tbuckley/cabot-search huggingface dataset:
Abstract 1259: HYAL4: The first study on a potential molecular driver and biomarker of invasive bladder cancer
Authors: Daley S. Morera, Sarrah S. Lahorewala, Soum D. Lokeshwar, Andre R. Jordan, Vinata B. Lokeshwar
Journal: Cancer Research (2019)

Abstract INTRODUCTION AND OBJECTIVE: The majority of morbidity and mortality in bladder cancer (BCa) patients is due to muscle invasive bladder cancer (MIBC). The prognosis of patients with MIBC could be improved by identification of novel biomarkers and therapeutic agents. Chondroitin sulfate proteoglycans are known to promote tumor growth and metastasis. However, a Chondroitinase (Chase) that degrades chondroitin sulfate has not been identified. HYAL4, a member of the glycosaminoglycan (GAG) degrading enzyme-family, potentially has Chase activity; however, HYAL4 (HY4) has not be studied in any biological system, normal or disease. In this study, we evaluated the expression of all six members of the GAG-degrading enzyme family in BCa specimens and evaluated HY4 functions in preclinical models of BCa. METHODS: Cohort 1: 79 bladder tissues (normal (NBL) = 31; tumor (TBL) = 52); cohort 2: 40 cystectomy specimens from MIBC patients who received adjuvant Gemcitabine plus cisplatin (G+C) treatment for metastatic disease with chemotherapy. Gene expression was measured by q-PCR in both cohorts. HY4 was either overexpressed (HY4) or knocked-down in immortalized normal urothelial (Urotsa) and 3 BCa cell lines. Transfectants were assayed for Chase activity, anchorage independent growth, motility, invasion, molecular signaling. Tumor growth and metastasis in intravesical examined in HT1376 bladder orthotopic model. RESULTS: In cohort 1 HYAL1, HYAL4 mRNA levels were significantly (6-13-fold) elevated in TBL tissues when compared to NBL tissues (P&amp;lt;0.001). HY4 levels were 7-fold elevated in MIBC. HY4 levels were an independent predictor of metastasis and death due to BCa (chi-sq: 6.9; P=0.0087; chi-sq: 7.59; P=0.006). In cohort 2, high HY4 levels significantly correlated with G+C treatment failure (chi-sq: 8.7; P=0.003) with &amp;gt; 80% accuracy. HY4-expressing transfectants secreted HY4 and Chase activity in their conditioned media. Overexpression of HY4 in normal urothelial and BCa cells significantly increased, while its knockdown abrogated, anchorage-independent growth, invasion, chemotactic motility (&amp;gt; 3-fold). HY4 expression induced Gemcitabine resistance (IC50: vector: 3.1 nM; HY4: 126 nM). HY4 expression upregulated a stem cell signature. Urothelial cells expressing HY4 formed tumors in NOD/SCID mice. HY4-expressing BCa cells metastasized to lung and spleen in an orthotopic BCa model. Citation Format: Daley S. Morera, Sarrah S. Lahorewala, Soum D. Lokeshwar, Andre R. Jordan, Vinata B. Lokeshwar. HYAL4: The first study on a potential molecular driver and biomarker of invasive bladder 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 1259.
Abstract 412: Application of a serial liquid biopsy ctDNA assay for monitoring efficacy of anti-angiogenic lung cancer therapy
Authors: Marek Minarik, Martin Svaton, Barbora Belsanova, Anastasiya Semyakina, Jan Baxa, Ondrej Fiala, Milos Pesek, Lucie Benesova
Journal: Cancer Research (2019)

Abstract INTRODUCTION: Patients in advanced stages of non-small cell lung carcinomas (NSCLC), who and unsuited for targeted biological therapy because of lack of actionable molecular predictors are frequently treated by anti-angiogenic therapy. The effectiveness of such therapy is primarily relying on imaging techniques including CT or hybrid PET/CT evaluating a combination of morphological factors (dimensions and volume) and, more recently, also functional parameters including the metabolic activity, tumor vascularization etc. The ability to track the course of the disease at the same time all of these parameters is prerequisite to enable timely monitoring and therapy change in case of an early detection of resistance. This study was aimed at utility of circulating-tumor DNA (ctDNA) as an tool for monitoring of therapy response. and assessment of phenotypic parameters of the tumor. PATIENTS AND METHODS: A total of 50 patients with confirmed Stage IV lung adenocarcinomas showing negativity on ALK, BRAF, EGFR, RET, ROS1 and MET predictors were prospectively enrolled into the study. Patients were treated under a standard protocol by a combination of paclitaxes/carboplatin/bevacizumab and followed by dual PET/CT. For each patient cytology tissue sample was subjected to test for a panel of somatic mutations. The found mutations were subsequently detected in ctDNA in plasma extracted from peripheral blood collected prior to therapy start and then in 1-month intervals during the therapy. The occurrence and quantity of ctDNA were correlated with the objective therapy response (RECIST) and to the functional imaging parameters of metabolic activity and vascularization. RESULTS: ctDNA was initially positive in 29 patients. ctDNA levels closely reflected the response to the therapy with complete or partial remission expressed as reduction or absence of ctDNA, while disease stabilization or progression signaled by persisting or increasing ctDNA levels. There was a borderline correlation between ctDNA and vascularization evaluated by dual PET/CT (p=0.055). CONCLUSION: In a subset of patients ctDNA can readily serve as a surrogate marker for semi-continuous monitoring of the effect of anti-angiogenic therapy. Work supported by Czech Ministry of Health project AZV 17-30748A. Citation Format: Marek Minarik, Martin Svaton, Barbora Belsanova, Anastasiya Semyakina, Jan Baxa, Ondrej Fiala, Milos Pesek, Lucie Benesova. Application of a serial liquid biopsy ctDNA assay for monitoring efficacy of anti-angiogenic lung cancer 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 412.
Abstract 16913: Maternal Obesity Impaired Mitochondrial Function of Term Fetal Heart in Sheep
Authors: Qiurong Wang, John F Odhiambo, Guadalupe L Rodríguez-González, Chaoqun Zhu, Ashley Smith, Peter W Nathanielsz, Stephen P Ford, Wei Guo
Journal: Circulation (2018)

Introduction: Studies in human and animals suggest that maternal obesity (MO) negatively impacts fetal heart development and cardiac function. Epidemiological studies indicate MO could result in increased incidences of cardiovascular diseases in the offspring. However, the underlying mechanisms are still not well elucidated. Our group has developed and characterized a diet-based sheep model of MO beginning before pregnancy as is common in humans to study the effect of MO on fetal heart function. Previously, we have observed compromised contractility and intracellular calcium in MO fetal cardiomyocytes. Here, we look into the mitochondrial function of the term fetal myocardium. Hypothesis: MO impairs fetal heart mitochondrial function and ATP synthesis. Methods: From 60 days before and through pregnancy, ewes were fed either 100% of National Research Council (NRC) recommendations (control, n=6) or 150% of NRC’s recommendations (MO, n=7). At 135-day gestation (Term 150 days), the fetal heart was quickly removed under general anesthesia, and cardiomyocytes were isolated and mitochondria were prepared. Mitochondrial biogenesis was measured by using Seahorse extracellular flux analyzer (XF96) on isolated cardiomyocytes and mitochondrial oxidative phosphorylation complex activity were measured with Abcam assay kits. Analysis by Student’s t-test: *p &lt; 0.05. Results: The Seahorse mitochondrial biogenesis data suggested that mitochondrial maximal and spare respiration rate were significantly reduced in MO fetal cardiomyocytes. More importantly, MO suppressed mitochondrial ATP production in MO fetal cardiomyocytes. The mitochondrial oxidative phosphorylation was downregulated in MO fetal myocardium. We found that complex I and IV enzyme activity was decreased in MO group. The activity of complex V, ATP synthase subunits, was reduced by 43% in MO fetal heart mitochondria. Conclusions: Our results suggest that MO induces stress uterus environment to fetal heart which impairs the mitochondrial function and ATP synthesis, which could be a possible mechanism of maternal obesity-induced cardiac contractile dysfunction.
Abstract 705: Tumor intrinsic PD-L1 is mediated by <i>BRAFV600E</i> and can regulate drug-induced apoptosis in human colon cancer
Authors: Daofu Feng, Krishnendu Pal, Debabrata Mukhopadhyay, Xin Liu, Haidong Dong, Shengbing Huang, Frank A. Sinicrope
Journal: Cancer Research (2019)

Abstract Resistance to chemotherapy remains a major obstacle to improving outcomes of cancer treatment. Recent data suggest intrinsic functions of immune checkpoint proteins, including PD-L1, that may be distinct from their immunoregulatory roles. We found that colorectal cancer (CRC) cells with mutant BRAF(V600E) or KRASalleles show increased PD-L1 transcripts and expression of cell surface PD-L1 protein compared to those with wild-type copies. Furthermore, ectopic expression of BRAFV600E or mutant KRAS induced PD-L1 whose upregulation was attenuated by inhibition of RAS-RAF-MEK-ERK signaling. Combined knockdown of MEK/ERK effectors c-JUN and YAP markedly reduced PD-L1. Knockout of PD-L1 in RKO cells resulted in a reduction in chemotherapy-induced DNA double strand breaks (pH2AX) and caspase-3 cleavage compared to parental cells. Results were confirmed in PD-L1 knockout MC38 murine CRC cells where re-expression of PD-L1, but not its deletion mutants, was shown to induced pH2AX and apoptosis. In cells with knockout of PD-L1, reductions in p-AKT and the BH3-only proteins BIM and BIK were observed that could be restored by re-expression of PD-L1. Treatment of cells with an anti-PD-L1 antibody reduced p-AKT, BIM and BIK, and also attenuated chemotherapy-induced apoptosis. Re-expression of BIM in PD-L1 knockout cells restored apoptosis. Murine tumor xenografts generated from cells with knockout of PD-L1 displayed resistance to oxaliplatin-induced tumor regression compared to tumors derived from parental cells. Using TCGA datasets, human CRCs with high vs low PD-L1 mRNA levels were significantly associated with better survival. In summary, we identified a non-immune function of tumor cell-intrinsic PD-L1 that upregulates BH3-only proteins BIM and BIK to promote apoptosis, thereby suggesting its potential as a predictive biomarker. Citation Format: Daofu Feng, Krishnendu Pal, Debabrata Mukhopadhyay, Xin Liu, Haidong Dong, Shengbing Huang, Frank A. Sinicrope. Tumor intrinsic PD-L1 is mediated by BRAFV600E and can regulate drug-induced apoptosis in human colon 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 705.
Inverting the Turing Test — Machine Learning to Detect Cognition in the ICU
Authors: David K. Menon, Srivas Chennu
Journal: New England Journal of Medicine (2019)

Responding to a verbal command such as "move your hand" with the appropriate motor action shows that a person can hear instructions, understand their meaning, engage regions of the brain to plan volitional movement, activate the motor cortex, and contract the appropriate muscles. Patients who do not perform the action are called "unresponsive." Early in the course of an acute and severe neurologic event, the absence of the ability to follow commands has traditionally been thought to signify either that the brain injury is so severe that consciousness will never recover or that the ability to follow commands, along with . . .
Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance
Authors: Marcus A. Couey, R. Bryan Bell, Ashish A. Patel, Meghan C. Romba, Marka R. Crittenden, Brendan D. Curti, Walter J. Urba, Rom S. Leidner
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard. <h3>Methods</h3> The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy. <h3>Results</h3> Median duration of I-O clinical trials data safety reporting was 90 days (82%&nbsp;≤&nbsp;90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE. <h3>Conclusions</h3> As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment – or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity.
Abstract P131: Racial Differences in the Response of Cardiorespiratory Fitness to Aerobic Exercise Training in Caucasian and African American Postmenopausal Women
Authors: Damon L Swift, Neil M Johannsen, Carl J Lavie, Conrad P Earnest, William D Johnson, Claude Bouchard, Steve N Blair, Timothy S Church, Robert L Newton
Journal: Circulation (2013)

Introduction: African American (AA) women have an elevated risk of cardiovascular disease and have been reported to have lower cardiorespiratory fitness compared to Caucasian Americans (CA) women. ...
Abstract 2761: Development of synthetic guide RNA libraries for CRISPR-mediated transcriptional activation screening for gain-of-function studies
Authors: Annaleen Vermeulen, Zaklina Strezoska, Sarah M. Dickerson, Maren M. Gross, Eldon T. Chou, Elena Maksimova, Matthew R. Perkett, Shawn McClelland, Anja V. Smith
Journal: Cancer Research (2019)

Abstract Functional gene analysis studies have been empowered by development of CRISPR-Cas9 gene knockout tools, however the CRISPR-Cas9 system has also been adapted for inhibition or activation of gene transcription. A nuclease-deactivated Cas9 (dCas9) can be fused to various effector domains to produce an RNA-guided transcription factor for either inhibition (CRISPRi) or activation (CRISPRa) of target genes. For overexpression studies, CRISPRa holds significant advantages over traditional vector-based gene expression, because genes are upregulated from their native promoter and endogenous genomic context. The majority of CRISPRa research performed to date has utilized single guide RNA (sgRNA) expressed from a DNA vector, primarily in the context of pooled lentiviral screening approaches. Here we describe the development of CRISPRa synthetic guide RNAs for the use in arrayed screening, so that we combine this next-generation transcriptional activation method with the ability to support more complex assays in a one-gene-per well format. Considerations for arrayed activation screens will be shown. The combination of gain-of-function from CRISPRa with loss-of-function using RNAi or canonical CRISPR-Cas9 for gene knockout allows for robust characterization of gene mechanisms and pathways. Citation Format: Annaleen Vermeulen, Zaklina Strezoska, Sarah M. Dickerson, Maren M. Gross, Eldon T. Chou, Elena Maksimova, Matthew R. Perkett, Shawn McClelland, Anja V. Smith. Development of synthetic guide RNA libraries for CRISPR-mediated transcriptional activation screening for gain-of-function studies [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 2761.
A health-related quality-of-life (HRQoL) analysis of pomalidomide + low-dose dexamethasone + daratumumab in relapsed refractory multiple myeloma (RRMM) after lenalidomide treatment.
Authors: Donna Ellen Reece, Nizar J. Bahlis, Christy Joy Samaras, Michael Sebag, Jesus G. Berdeja, Siddartha Ganguly, Jeffrey Matous, Kevin W. Song, Christopher Seet, Giampaolo Talamo, Mirelis Acosta-Rivera, Michael Bar, Donald Quick, Bertrand Marquess Anz, Gustavo A. Fonseca, Amit Agarwal, Weiyuan Chung, Faiza Zafar, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2019)

8025 Background: Treatment (Tx) of RRMM is complex and requires evaluation of disease and patient (pt) factors to maximize efficacy and minimize toxicity. HRQoL has become an important aspect of MM Tx, as survival has improved with therapeutic advances. Results of the ongoing phase 2 MM-014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low-dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in RRMM pts after first- or second-line lenalidomide (LEN)-based Tx failure. Here we report the impact of this regimen on HRQoL. Methods: RRMM pts with 1 to 2 prior Tx lines, LEN-based Tx as their most recent regimen, and progressive disease during or after their last Tx line received POM + LoDEX + DARA in 28-day cycles (MM-014 cohort B). HRQoL, an exploratory endpoint for cohort B, was assessed via EuroQol’s EQ-5D. Results: As of October 15, 2018, 108 pts were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ-5D completion rates for each cycle (1-6) were ≥ 88%. Mean change from baseline in the EQ-5D index and VAS health score was stable through 6 Tx cycles. At cycle 6, 28.8% and 39.0% of pts achieved minimum clinically important improvement in the EQ-5D index (≥ 0.1) and VAS health score (≥ 6), respectively. EQ-5D index values were stable, with a trend toward improvement in usual activities, pain/discomfort, and anxiety/depression (Table). Conclusions: In RRMM pts with early-line LEN Tx failure, HRQoL was maintained or trended toward improvement with POM + LoDEX + DARA, despite the combination of 3 drugs with distinct toxicities. These findings further support the earlier use of POM-based Tx in RRMM immediately after LEN failure. Clinical trial information: NCT01946477. [Table: see text]
Abstract 2797: Accumulation of neutrophils in the tumor microenvironment promotes resistance to immunotherapy in pancreatic cancer
Authors: Despina Siolas, Emily Vucic, Jane Cullis, Mark Choi, Dafna Bar-Sagi
Journal: Cancer Research (2019)

Abstract The prognosis for pancreatic cancer patients is unequivocally poor. This is due in part to the fibrotic and immunosuppressive microenvironment of pancreatic tumors, which serves as a physical barrier to chemotherapy and immunotherapy. Intratumoral genetic alterations can cause remodeling of the immune environment through distinct cellular mechanisms. Oncogenic Kras gene mutations are the most frequently occurring genetic event in pancreatic cancer, followed by transforming alterations in TP53. We show that CRISPR/Cas engineered KrasG12D;Trp53R172H pancreatic ductal tumors have a distinct immune profile characterized by an increase in neutrophils and a concomitant decrease in cytotoxic and Th1+ T cells. In addition, KrasG12D;Trp53R172H pancreatic ductal tumors have an increase in CXCL5, a chemokine involved in neutrophil accumulation. Analysis of publicly available datasets shows that increased neutrophil numbers significantly correlate with decreased survival in pancreatic cancer patients. Of clinical relevance, p53-Crispr/Cas engineered pancreatic tumors in mice are resistant to immunotherapy/chemotherapy combination treatment. This data supports the possibility of personalizing immunotherapy treatments based on immune profiles. Citation Format: Despina Siolas, Emily Vucic, Jane Cullis, Mark Choi, Dafna Bar-Sagi. Accumulation of neutrophils in the tumor microenvironment promotes resistance to immunotherapy in pancreatic 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 2797.
Time to CA19.9 nadir: a clue for defining treatment duration of primary chemotherapy in resectable PDAC
Authors: U. Peretti, M. Reni, S. Zanon, M. Macchini, E. Mazza, G. Balzano, D. Tamburrino, P. Arcidiacono, F. Massimo, L. Gianni
Journal: Annals of Oncology (2019)
Abstract 17429: The Efficacy of Serum Heart-Type Fatty Acid-Binding Protein (HFABP) Level for Patients Who Admitted to Cardiovascular Intensive Unit
Authors: Akihiro Shirakabe, Noritake Hata, Nobuaki Kobayashi, Takuro Shinada, Kazunori Tomita, Masafumi Tsurumi, Masato Matsushita, Hirotake Okazaki, Yoshiya Yamamoto, Masanori Yamamoto, Shinya Yokoyama, Kuniya Asai, Wataru Shimizu
Journal: Circulation (2013)

Background: The biomarkers to detect acute kidney injury (AKI) and predict adverse outcomes were unknown for cardiovascular intensive care patients. Methods: Seven-hundred twelve patients admitted ...