tbuckley/cabot-search huggingface dataset:
Abstract 4109: Functional profiling of 17,000 open reading frames identifies regulators of PDL1 expression in HNSCC
Authors: Jacqueline Mann, Samantha Devenport, Aditi Kulkarni, Rebecca Hoesli, Susan Foltin, Nicole Michmerhuizen, Alexey Nesvizhskii, Chad Brenner
Journal: Cancer Research (2019)

Abstract The interaction of Programmed Death Ligand 1 (PD-L1) with the PD-1 receptor serves as an immune checkpoint, dampening anti-tumor immunity. While immunotherapies targeting this pathway (Pembrolizumab and Nivolumab), were approved for use in recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) in 2016, overall response rates are low and few biomarkers have been identified to differentiate responders. We expect a more detailed understanding of PD-L1 checkpoint regulation in HNSCC to provide insight toward addressing these deficits. Thus, we developed a high- throughput screening protocol to discover signals modulating PD-L1 expression. We have employed a lentiviral open reading frame (ORF) library for overexpression of over 14,000 different genes in a pooled format. UM-SCC-49 cells transduced with this library were stained for cell surface PD-L1 and sorted by flow cytometry to select cells with enhanced PD-L1 expression. Sequencing of the selected sub-population was performed to determine ORFs enriched over an unsorted pool. To validate a role for individual target genes in modulating PD-L1 expression, monoclonal populations were expanded from the sorted pool and evaluated for PD-L1 expression. We confirmed increased PD-L1 expression in 7 of these cell lines over wild-type and LacZ overexpressing controls via western blotting and flow cytometry. Furthermore, we selected 5 ORFs of interest overrepresented in the sorted pool for further validation using stably expressed V5 tagged constructs. Target gene expression was confirmed by western blot, and enhanced cell surface PD-L1 expression was validated via flow cytometry for 4/5 cell lines. Thus, we provide evidence for successful identification of signals regulating PD-L1 using a novel high-throughput overexpression screen. Future experiments will aim to clarify the mechanism of PD-L1 induction in response to the signals identified here, and may ultimately provide a more thorough understanding of genetic factors modulating immunosuppression and response to immunotherapy in HNSCC patients. Citation Format: Jacqueline Mann, Samantha Devenport, Aditi Kulkarni, Rebecca Hoesli, Susan Foltin, Nicole Michmerhuizen, Alexey Nesvizhskii, Chad Brenner. Functional profiling of 17,000 open reading frames identifies regulators of PDL1 expression in HNSCC [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 4109.
Abstract 186: Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers
Authors: Yan Zhang, Dayong Zheng, Ting Zhou, Mohit Hulsurkar, Michael Ittmann, Long Shao, Martin Gleave, Wenliang Li
Journal: Cancer Research (2019)

Abstract The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression. Citation Format: Yan Zhang, Dayong Zheng, Ting Zhou, Mohit Hulsurkar, Michael Ittmann, Long Shao, Martin Gleave, Wenliang Li. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers [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 186.
Abstract 14203: Real-World Direct Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Medicare Beneficiaries With Fibrillation: A Subgroup Analyses by a History of Ischemic Stroke
Authors: Lanting Yang, Samir Saba, Yuting Zhang, Inmaculada Hernandez
Journal: Circulation (2018)

Introduction: It remains unknown whether the comparative effectiveness of direct oral anticoagulants (DOACs) and warfarin differs between patients with and without a history of stroke or transient ...
Abstract 2893: ALK amplification and rearrangements are recurrent targetable events in glioblastoma
Authors: Anne-Florence Blandin
Journal: Cancer Research (2019)

Abstract Anaplastic Lymphoma Kinase (ALK) expression, rearrangements, and single nucleotide variants have been reported in several brain tumor types, but the significance and function of each aberration in adults and children have not been clearly established. To determine the degree to which ALK represents a relevant therapeutic target in gliomas, we first examined ALK expression using immunohistochemistry (IHC) in a panel of 148 adult GBM and 49 pediatric GBM/high grade gliomas. We identified high ALK expression was most frequent in pediatric gliomas (32%, 16/49, IHC score 2+ or 3+). Copy arrays/sequencing and FISH for the ALK locus revealed high levelALK amplification in 31% of ALK-expressing cases (5/16) but was a rare event in gliomas overall. Whole-genome sequencing and RNA sequencing identified novel and recurrent PPP1CB-ALKfusions in 43% of ALK-expressing pediatric GBM (7/16), suggesting IHC may be an efficient means of screening for ALK aberrations as in the identification of EML4-ALK lung cancer. All ALK- amplified cases harbored PPP1CB-ALK fusion but 2 PPP1CB-ALK cases were copy neutral. The phosphatase PPP1CB was fused in-frame to ALK at exon 20 with preservation of the ALK kinase domain and predicted to activate via the same mechanism as other ALK rearranged cancers. ALKfusion proteins promoted cell proliferation and constitutive kinase activity and upregulated STAT and AKT signaling pathways. However, expression of novel ALK missense mutations in NSCs did not promote proliferation. Administration of ALK inhibitor Crizotinib reduced tumor growth in a PDX GBM from a patient with a novel ALK fusion. This work validates amplification and rearrangement of ALK as a highly recurrent driver event and therapeutic target in GBM, particularly in young children where it may be the sole driver event. Note: This abstract was not presented at the meeting. Citation Format: Anne-Florence Blandin. ALK amplification and rearrangements are recurrent targetable events in glioblastoma [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 2893.
Treatment response predictor using 31P MRS for CHOP and R-CHOP therapy in diffuse large B-cell lymphoma
Authors: Fernando Arias-Mendoza, Geoffrey Payne, Kristen Zakian, Marion Stubbs, Jaime Cruz-Lobo, Adam Schwarz, Amita Shukla-Dave, Franklyn Howe, Nicholas Maisey, David Cunningham, Harish Poptani, Mitchell Smith, Owen O'Connor, Ruth Pettengell, Martin Leach, Jason Koutcher, John Griffiths, Arend Heerschap, Jerry Glickson, Truman Brown
Journal: Cancer Research (2008)

3738  Introduction: Our multi-institutional research program has demonstrated in over 102 patients with various forms of non-Hodgkin9s lymphomas (NHL) that the sum of the 31P resonances of phosphoethanolamine plus phosphocholine [Etn-P + Cho-P] normalized by the total nucleotide triphosphates (NTP) in the tumor acquired prior to treatment initialization can predict treatment failure and drug-free survival. To make our results diagnosis- and treatment- specific, we selected patients with diffuse large B-cell lymphoma (DLBCL) treated with the standard therapy of cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone (CHOP) or similar treatments. We further divided these patients in those that did not have rituximab (R-) and those that did (R+), because this drug has recently shown dramatically increased response rates and drug-free survival. Our goal was to explore whether the addition of rituximab modified the predictive benefit of [Etn-P + Cho-P]/NTP. Procedures & Patients: Tumor areas of DLBCL patients were studied with in vivo 3D-localized, 1H-decoupled, nuclear Overhauser enhanced, 31P MR spectroscopy. A total of 22 patients with DLBCL were selected; 14 of them R- and eight R+. Results & Discussion: In both the R- and R+ groups the pre-treatment [Etn-P + Cho-P]/NTP showed significant differences between those patients that responded completely to therapy (CR) and those that did not (NCR). The mean ± standard error for the CR and NCR cases for the R- group were1.38 ± 0.23 (n = 9) and 2.35 ± 0.19 (n = 5) respectively (p
Abstract 2687: Dolasynthen–a novel, homogeneous Auristatin F hydroxypropyl amide antibody-drug conjugate platform
Authors: Dorin Toader, Marc Damelin, Anouk Dirksen, Shawn P. Fesler, Scott D. Collins, Barrett J. Nehilla, Jian Xu, Ling Xu, Kalli C. Cattcott, Alex Uttard, Winnie Lee, Susan Clardy, Cheri A. Stevenson, LiuLiang Qin, Patrick R. Conlon, Mariya V. Kozytska, Chen-Ni Chin, David H. Lee, Timothy B. Lowinger
Journal: Cancer Research (2019)

Abstract Dolasynthen is a novel, fully synthetic, structurally homogeneous platform that enables the construction of ADCs with tunable drug-to-antibody ratios (DAR), from a low of 2 to a high of 24. The resulting ADCs exhibit excellent physicochemical properties and fully homogeneous conjugates can be created through a variety of bioconjugation chemistries. Analogous to our first platform, Dolaflexin®, Dolasynthen is loaded with the proprietary payload Auristatin F hydroxypropylamide (AF-HPA) with precisely defined numbers of the cytotoxin per Dolasynthen scaffold.Studies that evaluate the tolerability and efficacy of Dolasynthen in preclinical models are described herein. ADCs containing a range of DAR values were generated following conjugation of Dolasynthen to two different monoclonal antibodies. The DAR of the ADCs was achieved by controlled reduction of native disulfide bonds in IgG1 antibodies, chromatographic fractionation, or through use of site-specific conjugation technologies. ADCs with both DAR6 and DAR12 were evaluated in vitro and also in vivo in the mouse, rat and monkey, for efficacy, tolerability and PK. Dolasynthen conjugates had excellent physicochemical properties and displayed the expected cell binding and in vitro cytotoxicities. In vivo pharmacology of Dolasynthen ADCs in in vivo xenograft models showed dose-dependent tumor growth inhibition at low mg/kg mAb doses. Tolerability in the rat at multiple doses was determined, including histopathological evaluation. Dolasynthen ADCs showed excellent PK characteristics in mouse, rat and NHP. Overall, the Dolasynthen platform appears to offer significant potential for clinical application. Citation Format: Dorin Toader, Marc Damelin, Anouk Dirksen, Shawn P. Fesler, Scott D. Collins, Barrett J. Nehilla, Jian Xu, Ling Xu, Kalli C. Cattcott, Alex Uttard, Winnie Lee, Susan Clardy, Cheri A. Stevenson, LiuLiang Qin, Patrick R. Conlon, Mariya V. Kozytska, Chen-Ni Chin, David H. Lee, Timothy B. Lowinger. Dolasynthen–a novel, homogeneous Auristatin F hydroxypropyl amide antibody-drug conjugate platform [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 2687.
David Oliver: The NHS doesn’t need more “restructuring”
Authors: David Oliver
Journal: BMJ (2019)

People are fond of saying that the NHS needs some sort of radical overhaul. On 25 June the Conservative leadership candidate Boris Johnson said that it “needs reform,” as it was “not getting the kind of support and indeed the kind of changes and management that it needs.”1 The perils of constant structural reorganisation have been described beautifully in the Nuffield Trust’s Doomed to Repeat report.2 Politicians and lobbyists never learn.

Weeks before, Kate Andrews, associate director of the Institute of Economic Affairs (IEA), had asserted on Jeremy Vine’s BBC show that the NHS was falling behind other systems and needed structural reform. The link was tweeted by the IEA, saying that “we really, really, really need to structurally reform the NHS.”3

Andrews has made numerous broadcast appearances making the same arguments, but the IEA’s ideological opposition to the NHS model,4 its small state, pro-market view of public services, …
Ixazomib, lenalidomide, and dexamethasone for patients with POEMS syndrome.
Authors: Angela Dispenzieri, Martha Lacy, Michelle Mauermann, Betsy LaPlant, Ronald S. Go, Prashant Kapoor, Nelson Leung, Yi Lisa Hwa, Amy Fonder, Francis Buadi, Suzanne R. Hayman, John Anthony Lust, David Dingli, Wilson I. Gonsalves, Taxiarchis Kourelis, Rahma M. Warsame, S. Vincent Rajkumar, Shaji Kumar, Morie A. Gertz
Journal: Journal of Clinical Oncology (2019)

8019 Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. Most of the information regarding treatment has been gleaned from retrospective data. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We designed a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF &gt; 200 pg/ml, a PS &lt; 3. There were two groups [gp] (intended enrollment 15 per gp): Gp A, 13 cycles for patients (pts) who had relapsed or refractory disease; Gp B, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant. Primary endpoint was VEGF complete response (CR = normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response, clinical responses including neurologic response were also studied. To date, 13 pts enrolled since 10/31/2016—4 to Gp A and 9 to Gp B. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 1/21/2019. Results: Median age was 55; 73% were male. So far, overall 64% met primary endpoint of VEGF CR (Table). The median follow-up of survivors is 12.4 mo (6, 24). 1 pt came off study for non-responsive disease and died thereafter. 38% of patients had grade 3+hematologic AE; 72% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection and hypotension in 2 each; atrial fibrillation, diarrhea, edema, dyspnea, and thromboembolism in 1 each. 4 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Clinical trial information: NCT02921893. [Table: see text]
Abstract 3965: Papillary Muscle Repositioning in Valve Replacement for Left Ventricualr Dysfunction: Ischemic Mitral Regurgitation
Authors: Farideh Roshanali, Mohammad Ali Yousefnia, Mohammad Hossein Mandegar
Journal: Circulation (2009)

Objective: The aim of this study was to investigate the feasibility of performing papillary muscle repositioning (PMR) for subvalvular-sparing mitral valve replacement procedures in patients with i...
Abstract P113: Lipid-related Genetic Variants and Lipid Outcomes in a Cohort of Chilean Children
Authors: Ann Von Holle, Anne Justice, Kari E North, Bárbara Angel, Estela Blanco, Sheila Gahagan, Misa Graff, José Santos
Journal: Circulation (2017)

Dyslipidemia is an important risk factor for chronic cardiometabolic diseases. Lipid traits are highly heritable and there are currently &gt;185 established loci influencing lipid levels in adults. Recent studies have confirmed that variants associated with lipids influence lipid levels across the lifecourse, and in ancestrally diverse populations. Given that Hispanic/Latinos (HL) shoulder much of the cardiometabolic burden in the United States, it is important to identify genetic variants that contribute the greatest risk for elevated lipid levels across life stages. Thus, our primary aim is to examine the association of known lipid variants with lipid traits identified in large study of adult participants from a Chilean infancy cohort of primarily European-descent. The sample assessed from 2008 to 2013 (n=546) had genotyping and well-measured lipid phenotypes (median age: 16.8 years, interquartile range: 16.6, 16.9). We assessed single variant associations using linear regression for high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), assuming an additive genetic model, adjusted for sex. Additionally, we regressed phenotypes onto weighted trait-specific polygenic risk scores (PRS). Only six variants from the Chilean sample met the a priori threshold of power &gt; 0.8. We found statistically significant effect sizes (mmol/l (se)) for four of the six variants: rs3764261 (0.16 (0.04)) and rs1532085 (0.05 (0.04)) for HDL and rs1260326 (0.34 (0.15)) and rs964184 (0.33 (0.15)) for TG. For each significant variant, direction of effect matched the multiethnic adult GWAS from which SNPs were selected. We compared our findings to a previous study in Finnish children at age 18 years (n=1,216) and found an opposite direction of effect for our significant HDL variants. Likewise, when comparing coefficients for the PRS between the Chilean and Finnish youth sample we found the association to be stronger in the Chilean sample for every trait and gender group with the exception of LDL for males. The lipid loci explained the least amount of total variance for LDL (males=4% and females=5%) and the most amount of variance for HDL (males=20% and females=14%). In conclusion, there is evidence that lipid loci from a HL sample of adolescents contain similar associations as those from European children and adults. Despite the small sample size and possibility for bias with different ancestral groups we found meaningful and statistically significant associations relating lipid loci in a HL cohort of Chilean adolescents with those found in European ancestral groups. These associations emphasize the importance of adolescence as a time for disease prevention given studies demonstrating both the persistence of associations between PRS and lipids over the life course and the increasing role PRS plays in predicting disease.
Abstract 2499: In vitro and in vivo efficacy of MCL1 inhibitor S63845 in small cell lung cancer
Authors: Yuto Yasuda, Hiroaki Ozasa, Takahiro Tsuji, Takashi Nomizo, Tomoko Yamamoto, Hitomi Ajimizu, Hironori Yoshida, Yuichi Sakamori, Toyohiro Hirai, Young Hak Kim
Journal: Cancer Research (2019)

Abstract MCL1 is a member of the BCL-2 family, which regulates apoptosis. Targeting MCL1 represents a potential breakthrough of cancer treatment. We tested S63845, a MCL1 inhibitor, in four SCLC cell lines (DMS114, DMS53, SW1271, and NCI-H69) and, in addition, one patient derived SCLC cell line (KTOR201). S63845 had greater efficacy in two of five SCLC cell lines (DMS114 and KTOR201). These two SCLC cell lines had higher expression of MCL1 and lower expression of BCL-XL, which is another member of the BCL-2 family. The other three SCLC cell lines (DMS53, SW1271 and NCI-H69) were resistant to S63845 and had a higher expression of BCL-XL or lower expression of MCL1. In vivo activity was evaluated in xenograft models. DMS114 was subcutaneously implanted into immunocompromised mice. When the tumor volume was reached 150-200 mm3, mice were administered with S63845 (25 mg/kg) or vehicle intravenously twice a week. S63845 showed significant antitumor efficacy in vivo. Finally, immunohistochemical evaluation of MCL1 and BCL-XL was assessed in SCLC obtained from 33 patients at Kyoto University Hospital. High MCL1 expression with low BCL-XL expression was observed in 16 specimens (48.5%).These data suggested that S63845 might be a powerful treatment of SCLC as a new therapeutic strategy. It is possible that the expressions of MCL1 and other members of the BCL-2 family predict the sensitivity of S63845. Citation Format: Yuto Yasuda, Hiroaki Ozasa, Takahiro Tsuji, Takashi Nomizo, Tomoko Yamamoto, Hitomi Ajimizu, Hironori Yoshida, Yuichi Sakamori, Toyohiro Hirai, Young Hak Kim. In vitro and in vivo efficacy of MCL1 inhibitor S63845 in small cell lung cancer [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 2499.
New discoveries of mdig in the epigenetic regulation of cancers
Authors: Qian Zhang, Chitra Thakur, Junwei Shi, Jiaying Sun, Yao Fu, Paul Stemmer, Fei Chen
Journal: Seminars in Cancer Biology (2019)

Mineral dust-induced gene (mdig) encodes a member of the evolutionarily conserved JmjC family proteins that play fundamental roles in regulating chromatin-based processes as well as transcription of the genes in eukaryotic cells. This gene is also named as myc-induced nuclear antigen 53 (MINA), nucleolar protein 52 (NO52) and ribosomal oxygenase 2 (RIOX2). Increased expression of mdig had been noted in a number of human cancers, esp. lung cancer. Emerging evidence suggests that the oncogenic activity of mdig is most likely achieved through its regulation on the demethylation of histone proteins, despite it lacks the structural identities of the demethylases. Here, we discuss the latest discoveries on the characteristics of the mdig protein and its roles in a wide variety of normal and carcinogenic processes. We will also provide perspectives on how mdig is involved in the maintenance and differentiation of the embryonic stem cells, somatic stem cells and cancer stem cells.