tbuckley/cabot-search huggingface dataset:
Uncovering a Link Between the Appendix and Parkinson Disease Risk
Authors: Rita Rubin
Journal: JAMA (2019)

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Abstract 11333: High Prevalence of Pulmonary Hypertension Complicates Care of Infants With Omphalocele
Authors: Shandee Hutson, Joanne Baerg, Sandhya Ramlogan, Adam Woelk, William Drake, Shawn St Peter, Andrew Hopper, Donna Goff
Journal: Circulation (2013)

Background: Many newborn infants born with an omphalocele present with significant respiratory distress at birth requiring mechanical ventilatory support and have clinical evidence of pulmonary hyp...
The truth about PHEICs
Authors: Johan Giesecke, Juliet Bedford, Delia Enria, Johan Giesecke, David L Heymann, Chikwe Ihekweazu, Gary Kobinger, Clifford Lane, Ziad Memish, Myoung-don Oh, Amandou Sall, Anne Schuchat, Kumnuan Ungchusak, Lothar Wieler
Journal: The Lancet (2019)
Update on lower-dose dasatinib 50 mg daily as frontline therapy in newly diagnosed chronic phase chronic myeloid leukemia (CML-CP).
Authors: Kiran Naqvi, Elias Jabbour, Jeffrey A Skinner, Kristin N Anderson, Musa Yilmaz, Nitin Jain, Alessandra Ferrajoli, Prithviraj Bose, Philip A. Thompson, Yesid Alvarado, Koichi Takahashi, Jan Andreas Burger, Gautam Borthakur, Zeev Estrov, Naveen Pemmaraju, Shilpa Paul, Sara Dellasala, Jorge E. Cortes, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2019)

7052 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. We previously reported dasatinib 50 mg daily to be active and better tolerated than the approved 100 mg daily dose (CANCER. 2018 Jul 1;124(13):2740-2747). We present an update on the efficacy and toxicity profile of lower dose dasatinib 50 mg orally daily in patients with early CML-CP. Methods: All patients presenting to our institution in early CML-CP were eligible to participate. Prior TKI therapy for up to 1 month was allowed. Responses were assessed according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122.872:884). Results: From March 2016 to March 2018, 81 patients have been enrolled. Median age is 47 years (20-84). Patients categorized by Sokal risk are: low 53; intermediate 22 and high 6. Median follow-up is 18 months (9-31). Cumulative response rates over time are shown below: At 3 months, 96% patients achieved early molecular response ( BCR-ABL PCR ≤10%). Median time to CCyR was 4.6 months, MMR 6.0 months, MR4.0 11.4 months and MR4.5 12.2 months. Eighteen patients had treatment interruption: pleural effusion 4 (possibly related 3, unrelated 1 due to pneumonia); gastrointestinal bleed 2; thrombocytopenia 3; transaminitis 2; renal dysfunction 1; asthma exacerbation 1; pneumonitis 1; lower extremity edema 1; myalgias 1, and pregnancy 2. Four patients had dose reductions: pleural effusion 3; myalgias 1. Four patients had dasatinib dose increased to 100mg: lack of CCyR at 6 months, 3; lack of MMR at 12 months, 1. Four patients are off study: no response 2, pneumonitis 1, and insurance 1. None of the patients have transformed or died. Conclusions: These updated results continue to support dasatinib 50 mg daily as an effective and safe dose for early CML-CP. Clinical trial information: NCT02689440. [Table: see text]
Abstract 16016: Adipose Tissue Secretory Changes and Low-Grade Inflammation Combine With Insulin Resistance and Vascular Dysfunction in Human Obesity
Authors: Francesca Schinzari, Manfredi Tesauro, Augusto Veneziani, Angela Barini, Umberto Campia, Nicola Di Daniele, Carmine Cardillo
Journal: Circulation (2017)

Introduction: Adipose tissue physiologically operates as a functional endocrine unit, participating in energy homeostasis and glucose/lipid metabolism. Dysregulation of its secretory pattern may oc...
Dual Antagonist of cIAP/XIAP ASTX660 Sensitizes HPV− and HPV+ Head and Neck Cancers to TNFα, TRAIL, and Radiation Therapy
Authors: Roy Xiao, Yi An, Wenda Ye, Adeeb Derakhshan, Hui Cheng, Xinping Yang, Clint Allen, Zhong Chen, Nicole C. Schmitt, Carter Van Waes
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Human papillomavirus–negative (HPV−) head and neck squamous cell carcinomas (HNSCC) harbor frequent genomic amplification of Fas-associated death domain, with or without concurrent amplification of Baculovirus inhibitor of apoptosis repeat containing (BIRC2/3) genes encoding cellular inhibitor of apoptosis proteins 1/2 (cIAP1/2). Antagonists targeting cIAP1 have been reported to enhance sensitivity of HPV−, but not HPV+ tumors, to TNF family death ligands (TNF and TRAIL) and radiation. Experimental Design: We tested a novel dual cIAP/XIAP antagonist ASTX660 in HPV+ and HPV− cell lines in combination with death ligands TNFα and TRAIL, and in preclinical xenograft models with radiation, an inducer of death ligands. The dependence of activity on TNF was examined by antibody depletion. Results: ASTX660 sensitized subsets of HPV− and HPV+ HNSCC cell lines to TNFα and TRAIL. These antitumor effects of ASTX660 are the result of both apoptosis and/or necroptosis among HPV− cells, and primarily by apoptosis (caspase 3 and caspase 8 cleavage) in HPV+ cells. ASTX660 enhanced restoration of protein expression and inhibitory activity of proapoptotic tumor suppressor TP53 in HPV+ HNSCC. Furthermore, ASTX660 combined with radiotherapy, an inducer of death ligands, significantly delayed growth of both HPV− and HPV+ human tumor xenografts, an effect attenuated by anti-TNFα pretreatment blockade. Conclusions: IAP1/XIAP antagonist, ASTX660, sensitizes HPV+ HNSCC to TNFα via a mechanism involving restoration of TP53. These findings serve to motivate further studies of dual cIAP/XIAP antagonists and future clinical trials combining these antagonists with radiotherapy to treat both HPV+ and HPV− HNSCC.
Clinical features, molecular aberrations, treatments, and outcomes in histiocytic sarcoma.
Authors: Gordon Ruan, Gaurav Goyal, Nabila Nora Bennani, Mithun Vinod Shah, Karen Rech, Ronald S. Go
Journal: Journal of Clinical Oncology (2019)

7020 Background: Histiocytic sarcoma (HS) is a rare and aggressive malignancy of the monocyte/macrophage lineage. There is a paucity of data on treatments and outcomes in HS. Methods: This is a retrospective study of patients with histologically confirmed diagnosis of HS from 2000-2018. Kaplan-Meier and log-rank tests were used to perform overall survival (OS) analyses. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Results: There were 27 patients in the study (median age 59; range 3-83) and 63% were males. Nine had unifocal involvement and 18 had multifocal disease. Common sites involved were lymph node (50%), soft tissue (40%), bone (36%), and bone marrow (22%). Two of 8 patients had the BRAF-V600E mutation. Next-generation sequencing was performed on 8 patients and showed ≥1 oncogenic alterations (DNMT3A, FLT4, KRAS, NRAS, NUP98, PTCH1, PTPN11, TP53, TSC1, PDGFR, or BRAF genes) as well as a CLIP2-BRAF fusion. The median OS for the cohort was 12 months. Factors associated with worse OS included multifocal disease (OS 10 vs. 125 months, p = 0.03; HR 5.0, CI 1.1-21.8) and marrow involvement (OS 3 vs. 43 months, p = 0.003; HR 8.9, CI 1.7-45.0). Twelve (44%) had surgery with median OS of 42 months (range 1-125). Fifteen had chemotherapy with median OS of 12 months (range 2-67; Table). Conclusions: HS is an aggressive neoplasm, with multifocal disease and bone marrow involvement portending worse outcomes. Most patients have somatic oncogenic alterations involving the MAPK-ERK pathway and other genes. Chemotherapeutic regimens have variable response rates but are not durable. More studies on targeted kinase inhibitors in HS are needed to improve outcomes. [Table: see text]
Abstract 3423: <i>HER2</i> amplification and microsatellite status distribution in Chinese gastric cancer patients
Authors: Jun Guo, Da Jiang, Wei Zhang, Ting Deng, Zhaojian Niu, Wenting Chen, Junping Shi, Shuirong Zhang, Lin Zhang
Journal: Cancer Research (2019)

Abstract Background:Amplification and/or overexpression of human epidermal growth factor receptor-2 (HER2, also known as ERBB2) were present in 6.1-23.0% of gastric cancer. In breast cancer, amplification and overexpression of the HER2 are associated with poor prognosis. Meanwhile, MSI-H patients have an improved prognosis in gastric cancer. However, little is known about the association of these two indicators in gastric cancer. Method:260 tumor tissues and matched normal from gastric cancer patients were included in this study to reveal HER2 amplification and microsatellite status distribution of Chinese patients with gastric cancer using deep next generation sequencing (NGS) targeting 450 cancer genes. Microsatellite status (MSS or MSI-H) were evaluated according to NGS algorithms. Result:Male to female ratio was about 2:1 with a mean age of 60 years old. 241 tumors were primary tumors and 19 were metastases. MSI-H was detected in 16 samples (6.2%) and HER2 amplification was detected in 18 samples (6.9%), which were consistent with the previously reported incidences. The proportion of MSI-H in metastatic lesions was higher than that in primary lesions, but the difference was not statistically significant (10.5% vs. 5.8%, P=0.33). The detection of HER2 amplification in metastatic foci and primary tumors had a similar trend as that in MSI-H (15.8% for metastatic foci vs. 6.2% for primary tumors, P=0.13). Interestingly, our study revealed that HER2 amplification was mutually exclusive with MSI-H in both primary and metastatic lesions. MSI-H/HER2amp-, MSS/HER2amp+, and MSS/HER2amp- subgroups accounted for 5.8%, 6.2%, and 88% in primary cancers, while MSI-H/HER2amp-, MSS/HER2amp+ and MSS/HER2amp- subgroups accounted for 10.5%, 15.8% and 73.7% in metastasis, respectively. Conclusion:We analyzed the distribution of HER2 amplifications and microsatellite status in Chinese patients with gastric cancer. The detection rate of HER2 amplifications and MSI-H was consistent with previous reports. Interestingly, our data showed that both HER2 amplifications and MSI-H have higher detection rate in metastases than that in primary lesions, and the two biomarkers were mutual exclusive in our cohort. Citation Format: Jun Guo, Da Jiang, Wei Zhang, Ting Deng, Zhaojian Niu, Wenting Chen, Junping Shi, Shuirong Zhang, Lin Zhang. HER2 amplification and microsatellite status distribution in Chinese gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3423.
Abstract 495: All-in-one flow cytometry staining panel for immune-cell profiling in syngeneic tumor models
Authors: Holger Weber, Janette Beshay, Cynthia Obodozie
Journal: Cancer Research (2019)

Abstract Checkpoint inhibitor treatment has become a common therapy of various cancer types; however, clinical data indicate that only few patients respond to this regimen due to attenuated anti-tumor immune response. Thus, it has been recognized as important to consider the immune response already during preclinical drug development to anticipate such clinical drawbacks and investigate the changes of immune cell populations after treatment. Flow cytometry is widely used for this kind of analysis. However, a comprehensive analysis of numerousness immune cell populations in one tumor is a major challenge when only limited material is available due to small tumor size of e.g. a tumor responding to the treatment or analysis at an early tumor developmental stage. A staining panel that allows the analysis of all major immune cell populations in a single staining would be a major advantage. Here we present an all-in-one flow cytometry panel based on 15 colors which permits the differentiation of the main immune cell populations in the tumor, such as T cells (CD4+, CD8+, Treg), NK cells, macrophages (M1/M2), MDSCs (neutrophils, M-MDSCs) and dendritic cells. To demonstrate the value of the panel, the immune cell content of CT26wt tumors was compared after subcutaneous, orthotopic or intra-mammary fat pad implantation. During tumor growth profiling of the immune population is performed every 4 days, starting at day 7 after implantation when tumor volume is still very small (50 - 100 mm3). A comprehensive overview is given with valuable insight into the immune biology of the tumor over time and with respect to different tumor sizes. The established all-in-one staining panel allows the direct comparison of immune cell populations with a single staining which improves the development of new immune-modulating drug candidates. Citation Format: Holger Weber, Janette Beshay, Cynthia Obodozie. All-in-one flow cytometry staining panel for immune-cell profiling in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 495.
Abstract 2011: Potassium usnate inhibits invasion and metastasis in colorectal cancer: Implication of clinical application of a water-soluble form of usnic acid in anticancer therapy
Authors: Yi Yang, Woo Kyun Bae, Kyung Hwa Lee, Kyung-Sub Moon, So-Yeon Park, Rui Zhou, Isa Taş, Chathurika Gamage, Sueun Lee, Chaeyong Jung, Kyung Keun Kim, Hyung-Ho Ha, Hangun Kim
Journal: Cancer Research (2019)

Abstract Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy. Citation Format: Yi Yang, Woo Kyun Bae, Kyung Hwa Lee, Kyung-Sub Moon, So-Yeon Park, Rui Zhou, Isa Taş, Chathurika Gamage, Sueun Lee, Chaeyong Jung, Kyung Keun Kim, Hyung-Ho Ha, Hangun Kim. Potassium usnate inhibits invasion and metastasis in colorectal cancer: Implication of clinical application of a water-soluble form of usnic acid in anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2011.
Abstract 981: Degradation of immuno-oncology targets via proprietary PROTAC platform integrating DNA-encoded library technology and rational drug design
Authors: Jannik N. Andersen, Andrew J. McRiner, Lynette A. Fouser, Junyi Zhang, Shilpi Arora, Michael Cordeau, Ying Zhang, John Cuozzo, Michael Briskin, Matt Clark, Diala Ezzeddine
Journal: Cancer Research (2019)

Abstract Since the first small molecule proteolysis targeting chimera (PROTAC) was reported about a decade ago, great progress has been made in the field of targeted protein degradation. Specially designed, small molecules can recruit the ubiquitin-proteasome system (UPS) to tag a protein of interest (POI) for degradation. Based on the ability to knock down a therapeutic POI (instead of inhibiting the target protein activity), this new modality has emerged as a paradigm-shifting approach and opened new avenues for small molecule drug discovery. At Xios Therapeutics, we have applied targeted protein degradation to a number of immuno-oncology (IO) drug targets and we present here the strategy and lessons learned from building our PROTAC platform in collaboration with X-Chem. Specifically, we have leveraged a vertical integration of DNA-encoded library screening (DEL), structural biology, medicinal chemistry, biochemical binding assays and cellular biomarker readouts for the rapid identification of cell potent degraders. We exemplify a modular, ‘fit-for-purpose’ PROTAC matrix that allows for rapid exploration of optimal E3 ligase-binders conjugated to a POI-binder using either existing or novel ligands identified via DEL. We delineate the structure-activity/property relationship (SAR and SPR) analysis of linker with VHL- and CRBN-based binders for a promising IO target achieving potent protein degradation (&amp;gt;90% degradation and nM DC50 potency) and pathway inhibition in cancer cells. Notably, our affinity-based screening of chemical libraries of unprecedented size (~200 billion molecules) with a priori knowledge of the vector point of attachment from the DNA barcode directly informs the rational design of bifunctional PROTAC molecules. In conclusion, our integrated approach allows us to find new, unexplored compound binding sites for both E3 ligases- and POI-binders that can be utilized by the PROTAC platform to create potent selective degraders and to access targets that have previously been considered undruggable. Citation Format: Jannik N. Andersen, Andrew J. McRiner, Lynette A. Fouser, Junyi Zhang, Shilpi Arora, Michael Cordeau, Ying Zhang, John Cuozzo, Michael Briskin, Matt Clark, Diala Ezzeddine. Degradation of immuno-oncology targets via proprietary PROTAC platform integrating DNA-encoded library technology and rational drug design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 981.
Abstract 18210: Quantitative Flow Cytometry Detects DNA Damage in Patients Undergoing Cardiac SPECT
Authors: Won H Lee, Patricia K Nguyen, Shijun Hu, Veronica Sanchez-Freire, Kazim Narsinh, Patricia de Almeida, Andrew S Lee, George Segall, Joseph C Wu
Journal: Circulation (2012)

Introduction: Radiation exposure to medical imaging has doubled in the last two decades, raising concerns for possible increased cancer risk. Despite being the primary source for low dose radiation...
Treatment patterns and outcomes among t(11;14) myeloma patients in a real-world setting.
Authors: Andrew David Norden, Shivam Mathura, Eric Hansen, Stuart L. Goldberg, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2019)

e19531 Background: There is uncertainty about the prognostic and predictive significance of t(11;14), long considered a standard risk cytogenetic abnormality in multiple myeloma (MM). This translocation is associated with elevated BCL-2 expression which may explain responses to venetoclax that have been reported previously. In a real-world database derived from EMR data, we sought to characterize real-world treatment patterns and outcomes from this unique MM cohort. Methods: Records for MM patients with t(11;14) diagnosed between 2000 and 2017 were identified in the COTA real-world database. Descriptive statistics were used to summarize the data. Results: 399 MM patients with t(11;14) were identified. Patient characteristics are summarized in the Table. The most frequent first-line treatments were bortezomib + dexamethasone + lenalidomide (134, 33.6%), bortezomib + cyclophosphamide + dexamethasone (69, 17.3%), and bortezomib + dexamethasone (60, 15.0%). Six (1.5%) patients received venetoclax. Response and progression-free survival data are being analyzed and will be presented at the meeting. Median overall survival was 14.3 (95% CI 10.4 – not yet reached) years. Conclusions: Real-world databases are useful in describing treatment patterns and outcomes in narrowly defined cohorts such as MM with t(11;14). The OS result reported here is unexpectedly long and will be fully explored prior to presentation. [Table: see text]
Discovery of a novel long noncoding RNA overlapping the LCK gene that regulates prostate cancer cell growth
Authors: Huy Q. Ta, Hilary Whitworth, Yi Yin, Mark Conaway, Henry F. Frierson, Moray J. Campbell, Ganesh V. Raj, Daniel Gioeli
Journal: Molecular Cancer (2019)

Virtually all patients with metastatic prostate cancer (PCa) will relapse and develop lethal castration-resistant prostate cancer (CRPC). Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements of many cellular biological processes, and may serve as therapeutic targets for combating PCa progression. Here, we have discovered in a high-throughput RNAi screen a novel lncRNA in PCa, and assessed the oncogenic effects of this lncRNA. Rapid amplification of cDNA ends and sequencing was utilized to identify a previously unannotated lncRNA lying within exon six and the 3'UTR of the lymphocyte-specific protein tyrosine kinase (LCK) gene. The levels of HULLK in the presence or absence of hormone and/or enzalutamide or coregulator inhibitors were measured by quantitative PCR (qPCR). The determination of HULLK transcription and localization were characterized by strand-specific qPCR and cellular fractionation followed by qPCR, respectively. The correlation between HULLK expression and prostate cancer Gleason score was analyzed by droplet digital PCR. CyQuant assays were conducted to evaluate the effects of knocking down HULLK with shRNAs or overexpressing HULLK on cell growth. In this study, a previously unannotated lncRNA lying within exon six and 3'UTR of the LCK gene was dramatically upregulated by androgen in a dose-dependent manner, and the anti-androgen enzalutamide completely blocked this hormone-induced increase. Therefore, we labeled this lncRNA "HULLK" for Hormone-Upregulated lncRNA within LCK. Binding sites for two AR coregulators p300 and Brd4 reside near the HULLK transcriptional start site (TSS), and inhibitors of these coregulators downregulated HULLK. HULLK is transcribed from the sense strand of DNA, and predominantly localizes to the cytoplasm. HULLK transcripts are not only expressed in prostate cancer cell lines, but also prostate cancer patient tissue. Remarkably, there was a significant positive correlation between HULLK expression and high-grade PCa in multiple cohorts. shRNAs targeting HULLK significantly decreased PCa cell growth. Moreover, cells overexpressing HULLK were hypersensitive to androgen stimulation. HULLK is a novel lncRNA situated within the LCK gene that may serve as an oncogene in PCa. Our data enhances our understanding of lncRNA biology and may assist in the development of additional biomarkers or more effective therapeutic targets for advanced PCa.