tbuckley/cabot-search huggingface dataset:
A phase I study of a selective PI3Kδ inhibitor YY-20394 in patients with relapsed or refractory B-cell malignancies.
Authors: Lugui Qiu, Junyuan Qi, Yuqin Song, Bo Jiang, Meifeng Tu, Lingyan Ping, Zengjun Li, Jun Zhu, Yuanyuan Xu, Hanying Bao, Zusheng Xu
Journal: Journal of Clinical Oncology (2019)

7563 Background: YY-20394, an oral highly selective PI3Kδ inhibitor was studied in a phase I trial for patients with relapse or refractory B-cell malignancies. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YY-20394. Methods: YY-20394 was given orally once daily (QD) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Only 1 subject was treated with starting dose 20 mg once daily, then subsequent cohorts used a 3+3 design and evaluated doses of 40, 80, 140 and 200 mg QD. Once a recommended Phase II (RP2D) dose is determined, a separate dose expansion part will enroll up to 12 patients at the RP2D. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria. Results: 22 patients were enrolled as of Jan 14th 2019. The patients including diffuse large B-cell lymphoma (DLBCL), n=2; follicular lymphoma (FL), n=8; follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL), n=3; mantle cell lymphoma (MCL), n=3; lymphoplasmacytic lymphoma (LPL), n=1; marginalzone B-cell lymphoma (MZBL), n=1 and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), n=4, received YY-20394 20 mg (n=1), 40 mg (n=3),80 mg (n=11),140 mg/day (n=3) or 200 mg/day (n=4) respectively. All the patients had heavy treatment and had received an average of 3.5 lines of therapy before participating in the current study including BTK inhibitor therapy and CAR-T treatment. All the patient have completed cycle 1 safety observation and no dose-limiting toxicities occurred. The most common nonhematologic TEAEs (all grades/grade≥3) were LDH elevation (36.4%/0%), pneumonia (18.2%/18.2%) and hyperuricemia (13.6%/4.5%). Gr≥3 hematologic TEAEs were neutropenia (13.6%), lymphocythaemia (9.1%), leukocytosis (4.5%) and leukopenia (4.5%). Of 19 patients evaluable for response, the overall objective response rate was 68% ((4CR + 9 PR)/19), with 86% ((3CR + 3PR)/7) in FL. The median duration of response is not available so far, the treatment for 11 subjects was still ongoing. The duration of response in 4 subjects with ongoing treatment has already over 8 months. PK parameters AUC 0-24h and C max were dose proportional with median T max 2 hours. Conclusions: YY-20394 is well tolerated and with promised objective response rates in patients with relapsed or refractory B-cell malignancies. Clinical trial information: NCT03757000.
Abstract 11247: 1.5T and 3T Quantitative Myocardial Perfusion Reserve for Detection of Relevant Coronary Artery Stenosis - A Comparison to Fractional Flow Reserve
Authors: Peter Bernhardt, Thomas Walcher, Wolfgang Rottbauer, Jochen Wöhrle
Journal: Circulation (2012)

Background: FFR is considered by many investigators to be a reliable standard to determine hemodynamic significant coronary artery stenosis. Quantitative perfusion analysis at 1.5T and 3T CMR is ca...
Abstract 19992: Delta PKC (dPKC) Binding to the “d” Subunit of F1Fo ATP Synthase (dF1Fo) Impairs Mitochondrial Energetics and Exacerbates Ischemia / Reperfusion Injury in Rats
Authors: Matthew Walker, Robert W Caldwell, Yisang Yoon, John A Johnson
Journal: Circulation (2015)

We have previously demonstrated delta PKC (dPKC) involvement in cardiac myocyte energy deprivation via its interaction with dF1Fo and have developed a peptide inhibitor [NH2-YGRKKRRQRRRMLATRALSLIGKRAISTSVC-COOH] of this interaction, which targets to the mitochondrial matrix / inner membrane. In the present study, a 10 min ligation of the left anterior descending coronary artery (LAD) increased dPKC-dF1Fo co-immunoprecipitation (co-IP) by 5-fold and elevated dPKC-phosphoserine 643 immunoreactivity (a dPKC autophosphorylation site 56 +/- 17% (n=7, p&lt;0.01) in mitochondria isolated from the left ventricular (LV) region at risk for ischemic injury (RAR). Intravenous (I.V.) injection of the dPKC-dF1Fo inhibitor (5 ug/kg) 20 min beforehand attenuated the co-IP by 71 +/- 13% (p&lt;0.001, n=8). Blockage of the IP correlated with transient increases in cytochrome oxidase subunit IV (1.6-fold (p&lt;0.05, n=8) and beta-tubulin (1.4-fold, (p&lt;0.001, n=8), without changes in autophagy marker proteins (LC3II and p62) or mitochondria release of cytochrome c. The dPKC-dF1Fo inhibitor given I.V. prior to 30 min of ischemia by coronary ligation, and 3 hr of reperfusion, reduced 2,3,5-triphenyltetrazolium chloride-monitored infarct size by 29 +/- 7 % (n=6, p&lt;0.001). This protection was correlated with a 1.7 +/- 0.2-fold (n=6, p&lt;0.02) enhancement of ATP levels, a 2-fold reduction in tissue t-carbonyls / oxidative stress markers and a 61 +/- 12% (p&lt;0.001, n=8)) reduction in Ca++-induced mitochondrial swelling. The inhibitor peptide also improved ADP (state 3) (1.5 +/- 0.2-fold (p&lt;0.05, n=6) and maximal (FCCP)-stimulated (1.6 +/- 0.1-fold (p&lt;0.03, n=6)) respiration and JC-1 monitored mitochondrial membrane potential (1.6 +/- 0.1-fold (n=6, p&lt;0.03) following IR injury. This mitochondrially-targeted peptide therefore, protects against ATP loss, oxidative stress, mitochondrial swelling and infarction in vivo, which correlates with improved mitochondrial energetics. We propose it has potential as a first-in-class therapeutic for the treatment of cardiac IR injury.
Upstaging the R-ISS classification of newly diagnosed multiple myeloma (NDMM) patients (pts) by quantifying circulating clonal plasma cells (cPCs) via multiparametric flow cytometry (MFC).
Authors: Wilson I. Gonsalves, Dragan Jevremovic, Angela Dispenzieri, Francis Buadi, David Dingli, Martha Lacy, Prashant Kapoor, Yi Lin, Taxiarchis Kourelis, Eli Muchtar, John Anthony Lust, Stephen J. Russell, Ronald S. Go, Suzanne R. Hayman, Nelson Leung, Steven R. Zeldenrust, Robert A. Kyle, Morie A. Gertz, S. Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2019)

8031 Background: Our prior studies identified the prognostic significance of ≥400 cPCs/150,000 analyzed events quantified by MFC in NDMM. We evaluated if a similar quantification of cPCs using MFC can add prognostic value to the current R-ISS classification of NDMM pts. Methods: We evaluated all NDMM pts seen at the Mayo Clinic, Rochester from 2009-2017 who had their peripheral blood samples evaluated by 6-color MFC prior to therapy. The cPCs detected were reported as the number of clonal events/150,000 collected total events. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: This cohort consisted of 566 consecutive pts with NDMM with a median age of 66 years (27-95). The distribution of the R-ISS classification of this cohort is as follows: Stage 1- 128 (23%) pts, Stage 2- 369 (65%) pts and Stage 3- 69 (12%) pts. The median number of cPCs was 59 (0-46,412) / 150,000 events. The median time-to-next-treatment (TTNT) and overall survival (OS) for pts with ≥400 cPCs (n = 140, 25%) was 19 months and 46 months compared with 34 months and 77 months for those with &lt; 400 cPCs respectively (n = 426, 75%) (p &lt; 0.001 for both). The median TTNT and OS for pts based on their R-ISS classification as well as with and without the presence of ≥400 cPCs by MFC was as follows in the following Table. Conclusions: Quantifying ≥400 cPCs/150,000 analyzed events by MFC can potentially upstage the R-ISS classification of a subset of NDMM pts with stage I and II disease and identify those pts with a worse than expected survival outcome.[Table: see text]
Abstract 3493: Tumor treating fields (TTFields) significantly alters how tumor cells repair double stranded breaks using homeologous Alu sequences
Authors: Maria E. Morales, Tiffany K. Kaul, Prescott L. Deininger
Journal: Cancer Research (2019)

Abstract Tumor Treating fields (TTfields) are an FDA-approved therapeutic modality that utilizes low intensity alternating electric fields. Although the therapy’s primary mechanism seems to cause aberrant mitosis in dividing cells and subsequently cellular death, TTfields have also been reported to alter DNA repair pathways. Recent reports showed that chromosomal double strand breaks (DSBs) repair is delayed after TTfields treatment of glioma cells. DSBs are often repaired by error-prone pathways that can be influenced by proximity of repetitive sequences, such as Alu elements. Alu elements are known to contribute to genetic instability though homeologous recombination due to their sequence similarity and high density in the genome. We find that different tumor cells resolve the Alu heteroduplexes formed during DNA repair in different ways. To understand the molecular mechanisms underlying the biological effects of TTfields exposure, we examined mechanistic aspects of DNA repair using our previously published Alu/Alu recombination system in HEK293 and HeLa cells. Of note, our assay probes the recombination properties that occur in the cells that survive TTfields treatment, thus providing potential insights into therapeutic resistance. Our Alu/Alu recombination system is able to efficiently measure both the rate of Alu/Alu recombination (Single Strand Annealing-SSA), as well as Alt-Non Homologous End Joining (Alt-NHEJ) deletions that cause a deletion in the vicinity of the two Alu elements in the system. Sequence verification confirmed that most of the genetic deletions that occurred post TTfields treatment were the result of Alu/Alu recombination events that predominantly arose from repair by SSA in HEK293 and HeLa. This increase in SSA repair could be the result of SSA-intermediates that escaped heteroduplex rejection. These observations suggest the possibility that treatment of TTfields significantly alters how tumor cells repair DSBs using homeologous Alu sequences. Citation Format: Maria E. Morales, Tiffany K. Kaul, Prescott L. Deininger. Tumor treating fields (TTFields) significantly alters how tumor cells repair double stranded breaks using homeologous Alu sequences [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 3493.
Abstract 743: Fusion gene identification from common cancer cell lines and comparison to primary tumors
Authors: Neetha Nanoth Vellichirammal, Abrar Albahrani, Jasjit K. Banwait, You Li, Babu Guda
Journal: Cancer Research (2019)

Abstract Fusion transcripts, frequently observed in cancer, contribute to oncogenicity by either altering the expression of tumor suppressors/proto-oncogenes or modifying the original function of a protein resulting in an abnormal chimeric protein that stimulates tumorigenesis. Cancer cell lines, extensively used as in-vitro molecular models to study biological processes related to cancer, often do not represent the genomic profiles of primary tumors. To examine the true representation of the cancer cell lines, we examined fusions in tumor- derived cancer cell lines from 20 cancer types in the Cancer Cell Line Encyclopedia (CCLE) and compared them to fusions present in the primary tumors from the TCGA (The Cancer Genome Atlas). ChimeRScope, an alignment-free algorithm developed by our group, was used to screen fusion genes using level 1 paired-end RNA sequencing read data from CCLE and TCGA (GDC data portal). A total of 8,883 primary tumor samples, 730 normal samples spanning 33 cancer types from TCGA, and 802 common laboratory cell lines from CCLE were analyzed in this study. The pool of recurrent fusions identified from CCLE was vastly different from those identified in primary tumors with merely 2% of an overlap. Canonical fusions were found to be more common than non-canonical fusions (fusions containing genes in antisense strand) between TCGA and CCLE. Hierarchical clustering analysis of both canonical and non-canonical recurrent fusions in CCLE and TCGA clustered the primary tumors and cell lines into separate clusters, revealing that fusions in cell lines are vastly different from primary tumors. However, canonical and non-canonical fusion profiles of endometrial cancer cell lines were very similar to female primary tumors (ovarian and breast) and thyroid cancer cell lines were similar to bladder cancer in TCGA. The results from this study indicate that the recurrent fusions in common cancer cell lines harbor fusions that are significantly different from primary tumors. Citation Format: Neetha Nanoth Vellichirammal, Abrar Albahrani, Jasjit K. Banwait, You Li, Babu Guda. Fusion gene identification from common cancer cell lines and comparison to primary tumors [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 743.
Abstract 4623: Notch3 in lung adenocarcinoma pathogenesis and heterogeneity
Authors: Kieren D. Marini, Stanley Leung, Alex Lee, Alejandro Sweet-Cordero
Journal: Cancer Research (2019)

Abstract Lung cancer is the leading cause of cancer related death worldwide. Non-small lung cancer accounts for 85% of diagnoses and the predominant subtype is lung adenocarcinoma (LUAD). LUAD has a less than 20% response rate to conventional chemotherapy and despite identification of several therapeutic targets, the majority of diagnoses continue to lead to death, highlighting the need for better treatments. Notch signaling in mammals is complex, with multiple receptors, ligands and modifiers. Notch ligands at the surface of one cell interact with receptors on an adjacent cell, triggering cleavage and nuclear translocation of the intracellular domain which interacts with Rbpj/Csl to control the transcription of target genes. In LUAD, significant evidence suggests that Notch plays an oncogenic role. Previously, we identified a population of Tumor Propagating Cells (TPC), which had greater capacity for tumor formation and are enriched after treatment with cisplatin. The TPC population was defined by the expression of CD24, ITGB4 and was Notch high. Further functional validation showed that specifically Notch3 contributes to this propagation phenotype and is key in establishing functional intra-tumoral heterogeneity. However, the TPC population is still heterogeneous and likely only a subset of these cells are true TPCs. Furthermore, the gene expression signature of the mouse TPCs has prognostic significance in human LUAD, however the TPC population hasn’t been defined in human patients, limiting our ability to target the Notch pathway therapeutically. To assess the heterogeneity of the mouse TPC population we performed FACS on tumors from KrasLSLG12D; Tp53flox/flox; YFPLSL twelve weeks after tumor initiation via AdCre. Tumors were sorted for bulk population (YFP+Lin-) and for TPC (YFP+Lin-CD24+ITGB4+Notchhi) population and single cell sequencing was performed using the 10X genomics platform. We hypothesize that aberrant Notch3 signaling is a critical pathway for survival in at least some LUAD and that Notch activation leads to gene expression changes that are important for driving human LUAD maintenance. Patient-derived xenografts (PDX) more closely recapitulate important aspects of human cancer, particularly with regards to the role of intratumoral heterogeneity and self-renewal pathways. To characterize Notch3 expressing cells in human LUAD, we performed FACS on our cohort of LUAD PDXs and sorted the Notch3+ population. We found expression of Notch3 and expression of Notch ligand Jagged2 in all LUAD tumors regardless of driver mutation. Citation Format: Kieren D. Marini, Stanley Leung, Alex Lee, Alejandro Sweet-Cordero. Notch3 in lung adenocarcinoma pathogenesis and heterogeneity [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 4623.
Abstract 4276: Inhibition of USP14 decrease tumorigenesis via autophagy in lung cancer
Authors: MINSOO PARK, Min Ji Kim, Peter Chang Whan Lee
Journal: Cancer Research (2019)

Abstract The ubiquitin proteasome system (UPS) is the primary pathway through which the levels of regulatory proteins are controlled. Dysregulation of components within the UPS have been linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme USP14 is associated with proteasome where it is trimming ubiquitin chain on the substrate. In our current study, we unexpectedly found that USP14 levels were elevated in lung cancer patients. USP14 inhibitor, IU1-47 and siUSP14, significantly decreased cell proliferation, migration, and invasiveness in lung cancer cells. Inhibition of USP14 induced the alteration of LC3-I to LC3-II which leads to autophagic cell death not but apoptosis. Thus our finding suggests that USP14 plays a crucial role in tumorigenesis and USP 14 inhibitor is a potent drug for lung cancer treatment. Citation Format: MINSOO PARK, Min Ji Kim, Peter Chang Whan Lee. Inhibition of USP14 decrease tumorigenesis via autophagy in 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 4276.
Abstract 691: Simulating TTFields-induced temperature changes within a patient’s brain - a proof of concept study
Authors: Ariel Naveh, Ze'ev Bomzon
Journal: Cancer Research (2019)

Abstract Introduction: TTFields is an antimitotic cancer treatment that utilizes low intensity (1-3 V/cm) alternating electric fields in the intermediate frequency (100-300 kHz) that are delivered in two orthogonal directions using 2 pairs of transducer arrays. TTFields are currently approved for Glioblastoma Multiforme (GBM). Preclinical studies show that the effect of TTFields is intensity-dependent with a therapeutic threshold of 1 V/cm, and that as the intensity rises so does the efficacy. However, delivery of high field intensities could result in temperature increases within the body that lead to thermal damage to tissue. In practice, during treatment with TTFields, tissue heating is limited by a closed loop that adjusts the delivery of TTFields to ensure that skin temperature remains within the safety limits. Since heating limits the intensity at which TTFields is delivered, accurate models of tissue heating during TTFields therapy could provide insights into new approaches for the delivery of TTFields. Since measuring the temperature spatial distribution within a patient’s brain is extremely challenging, simulating the heat flow within the head during treatment is a more practical approach. Here, we present preliminary results from a study aimed at developing a valid computational model of heat transfer in the head during TTFields therapy. Method: A realistic computational head model of a healthy male was used in this study. Virtual transducer arrays were placed on the head. To simulate the delivery of TTFields to the brain, we used ZMT's Sim4Life v4.0 electro-quasi-static solver. The results of the electric field simulation were then used as heat source for the heat simulation. The heat simulation solves the Pennes bio-heat model, taking into account tissue heat capacity and conductivity, and also accounting for heat convection through blood perfusion. Sensitivity analysis was performed to establish the sensitivity of the temperature distribution within the brain to the thermal properties of the various tissue types. Results: Average temperatures within the brain tissue were well below 38° C for all simulations. Temperature distributions within the brain were highly sensitive to the perfusion coefficient assigned to the cerebrospinal fluid as well as other tissues.Conclusions: We have established a computational framework for investigating heat transfer in the brain during TTFields therapy. Further work is needed to correctly establish the thermal properties of the various tissue types. This may require experimental measurements in which the heat transfer model is fine-tuned and validated. Citation Format: Ariel Naveh, Ze'ev Bomzon. Simulating TTFields-induced temperature changes within a patient’s brain - a proof of concept study [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 691.
Abstract 821: DNA hypermethylation of <i>IRX4</i> is a frequent event that may confer growth advantage to pancreatic cancer cells
Authors: Kanchan Chakma, Zhaodi Gu, Fuyuhiko Motoi, Michiaki Unno, Akira Horii, Shinichi Fukushige
Journal: Cancer Research (2019)

Abstract Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to the loss of key cellular pathways in tumorigenesis. Methyl-CpG targeted transcriptional activation (MeTA) reactivates hypermethylation-mediated silenced genes in a different way from DNA demethylating agents. Previous study using microarray coupled with MeTA (MeTA-array) identified seven commonly hypermethylation-mediated silenced genes in pancreatic cancer cell lines. In this study, IRX4 (Iroquois homeobox 4) was focused on because IRX4 was located at chromosome 5p15.33 where one of pancreatic cancer susceptibility loci has been identified through genome-wide association study (GWAS). IRX4 has also been identified as a candidate tumor suppressor gene in prostate cancer. IRX4 was greatly downregulated in all of the analyzed 12 pancreatic cancer cell lines by promoter hypermethylation. In addition, IRX4 promoter region was found to be frequently and specifically hypermethylated in primary resected pancreatic cancers (15/22: 68%); corresponding normal pancreatic tissues were unmethylated. To examine whether IRX4 has the growth inhibitory effect on pancreatic cancer cell lines, colony formation assay using PK-1 and PK-9 cell lines has been performed; compared with empty vector-transfected cells, IRX4 expression vector-transfected cells formed significantly reduced number of colonies. Furthermore, tetracycline-inducible IRX4 expressing vector system was constructed and a pancreatic cancer cell line PK-1 was analyzed for further functional investigation; induction of IRX4 suppressed cell growth in PK-1. Our results suggest that DNA methylation-mediated silencing of IRX4 is a frequent event that may confer growth advantage to pancreatic cancer cells and MeTA may be a powerful tool to search critical hypermethylated genes in tumorigenesis. Citation Format: Kanchan Chakma, Zhaodi Gu, Fuyuhiko Motoi, Michiaki Unno, Akira Horii, Shinichi Fukushige. DNA hypermethylation of IRX4 is a frequent event that may confer growth advantage to pancreatic cancer cells [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 821.
Abstract 17985: The Association Between Myocardial Fibrosis and Increasing QRS Duration Among Sudden Cardiac Death Victims
Authors: Lauri Holmstroem, Anette Haukilahti, Tuomas Kentta, Antti Kiviniemi, Tomi Toukola, Samuli Lepojarvi, Lasse Pakanen, Marja-Leena Kortelainen, Heikki Huikuri, Juhani Junttila
Journal: Circulation (2017)

Background: Myocardial fibrosis has well established role in sudden cardiac deaths (SCD). Intraventricular conduction defect (IVCD) may be a surrogate of accumulated fibrosis. We aimed to find mani...