tbuckley/cabot-search huggingface dataset:
Abstract 4695: Functional group elaboration of a low molecular weight fragment to yield the novel BET family bromodomain inhibitor ABBV-075
Authors: Keith McDaniel, Le Wang, George Sheppard, Steve Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Robert Mantei, Chang Park, Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Scott Warder, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise Wilcox, Rongqi Wang, Terry Magoc, Ganesh Rajaraman, Andrew Petros, Sanjay Panchal, Chaohong Sun, Guowei Fang, Steven W. Elmore, Saul Rosenberg, Yu Shen, Warren Kati
Journal: Cancer Research (2016)

Abstract Phenotypic cell-based screening assays combined with affinity chromatography and mass-spectrometry identified the BET family of bromodomains as potential targets for blocking proliferation in a variety of cancer cell lines. Lead-finding investigations included screening a library of compounds with an average molecular weight of 225 for binding to the 13C-labeled 2nd bromodomain of BRD4 using 2-dimensional NMR. A pyridazinone fragment emerged from this effort that possessed weak binding affinity (Kd = 130 uM). The binding affinity was improved by roughly 100,000-fold through an X-ray structure enabled medicinal chemistry program that included moving to a pyrrolopyridone core along with judicious placement of additional functional groups. Antiproliferative potencies strongly correlated with potencies in a cell-based target engagement assay, suggesting that the antiproliferative effects resulted from the inhibition of BRD4/BET protein function. In vitro metabolite ID studies in rat liver microsomes helped identify sites of oxidative metabolism. The addition of fluorine atoms at these locations improved rat in vitro microsomal stability that translated to low in vivo clearance and high oral exposure in rat. The final molecule, ABBV-075, exhibited long half-lives and low unbound clearances in rat, mouse, dog and monkey. ABBV-075 demonstrated significant tumor growth inhibition in mouse flank xenograft studies representing diverse hematological and solid tumor malignancies and recently entered Phase I clinical studies. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Keith McDaniel, Le Wang, George Sheppard, Steve Fidanze, John Pratt, Dachun Liu, Lisa Hasvold, Robert Mantei, Chang Park, Aparna Sarthy, Leiming Li, Daniel H. Albert, Xiaoyu Lin, Scott Warder, Emily Faivre, Mai H. Bui, Xiaoli Huang, Denise Wilcox, Rongqi Wang, Terry Magoc, Ganesh Rajaraman, Andrew Petros, Sanjay Panchal, Chaohong Sun, Guowei Fang, Steven W. Elmore, Saul Rosenberg, Yu Shen, Warren Kati. Functional group elaboration of a low molecular weight fragment to yield the novel BET family bromodomain inhibitor ABBV-075. [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 4695.
Circulating tumor DNA mutational profiling by targeted next generation sequencing guides personalized treatments in multiple cancer types.
Authors: Yang Shao, Xiaoling Tong, Xiaonan Wang, Zhili Chang, Yu Mao, Xue Wu
Journal: Journal of Clinical Oncology (2016)

1581 Background: Cancer is a disease of genetic alterations. Comprehensive genetic diagnosis is needed to match each patient to appropriate cancer therapy. However, acquisition of representative tumor samples is invasive and often infeasible. As tumor-derived fragmented DNA, circulating tumor DNA (ctDNA) is becoming a promising non-invasive biomarker for cancer mutational profiling. However, most recent studies focused on utilizing ctDNA in monitoring tumor burden; and none of them have systematically evaluated its clinical application on mutational profiling to guide personalized treatments. Methods: We implemented targeted next generation sequencing (NGS) with a customized pan-cancer gene panel of 382 cancer-relevant genes and 16 genes frequently rearranged in solid tumors on 605 prospective clinical ctDNA samples of multiple cancer types. A two-tiered study was designed with a training cohort containing patient ctDNA samples and matched archived formalin-fixed paraffin-embedded (FFPE) or frozen tissue samples (n = 344), followed by a validation cohort with patients with ctDNA samples only (n = 261). Results: In the training cohort, a high concordance of mutation spectra was observed between matched tumor and ctDNA samples coverinig all classes of genetic alterations. The test results from the validation cohort (ctDNA only) showed highly similar trends in several aspects compared to the training cohort, including mutation detection rate, number of mutations per patient and mutant allele frequencies. Overall, tumor-specific mutations were identified in 87% of ctDNA samples. 71% of patients have at least one actionable mutation, 76% of which have suggested drugs approved or in clinical trials. Conclusions: Taken together, our results strongly suggest that targeted NGS-based ctDNA mutational profiling is a sensitive and non-invasive tool to monitor tumor development and treatment response. With the flexibility to update customized targeted gene panel in order to adapt to different tumor types and to incorporate new discoveries, it offers a cost-effective platform as a routine clinical test to guide cancer treatment.
Abstract 1002: IDH1 promotes tumor growth and resistance to targeted therapies in the absence of mutation
Authors: Alexander H. Stegh
Journal: Cancer Research (2016)

Abstract Metabolic abnormalities of cancers provide opportunities for novel tumor-specific therapies. Isocitrate dehydrogenases (IDHs) are enzymes of the tricarboxylic acid (TCA) cycle that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and the reduction of NADP+ to NADPH. Oncogenic mutations in two IDH-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico analysis of The Cancer Genome Atlas (TCGA) data combined with wet-bench analysis of tumor extracts indicate that non-mutated IDH1 mRNA and protein is commonly overexpressed in primary GBM. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs survival of animal subjects bearing patient-derived xenografts (PDXs). On molecular levels, diminished IDH1 activity results in reduced α-KG and NADPH production, which is paralleled by deficient metabolic flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common mechanism of metabolic adaptation of GBM to support macromolecular synthesis, aggressive growth, and therapy resistance. Citation Format: Alexander H. Stegh. IDH1 promotes tumor growth and resistance to targeted therapies in the absence of mutation. [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 1002.
Abstract 75: Mouth-to-Face-Shield Ventilation Impairs CPR Quality Compared to Mouth-to-Pocket-Mask Ventilation: A Randomized Study
Authors: Kasper Adelborg, Katrine Bjørnshave, Martin B Mortensen, Eirild Espeseth, Anne Wolff, Bo Løfgren
Journal: Circulation (2013)

Objective: Effective ventilations are essential when resuscitating a drowning victim. Ventilation is necessary to treat hypoxia however interruptions in chest compressions should be minimized. Surf lifeguards may be reluctant to perform rescue breathing using mouth-to-mouth ventilation. Using a face shield or face mask may be reasonable. The most optimal ventilation technique among surf lifeguards is currently unknown. The aim of this study was to compare the effect of mouth-to-face-shield ventilation (MFV) and mouth-to-pocket mask ventilation (MPV) on CPR quality. Methods: We invited professional paid surf lifeguards to participate in the study. Each surf lifeguard was randomized to perform 2 x 3 minutes of single-rescuer CPR on a resuscitation manikin using MFV (AMBU® LifeKey) and MPV (Laerdal Pocket MaskTM). Data were collected from resuscitation manikin and from video recordings. Results: In total 30 surf lifeguards were included (mean age: 25.1 year; 21 male, 9 female). MFV (mean±s.d.: 8.6+/-1.7 s) significantly increased interruptions in chest compressions compared to MPV ventilation (6.9+/-1.2 s, p&lt;0.0001). The proportion of effective ventilations (visible chest rise) was reduced using MFV (82%) compared to MPV (100%, p=0.0002). Tidal volume was higher using MPV (0.45+/-0.20 L) compared to MFV (0.36+/-0.20 L, p= 0.006). No differences in inspiratory times were observed between MFV and MPV. Conclusion: MFV increases interruptions in chest compressions, reduces the proportion of effective ventilations and decreases delivered tidal volumes when compared to MPV. This suggests that CPR quality is impaired using MFV compared to MPV among surf lifeguards.
Abstract 1748: The relationship between nut consumption and risk of colorectal cancer
Authors: Jeeyoo Lee, Aesun Shin, Jeonghee Lee, Ji Won Park, Jae Hwan Oh, Jeongseon Kim
Journal: Cancer Research (2016)

Abstract Introduction Nuts consumption has been associated with reduced risk of obesity, diabetes mellitus, and cardiovascular diseases. However, the association between nuts and colorectal cancer risk remains unclear. Objective In this study, we aimed to investigate the relationship between nuts consumption and colorectal cancer risk in a case-control study. Methods A case-control study was conducted with 923 colorectal cancer patients and 1846 controls recruited from the National Cancer Center in Korea. Information on dietary intake was collected using a food frequency questionnaire (FFQ) with 106 items. Nuts consumption level was classified by sex-specific quartile of control group. Binary and polytomous logistic regression models were used to estimate odds ratios (OR) and their 95% confidence intervals (CI) for the association between nuts consumption and colorectal cancer risk. Results High nuts consumption was strongly associated with a reduced risk of colorectal cancer in women (OR, 0.18; 95% CI 0.10-0.32 for highest vs. lowest quartile) and similar inverse association was observed for men (OR, 0.36; 95% CI 0.25-0.52). In subsite analysis, adjusted ORs (95% (CI)) comparing the highest vs the lowest quartile of nuts consumption were: 0.49 (0.24-0.99) for proximal colon cancer, 0.38 (0.23-0.64) for distal colon cancer, and 0.29 (0.18-0.46) for rectal cancer in men. An inverse association was also found in women for proximal colon cancer (0.16 (0.05-0.51)), distal colon cancer (0.16 (0.07-0.37)) and rectal cancer (0.25 (0.12-0.51)). Conclusion We found a statistically significant association between higher nuts intake and reduced risk of colorectal cancer and the association was observed for all subsites of colorectum in both men and women. Citation Format: Jeeyoo Lee, Aesun Shin, Jeonghee Lee, Ji Won Park, Jae Hwan Oh, Jeongseon Kim. The relationship between nut consumption and risk of colorectal 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 1748.
Partial recovery of microbiomes after antibiotic treatment
Authors: Frédéric Raymond, Maxime Déraspe, Maurice Boissinot, Michel G. Bergeron, Jacques Corbeil
Journal: Gut Microbes (2016)

Antibiotics profoundly affect the gut microbiome and modulate microbial communities. We recently observed that antimicrobial drugs also impact the abundance and distribution of antibiotic resistance genes. In this addendum, we reanalyze our ∼1 trillion nucleotide shotgun metagenomic dataset to quantify comprehensive genomic differences at the sequence level before and after antibiotic treatment. We show that 7 day exposure to cefprozil leads to a statistically significant loss of metagenome sequences. Recovery of gut microbiomes 3 months after antibiotherapy was characterized by the emergence of new genome sequences not observed prior to antibiotic exposure. Participants with low initial gut microbiome diversity had an increased amount of sequences related to antibiotic resistance. Therefore, we suggest that while the taxonomical composition of microbiomes is partially affected by the antibiotic, the genomic content and population structure of bacterial communities is noticeably impacted.
Abstract 4585: ROR1 sustains caveolae and RTK-mediated survival signaling as a scaffold of cavin-1 and CAV1 in lung cancer
Authors: Tomoya Yamaguchi, Can Lu, Lisa Ida, Kiyoshi Yanagisawa, Jiro Usukura, Jinglei Cheng, Naoe Hotta, Yukako Shimada, Hisanori Isomura, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi
Journal: Cancer Research (2016)

Abstract TTF-1/NKX2-1, a homeobox-containing transcription factor indispensable for lung morphogenesis, was previously identified by four independent groups including us, as a “lineage-survival” oncogene involved in the pathogenesis of lung adenocarcinoma. We have further shown that TTF-1/NKX2-1 induces expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn plays a “sustainer” role for EGFR-mediated signaling. Interestingly, ROR1 knockdown effectively overcame EGFR-TKI resistance-conferring, HGF-mediated bypass signaling through MET, suggesting that ROR1 sustains not only EGFR but also additional RTK signaling. However, the underlying mechanism remained rather elusive. We report here an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. Caveolae are 50-100 nm invaginations of the plasma membrane that play various physiological roles, including function as a platform for insulin-induced signaling in adipose tissue. We found that ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane in a kinase-independent manner, thereby preventing the lysosomal degradation of CAV1, as well as consequential caveolae formation. Caveolae structures and prosurvival signaling towards AKT through multiple RTKs such as MET and IGF-IR are consequently sustained. The present findings thus provide mechanistic insight into how ROR1 inhibition can overcome EGFR-TKI resistance due to bypass signaling via diverse RTKs, which is currently a major clinical obstacle. Inhibition of prosurvival signaling and proliferation of lung cancer cells could be recapitulated by knocking down cavin-1 or CAV1, but they are unlikely to be suitable molecular targets for NSCLC treatment due to their crucial physiological functions in various organs even at low expression levels. In this regard, it should be noted that ROR1 is considered to be an onco-embryonic antigen with tumor-specific expression in adults. Taken together, development of novel therapeutic means to inhibit the scaffold function of ROR1 and thereby attack the cancer's “Achilles heel” is thus anticipated to be an attractive approach for improved treatment of this devastating cancer. Citation Format: Tomoya Yamaguchi, Can Lu, Lisa Ida, Kiyoshi Yanagisawa, Jiro Usukura, Jinglei Cheng, Naoe Hotta, Yukako Shimada, Hisanori Isomura, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi. ROR1 sustains caveolae and RTK-mediated survival signaling as a scaffold of cavin-1 and CAV1 in lung 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 4585.
Implantable Cardioverter-Defibrillator Use in Patients With Left Ventricular Assist Devices
Authors: Kairav Vakil, Felipe Kazmirczak, Neeraj Sathnur, Selcuk Adabag, Daniel J. Cantillon, Erich L. Kiehl, Ryan Koene, Rebecca Cogswell, Inderjit Anand, Henri Roukoz
Journal: JACC Heart Failure (2016)
ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals
Authors: Lara Ordóñez-Gutiérrez, Adrián Posado-Fernández, Davoud Ahmadvand, Barbara Lettiero, Linping Wu, Marta Antón, Orfeu Flores, Seyed Moein Moghimi, Francisco Wandosell
Journal: Biomaterials (2016)
Abstract 5031: Melanoma progression involves a profound nuclear to cytoplasmic shift of the transcription factor SUM-6 (specifically upregulated in melanoma gene six)
Authors: Laura J. Graziano, Xue Zhang, Yabin Cheng, Gang Wang, Mingwan Su, Magdalena Martinka, Youwen Zhou
Journal: Cancer Research (2016)

Abstract INTRODUCTION: SUM-6 is a human homeobox gene that encodes for a transcription factor, which plays a key role in normal embryogenesis. Overexpression of both the gene and nuclear protein has been shown to occur in a variety of cancers such as breast, colorectal, and pancreatic, and has been demonstrated to promote tumorigenesis. The purpose of the current study was to evaluate the expression of the SUM-6 protein, its clinical relevance, and biological function in melanoma. EXPERIMENTAL PROCEDURES: Immunohistochemistry using a specific SUM-6 antibody was performed on a tissue microarray consisting of 438 patient biopsies, which included benign and malignant melanocytic tumors. Double-blinded scoring of distinct nuclear and cytoplasmic SUM-6 staining was performed. SPSS 16.0 statistical package and Microsoft Excel were used to carry out the analyses of data. Analyses included the χ2 test and univariate analysis by the log-rank test in conjunction with the Kaplan-Meier survival curve for visualization. RESULTS: Nuclear staining of SUM-6 was detected in 100% of normal nevi (n = 19), 81% of dysplastic nevi (n = 32), 87% of melanoma in situ (n = 23), 79% of primary melanoma (n = 219), and 53% of metastatic melanoma (n = 145), whereas cytoplasmic staining was detected in 63%, 94%, 56%, 94%, and 97%, respectively. Univariate analysis revealed that five year disease-specific survival decreased significantly when SUM-6 was excluded from the nucleus and when SUM-6 levels were elevated in the cytoplasm (p = 0.001 and 0.019, respectively). CONCLUSIONS: We concluded that melanoma progression and metastasis is associated with a profound shift of transcription factor SUM-6 from the nucleus to the cytoplasm. It is interesting to note that in most other cancers, the SUM-6 protein was instead overexpressed in the nucleus. The patients in whom SUM-6 was excluded from the nucleus demonstrated a significantly worse prognosis than the patients who retained nuclear expression. These findings suggest that either the absence of nuclear expression or elevated cytoplasmic presence (or both) of SUM-6 may play a role in the progression of malignant melanoma. Citation Format: Laura J. Graziano, Xue Zhang, Yabin Cheng, Gang Wang, Mingwan Su, Magdalena Martinka, Youwen Zhou. Melanoma progression involves a profound nuclear to cytoplasmic shift of the transcription factor SUM-6 (specifically upregulated in melanoma gene six). [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 5031.
Abstract 4134: Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma
Authors: Pratistha Koirala, Michael Roth, Jonathan Gill, Jordan Chinai, Sajida Piperdi, David Geller, Bang Hoang, Vincent Poon, Xingxing Zang, Richard Gorlick
Journal: Cancer Research (2016)

Abstract Purpose: Over the past four decades, osteosarcoma (OS) survival rates have remained stagnant. There is a need to identify novel therapies to target OS. In this study we examined the expression of Programed Death Ligand 1 (PD-L1) and defined the tumor microenvironment in OS in order to assess the feasibility of utilizing immune checkpoint inhibitors as a treatment modality. Experimental Design: PD-L1 expression in OS was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (qRT-PCR) (n = 21) and western blotting (n = 9). IHC was used to determine presence of tumor infiltrating lymphocytes and antigen presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with the presence of immune cells and with event free survival in OS. Results: PD-L1 is expressed in up to 25% of primary OS tumors. Of the PD-L1 positive tumors the majority were also PD-1 positive (92% vs 8%, p = 0.002). In addition, the presence of immune cells in the tumor mass was significantly associated with PD-L1 expression. Although all immune cell types examined were present in OS, only infiltration by APCs, specifically CD1a positive dendritic cells (48.6% vs. 51.4%, p = 0.0010) and CD68 positive macrophages (70.3% vs. 29.7%, p = 0.0316), was associated with worse outcomes. PD-L1 expression was significantly associated with worsened survival (21.6% pos. vs. 78.4% neg., p = 0.0146). Conclusions: For the first time we have identified PD-L1 expression or presence of CD1a or CD68 positive antigen presenting cells as prognostic markers for worsened outcome in OS. Furthermore, we show that IHC is a valid detection method for PD-L1 in OS. With up to 25% of OS patients expressing PD-L1, this study provides rational for targeting the PD-L1:PD-1 axis for immunotherapy in OS. Citation Format: Pratistha Koirala, Michael Roth, Jonathan Gill, Jordan Chinai, Sajida Piperdi, David Geller, Bang Hoang, Vincent Poon, Xingxing Zang, Richard Gorlick. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. [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 4134.