tbuckley/cabot-search huggingface dataset:
Abstract 4593: Inhibition of invasion of HER2-positive breast cancer cells by lysosome targeting drugs
Authors: Malene B. Hansen, Maria Postol, Davig A. Egan, Marja Jäättelä, Tuula Kallunki
Journal: Cancer Research (2019)

Abstract Up to 20% of all breast cancers are over-expressing HER2/ErbB2, leading to malignant and invasive cancers with a poor patient outcome. Though good ErbB2-targeting treatments have been developed, metastasis formation and drug resistance are still major challenges for the long-term cure. This project aims to find out if some of the numerous pre-existing compounds and clinically approved drugs can be repurposed to treat or improve the treatment of HER2/ErbB2-positive breast cancer. We have therefore set up a high-throughput and high-content screen of the Prestwick Chemical Library to identify drugs that can reverse the ErbB2-induced, invasion-promoting, peripheral distribution of lysosomes. Using a breast cancer cell model expressing N-terminally truncated version of ErbB2, we mimic breast cancer that is resistant to the currently used antibodies, trastuzumab and pertuzumab. This cell line shows a highly invasive phenotype with increased activation of the lysosomal proteases, cysteine cathepsin B and L, as well as anterograde movement of lysosomes. This repositioning of the lysosomes enables them to fuse with the plasma membrane and empty their acidic and hydrolyzing content to the extracellular matrix, promoting invasion. Treatment with the clinically used drug lapatinib will reverse this phenotype. The cells ability to reverse the phenotype, through increasing the number of perinuclear lysosomes while removing lysosomes form cellular protrusions, was evaluated for each screened drug, using the ImageXpress Micro Confocal High-Content Imaging System. We have hereby identified eight drugs that can redirect lysosomes from the invadosome-like cellular protrusions to their non-invasive perinuclear position in ErbB2 expressing breast cancer cells. We are currently analyzing the impact of these drugs on breast cancer cell invasion though migration assays and three-dimensional invasion assays. We are also addressing their effect on lysosomal membrane permeabilization, lysosomal pH and investigating their effect on proteins that are known to be involved in lysosomal distribution. Clinically, our findings may facilitate repurposing or new development of drugs to treat HER2/ErbB2-positive and invasive breast cancers that are resistant to current treatments. Citation Format: Malene B. Hansen, Maria Postol, Davig A. Egan, Marja Jäättelä, Tuula Kallunki. Inhibition of invasion of HER2-positive breast cancer cells by lysosome targeting drugs [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 4593.
Effect of gilteritinib on survival in patients with <i>FLT3</i>-mutated <i>(FLT3</i><sup>mut+</sup>) relapsed/refractory (R/R) AML who have common AML co-mutations or a high <i>FLT3</i>-ITD allelic ratio.
Authors: Mark J. Levis, Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Pau Montesinos, Maria R. Baer, Richard A. Larson, Wen-Chien Chou, Hisayuki Yokoyama, Christian Recher, Sung-Soo Yoon, Jason E Hill, Matt Rosales, Charles Liu, Erkut Bahceci
Journal: Journal of Clinical Oncology (2019)

7000 Background: The FLT3 inhibitor, gilteritinib, showed superior response and overall survival (OS) compared with salvage chemotherapy (SC) in patients (pts) with FLT3 mut+ R/R AML in the phase 3 ADMIRAL study. We analyzed the impact of baseline co-mutations and FLT3-ITD allelic ratio (AR) on response and OS. Methods: A total of 37 recurrently mutated genes in AML (Archer Core Myeloid Panel) were analyzed by next-generation sequencing; the cutoff for co-mutation positivity (co-mut+) was ≥0.027. Baseline FLT3-ITD AR ( FLT3-ITD to FLT3 wild-type DNA) was measured by the LeukoStrat CDx FLT3 Mutation Assay. The median FLT3-ITD AR value of 0.77 was used to define high (≥0.77) vs low (&lt;0.77) FLT3-ITD AR. Results: Analysis of 361 FLT3 mut+ pts identified four major co-mutation cohorts, each with ≥10% of pts: NPM1 (n=173; 47.9%), DNMT3A (n=115; 31.9%), DNMT3A/NPM1 (n=86; 23.8%) , and WT1 (n=65; 18.0%). In addition, seven pts (1.9%) had all three co-mutations (ie, NPM1, DNMT3A, and WT1). The gilteritinib arm had superior response rates and OS across all four major co-mutation cohorts, with the greatest survival benefit in pts with DNMT3A/NPM1 co-mut+ (Table). In FLT3-ITD AR analyses (n=335), gilteritinib conferred longer OS than SC in pts with a high or low FLT3-ITD AR (gilteritinib: high FLT3-ITD AR, 7.1 mos vs low FLT3-ITD AR, 10.6 mos; SC: high FLT3-ITD AR, 4.3 mos vs low FLT3-ITD AR, 6.9 mos). In both arms, OS was longer in the low FLT3-ITD AR cohort than the high FLT3-ITD AR cohort but the difference in the gilteritinib arm was not statistically significant (gilteritinib: HR=1.341, P=0.0712; SC: HR=2.01, P=0.0021). Conclusions: The ADMIRAL trial shows that the clinical benefit of gilteritinib in FLT3 mut+ R/R AML is maintained regardless of NPM1, DNMT3A, DNMT3A/ NPM1, or WT1 co-mut+ or high FLT3-ITD AR. Clinical trial information: NCT02421939. [Table: see text]
Abstract 3182: Directed screening TCRs against Ras mutations in mCRC patients
Authors: Jijun Yuan
Journal: Cancer Research (2019)

Abstract Ras gene is involved in many signaling pathway to regulate cell proliferation, metabolism and motility, for example MAPK and PI3K pathway. Ras mutation is constitutively active to drive uncontrolled cell proliferation that results in malignant transformation. Ras mutation frequently occurs in human malignancy, for example pancreatic cancer (98%), colorectal cancer (45%) and lung cancer (31%). Drug development targeting Ras mutation was not succeed despites decades of effort in small molecule fields. T cell receptor (TCRs) can recognize processed and presented neoantigens on human leukocytes antigen (HLA). Ras G12D mutation was report as neoantigen and could be recognized by tumor infiltrating lymphocytes restricted by HLA-C0802 in mCRC patients. We assume that human TCR repertoire encompassing specific TCRs against Ras mutation restricted by other HLAs in Chinese patients. We design a novel synthetic presentation mRNA construct which harboring all pathogenic Ras mutations. The construct significantly enhanced Ras mutation peptides presentation on HLAs (&amp;gt;60%) compared with conventional used construct. We developed a directed screening method to identify T cell clone against Ras mutation restricted by Chinese pop HLAs in tumor infiltrating lymphocytes and sequenced TCRs by using 10xGenomics. We identified several TCRs that showed effector function against Ras mutation in China mCRC patients for further developing TCR-T cell therapy. Citation Format: Jijun Yuan. Directed screening TCRs against Ras mutations in mCRC 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 3182.
Associations with Corneal Hysteresis in a Population Cohort
Authors: Bing Zhang, Yusrah Shweikh, Anthony P. Khawaja, John Gallacher, Sarah Bauermeister, Paul J. Foster, Tariq Aslam, Sarah A. Barman, Jenny H. Barrett, Paul Bishop, Peter Blows, Catey Bunce, Roxana O. Carare, Usha Chakravarthy, Michelle Chan, Sharon Y.L. Chua, David P. Crabb, Philippa M. Cumberland, Alexander Day, Parul Desai, Bal Dhillon, Andrew D. Dick, Cathy Egan, Sarah Ennis, Paul Foster, Marcus Fruttiger, John E.J. Gallacher, David F. Garway-Heath, Jane Gibson, Dan Gore, Jeremy A. Guggenheim, Chris J. Hammond, Alison Hardcastle, Simon P. Harding, Ruth E. Hogg, Pirro Hysi, Pearse A. Keane, Sir Peng T. Khaw, Anthony P. Khawaja, Gerassim dos Lascaratos, Andrew J. Lotery, Tom Macgillivray, Sarah Mackie, Keith Martin, Michelle McGaughey, Bernadette McGuinness, Gareth J. McKay, Martin McKibbin, Danny Mitry, Tony Moore, James E. Morgan, Zaynah A. Muthy, Eoin O’Sullivan, Chris G. Owen, Praveen Patel, Euan Paterson, Tunde Peto, Axel Petzold, Jugnoo S. Rahi, Alicja R. Rudnikca, Jay Self, Sobha Sivaprasad, David Steel, FRCOphth, Irene Stratton, Nicholas Strouthidis, Cathie Sudlow, Dhanes Thomas, Emanuele Trucco, Adnan Tufail, Veronique Vitart, Stephen A. Vernon, Ananth C. Viswanathan, Cathy Williams, Katie Williams, Jayne V. Woodside, Max M. Yates, Jennifer Yip, Yalin Zheng
Journal: Ophthalmology (2019)
Abstract 4742: The influence of cellular developmental state on response to therapeutics in glioblastoma
Authors: Oluwademilade Nuga, Ana deCarvalho, Douglas Ruden, Stephen Brown, Indrani Datta, Tathianne Malta
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is an aggressive tumor treated with ionizing radiation (IR) and temozolomide (TMZ). Here we investigate how developmental state of glioblastoma cells: cancer stem cells (CSC) or differentiated cells, influences cellular response to treatment. Tissue from untreated primary GBM tumors representing diverse genotype were dissociated and cultured in conditions selective for CSCs, which were subsequently differentiated into an astrocytic phenotype by culturing in media supplemented with 2% FBS. Stemness index was evaluated using a machine learning predictive algorithm. Sensitivity of both isogenic CSC and serum differentiated cell (SDC) populations to TMZ and IR was determined by non-linear fitting of dose-response curves, using CellTiterGlo to measure cell viability (n=5) . CSCs and SDCs were then subjected to sub-lethal TMZ, IR (4 Gy), or control treatments, in triplicate. Cells were harvested, and DNA was isolated and Illumina 450k DNA methylation array data was analyzed by using the Methylumi package in R software. RNA was isolated for sequencing, and differentially expressed genes were determined by NOISeq R package. Our results show that GBM CSCs are more vulnerable to both TMZ and IR treatment than the isogenic SDCs. Transcriptome profiling show that IR leads to increase in p53 mediated expression of pro-apoptotic genes such as MDM2, PUMA and BCL2 binding protein relative to control in CSCs. In differentiated cells, IR lead to an increase in WNT signaling, DNA-repair activity and histone modification /remodeling proteins. Enrichment analysis using Fisher’s exact test identified significant enrichment in lipid, fatty acid and metabolic processes as well as receptor tyrosine signaling. Globally, CSCs exhibited a decrease in protein coding genes and increase in regulatory RNA expression. DNA methylation show a global increase in CpG promoter methylation in differentiated cells relative to isogenic stem-like counterparts. We recovered significant differentially methylated probes between treatment groups (Wilcoxon signed rank test) as well as a global increase in CpG promoter methylation in IR treated cells relative to control. These findings underscore the challenge of treating a highly heterogeneous tumor and challenge a strategy of inducing differentiation to increase GBM sensitivity to treatment. Citation Format: Oluwademilade Nuga, Ana deCarvalho, Douglas Ruden, Stephen Brown, Indrani Datta, Tathianne Malta. The influence of cellular developmental state on response to therapeutics 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 4742.
Sézary syndrome: The cause of erythema revealed by the blood film
Authors: Richard Hinton, Eva Yebra‐Fernandez, Barbara J. Bain
Journal: American Journal of Hematology (2019)

A 92-year-old woman was admitted from a dermatology clinic with erythroderma and dehydration. She had a history of fluctuating skin rashes for many years, hypertension and peripheral edema. On admission, her blood count showed: white cell count 7.9 x 109/L, hemoglobin concentration 118 g/L, and platelet count 218 x 109/l. A blood film showed the lymphocyte count to be 2.25 x 109/L, some of these cells having been counted as monocytes by the automated counter (Abbott Alinity). Many of the lymphoid cells were strongly suspicious of Sézary cells. Intact cells (Image, top panel) had a high nucleocytoplasmic ratio and weakly basophilic cytoplasm; the nuclei had tightly interwoven lobes, which were apparent with careful focusing. The lobulation was more readily apparent in smear cells (Image, bottom panel). Sézary syndrome was suspected and was confirmed by immunophenotyping and clonality analysis. Flow cytometric immunophenotyping showed an abnormal mature post-thymic T-cell population that accounted for 95% of lymphocytes. This population displayed low/intermediate forward scatter (FSC) and side scatter (SSC) with weak expression of CD3 and CD4, expression of CD5 and CD28, and no expression of CD2, CD7, CD8, CD56 or activation markers. T-cell clonality studies showed a clonal population with rearrangement of the TRG locus. Computed tomography revealed widespread lymphadenopathy. There are a number of hematological conditions that can present with cutaneous manifestations so that a blood film is always indicated when a skin condition is undiagnosed. Because of the dense chromatin and interwoven lobes, the recognition of the cerebriform nuclei of Sézary syndrome can be difficult. We observed in this patient that when the neoplastic cells had been slightly crushed during the spreading of the film, the nuclear lobulation was more apparent. Examination of smear cells can be similarly useful in T-prolymphocytic leukemia, revealing nucleoli that can be more difficult to detect in an intact cell when the chromatin is very dense. Nothing to report.
Venous thromboembolism risk with contemporary lenalidomide-based regimes for multiple myeloma: A systematic review and meta-analysis.
Authors: Rajshekhar Chakraborty, Irbaz Bin Riaz, Saad Malik, Naimisha Marneni, Alex Mejia Garcia, Faiz Anwer, Alok A. Khorana, S. Vincent Rajkumar, Shaji Kumar, M. Hassan Murad, Zhen Wang, Safi U. Khan, Navneet S. Majhail
Journal: Journal of Clinical Oncology (2019)

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]
Abstract SY21-02: Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break
Authors: Parker S. Sulkowski, Sebstian Oeck, Jing Li, Brian Shuch, Megan C. King, Ranjit S. Bindra, Peter M. Glazer
Journal: Cancer Research (2019)

Abstract Elevated levels of the metabolites, 2-hydroxyglutarate (2HG), fumarate, and succinate, can occur in human malignancies due to somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes or germline mutations in fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes, respectively. Mutations in IDH1 and IDH2 are found in a large number of human malignancies, most notably gliomas and acute myelogenous leukemias, along with cholangiocarcinomas, chondrosarcomas, and melanomas. Inherited mutations in FH and SDH, are linked to the familial cancer predisposition syndromes, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC), respectively. These structurally related metabolites inhibit α-ketoglutarate-dependent enzymes, including dioxygenases that modify chromatin. We have shown that they consequently suppress the pathway of homology-dependent DNA repair (HDR), conferring an exquisite sensitivity to PARP inhibitors that is currently being tested in clinical trials. In this presentation, we will discuss our recent work elucidating the mechanistic basis for this suppression of DNA repair. Rather than acting indirectly through epigenetic regulation of gene expression, we find that these metabolites act directly by inhibiting HDR factor recruitment to DNA double-strand breaks (DSBs). The metabolites inhibit the lysine demethylases, KDM4A/B, causing aberrant hypermethylation of H3K9 and disrupting signaling at the break, thereby delaying the stepwise recruitment of key HDR factors. These results define a novel mechanism of decreased DNA repair in oncometabolite producing human tumors and may provide the basis for the rational design of novel therapeutic strategies for these malignancies. Citation Format: Parker S. Sulkowski, Sebstian Oeck, Jing Li, Brian Shuch, Megan C. King, Ranjit S. Bindra, Peter M. Glazer. Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break [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 SY21-02.
Letter to the Editor: Incidence and Mortality of Acute on Chronic Liver Failure Using Two Definitions in Patients With Compensated Cirrhosis
Authors: Narendra S. Choudhary, Neeraj Saraf, Sanjiv Saigal, Arvinder S. Soin
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Acute‐on chronic liver failure (ACLF) is characterized by sudden worsening attributed to an acute event superimposed on chronic liver disease and is associated with organ failure and significant short‐term mortality.1 ACLF not responding to medical treatment in early course is associated with poor spontaneous survival in the absence of liver transplantation.2 There are important differences in the definitions of ACLF given by the Asian Pacific Association for the Study of the Liver (APASL) and the European Association for the Study of the Liver (EASL). The APASL definition is also applicable to chronic liver disease without cirrhosis and has definite cut‐off points of bilirubin and international normalized ratio,3 whereas the EASL definition is vague and consistes of acute decompensation, organ failure, and a high 28‐day mortality rate.4 There is no good comparison available for APASL and EASL criteria. Mahmud et al. should be congratulated for comparison of APASL and EASL criteria in a large cohort.5 A total of 783 patients had EASL and APASL ACLF, 4,296 had EASL ACLF alone, and 574 had APASL ACLF alone. The 28‐ and 90‐day mortalities were slightly higher for APASL ACLF. Median bilirubin at diagnosis of EASL‐alone ACLF was 2.0 mg/dL. The investigators concluded that there was a significant discord in ACLF events by EASL and APASL criteria. The study raises two important and interesting queries. Which definition (APASL or EASL) picked up ACLF early in patients who fulfilled both of the criteria (n = 783) after acute event? A definition that picked up a diagnosis of ACLF early may change the natural course of ACLF by offering aggressive management in these potentially sick patients. The second question is related to survival of these patients. The patients fulfilling both of these criteria should be sicker and may have worse outcome than APASL ACLF or EASL alone because of having both hepatic dysfunction (which may be absent in EASL ACLF) and organ failures (which may be absent in APASL ACLF). If survival of patients fulfilling criteria of both APASL and EASL ACLF is worse than APASL ACLF or EASL ACLF, this group may be considered for early transplantation. The investigators can compare survival of APASL ACLF, EASL ACLF, and both APASL and EASL ACLF. It would be quite useful for current understanding of ACLF if the above queries can be addressed.
A Reckoning and Research Agenda for Neuroimaging in Psychiatry
Authors: Amit Etkin
Journal: American Journal of Psychiatry (2019)

Human neuroimaging has been a core component of both research in psychiatry and conceptual models of the brain circuit-level mechanisms underlying psychopathology. Despite landmark neuroimaging research over the past 25 years, we still lack the level of precision and insight needed for bringing neuroimaging tools into clinical care contexts. This brief review examines historical research trends in psychiatric neuroimaging, as well as the basic assumptions underlying current efforts, in order to understand factors that have limited the impact of neuroimaging efforts thus far. These factors include the pitfalls of case-control designs, confounders inherent in associational research approaches, and the challenges in embracing fully data-driven analyses. Several critical gaps emerge, the addressing of which could provide the critical new insights that have long been sought from neuroimaging. These include transitioning from group-to individual-level analyses (and through this to intervention studies carried out robustly at the level of individual patients), building “big data” from a longitudinal perspective and not only a cross-sectional one, a greater focus on identifying causal mechanisms, and the development of tools such as electroencephalography in addition to the dominant MRI methods to aid translation to real-world clinical care. Despite the still-unrealized potential of psychiatric neuroimaging, there is now much to be excited about as previous learnings are converted into fundamentally new directions. Indeed, we may now be at an inflection point for neuroimaging if the typical study designs are left in the past and the field systematically and thoughtfully embraces the challenges that the past 25 years of research have now made apparent.