% in Control, P = 0.003; median nadir 298 vs. 196 days, P < 0.001), compared to those with ≤ 12% tumor burden (median DpR -93% vs. -94%, P = 0.763; median nadir 243.5 vs. 220 days, P = 0.152). PFS in the liver by competing risk analysis was significantly longer in patients with > 12% hepatic tumor burden receiving SIRT vs. Control (median 27.2 vs. 13.1 months, P = 0.003), whereas complete response [CR] for SIRT vs. Control was more common in patients with ≤ 12% liver tumor burden (12.9% vs.3.5%; P = 0.001). Conclusions: The present study integrates baseline tumor volume into the analysis of volumetric DpR modelled from existing unidimensional target lesion assessment. In SIRFLOX, the addition of SIRT to standard chemotherapy significantly increased hepatic DpR. The impact of SIRT on PFS was greatest in patients with a baseline tumor burden > 12%, whereas the impact on CR rate was greater where tumor burden was < 12%. Clinical trial information: NCT00724503.
Abstract 4750: Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer
Authors: Kevin Yan, Ezequiel Ramirez, Xuejun Gu, Kevin Albuquerque
Journal: Cancer Research (2017)

Abstract Background and Purpose: To determine significant factors predictive for severe hematologic toxicity (HT) in cervical cancer patients with para-aortic lymph node (PALN) metastasis treated with concurrent chemoradiation with a specific focus on radiation dose to total bone marrow (BMTOT) and active bone marrow (BMACT). To create a nomogram using significant factors to predict HT in these patients. Material and Methods: 38 Patients with cervical cancer and PALN metastasis who underwent 18F-FDG-PET / CT before treatment with extended field radiation therapy (EFRT) and concurrent cisplatin were analyzed. BMACT was defined as the region within BMTOT with a standardized uptake value (SUV) greater than or equal to the mean for the individual. Blood counts were collected weekly from the beginning of radiation treatment to the end of radiation treatment. HT was graded based on the guidelines set by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Results: 19 patients (50%) had Grade 3 or higher hematologic toxicity (HT3+), not including lymphocyte toxicity. Patients who were obese (n=12) were less likely to get HT3+ compared to patients who were not obese (p=0.03) despite getting the same weight related dose of chemotherapy. Volume of BMTOT receiving 20 Gy, 30 Gy, and 45 Gy were significant predictors for HT3+ at 78.56% (p=0.01), 47.14% (p=0.00), and 20.36% (p=0.01) respectively. Volume of BMACT receiving 10 Gy, 20 Gy, 30 Gy, and 45 Gy were significant predictors for HT3+ at 95.50% (p=0.03), 80.52% (p=0.05), 59.64% (p=0.03), and 31.74% (p=0.01) respectively. Through logistic regression, the probability of developing HT3+ is given by the equation: Prob(HT3+) = 1 / (1 + exp(7.34 + 0.22*BMI - 0.44*Mean Dose to BMTOT)). Patients who had HT3+ received an average of 4 cycles of chemotherapy and 62 days of treatment time, significantly different than the 4.74 chemotherapy cycles and 53 days of treatment in patients without HT3+ (p=0.05, 0.00 respectively). Conclusions: Both higher patient BMI and bone marrow irradiation were associated with HT3+. A simplified nomogram has been created to predict HT3+ in these patients. Radiation parameters have been identified for cervical cancer patients with PALN involvement receiving EFRT concurrently with chemotherapy. Bone marrow sparing approaches for EFRT need to be addressed to improve patient care. Citation Format: Kevin Yan, Ezequiel Ramirez, Xuejun Gu, Kevin Albuquerque. Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical 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 4750. doi:10.1158/1538-7445.AM2017-4750
Abstract 4318: Role of Bcl-2 in hematological cancer formation
Authors: Abigail V. Fortier, Ally Koh, Lisa Stanovski, Alisa Kepner, Supriya Jain, Misha Ul-Islam, Ellie Walter, Lawrence Boise
Journal: Cancer Research (2017)

Abstract B cell leukemia/lymphoma 2 (BCL-2) is a 26 kilodalton, amphipathic, anti-apoptotic protein located on the outer mitochondrial membrane. BCL-2 interacts with other anti-apoptotic and pro-apoptotic factors in order to regulate apoptosis. If a structural change occurs on the BCL-2 gene, overexpression of the BCL-2 protein can result. This causes a change in the ratio of BCL-2 to its BCL-2 Homologous 3 (BH3) ligands, preventing the release of the apoptotic signal. The primary change associated with BCL-2 overexpression in lymphomas is a t(14;18) chromosomal translocation, which causes an increase in BCL-2 transcription. The upregulation of the oncogene allows for the survival of the mutated B cells by raising the apoptotic threshold, which then dislodges regular lymphocytes in the bone marrow or lymph nodes. Lack of cell death due to overexpression of BCL-2 has been linked to hematological malignancies, specifically lymphomas and myelomas. Both B-lymphocytic cancers can result from alterations of the immunoglobulin heavy chain locus on chromosome 14. While BCL2 translocation can cause Follicular Lymphoma, BCL2 over-expression is observed in many other tumor types and likely contributes to cancer progression and drug resistance in these tumors. Treatments to inhibit BCL-2 include attempts at activation and overexpression of the pro apoptotic BH3 proteins, BCL-2 Associated X Protein (BAX) and BCL-2 Associated K protein (BAK), and creation of BH3 mimetics. Indeed, the FDA approved the BCL2 inhibitor Venetoclax (ABT-199) earlier this year for the treatment of Chronic Lymphocytic Leukemia. These treatments could help cause cancer cell death by binding to targeted anti-apoptotic proteins and causing the signal for apoptosis to be released. This could neutralize the cancerous effects of the BCL-2 oncogene upregulation. Walton High School SMART (Students Modeling A Research Topic) Team used the computer program JMOL to create a 3D printed model of BCL-2 and composed a review poster of our secondary research to investigate and demonstrate the relationship between the structure and function of this molecule. Citation Format: Abigail V. Fortier, Ally Koh, Lisa Stanovski, Alisa Kepner, Supriya Jain, Misha Ul-Islam, Ellie Walter, Lawrence Boise. Role of Bcl-2 in hematological cancer formation [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 4318. doi:10.1158/1538-7445.AM2017-4318
Abstract LB-073: Proteomic characterization reveals a molecular portrait of nasopharyngeal carcinoma differentiation
Authors: Zhefeng Xiao, Guiying Zhang, Yongheng Chen
Journal: Cancer Research (2017)

Abstract Nasopharyngeal carcinoma (NPC) is categorized into three different differentiated subtypes by World Health Organization (WHO). Based on an earlier comparative proteomic database of the three histological subtypes, the study was to deepen our understanding of molecular mechanisms associated with NPC differentiation through bio-information mining. Among the three subtypes were 194 differentially expressed proteins (DEPs) of 725 identified proteins. Two DEPs, heat shock protein family B (small) member 1 (HSPB1) and keratin 5 (KRT5), were validated in a series of NPC tissue samples by using immunohistochemistry. Quantified protein families including keratins, S100 proteins (S100s) and heat shock proteins exhibited characteristic expression alterations. Comparisons of predicted bio-function activation states among different subtypes, including formation of cellular protrusion, metastasis, cell death, and viral infections, were conducted. Canonical pathway analysis inferred that Rho GTPases related signaling pathways regulated the motility and invasion of dedifferentiated NPC. In conclusion, the study explored the proteomic characteristics of NPC differentiation, which could deepen our knowledge of NPC tumorigenesis and allow the development of novel targets of therapeutic and prognostic value in NPC. Citation Format: Zhefeng Xiao, Guiying Zhang, Yongheng Chen. Proteomic characterization reveals a molecular portrait of nasopharyngeal carcinoma differentiation [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-073. doi:10.1158/1538-7445.AM2017-LB-073