tbuckley/cabot-search huggingface dataset:
Abstract 879: Nicotine-induced oxidative stress causes epigenetic alterations during malignant transformation of human kidney epithelial cells
Authors: Yuwei Chang, Kamaleshwar Singh
Journal: Cancer Research (2019)

Abstract Nicotine is a component of cigarette smoke and mounting evidence implicates tobacco smoking in kidney cancer development. Whether nicotine alone can cause kidney cancer is not clear. Moreover, the underlying molecular mechanisms for nicotine-induced carcinogenesis is still not well-understood. Therefore, the objective of this study was to determine if chronic exposure to nicotine results in malignant transformation of HK-2 kidney epithelial cells. The data revealed that chronic exposure to nicotine induced growth and malignant transformation in HK-2 cells. Additionally, the nicotine-exposed cells had inherently increased levels of intracellular ROS, and acquired stem cell-like sphere formation, as well as epithelial-mesenchymal-transition (EMT) changes during malignant transformation. Treatment with antioxidant NAC resulted in abrogation of EMT and stem cell-like sphere in HK-2 cells, suggesting the role of nicotine-induced ROS in these morphological changes. Additionally, epigenetic reagents 5-aza-2'-deoxycytidine and trichostatin A also diminished stem cell-like sphere in nicotine-exposed HK-2 cells. The nicotine also induced changes in the expression of epigenetic genes (DNMT3a, DNMT3b, and HMT1) and these changes were reversed by NAC treatment. This further supports the role of nicotine-induced ROS in epigenetic changes during malignant transformation of HK-2 cells. The altered levels of pAKT in low dose nicotine exposed cells were restored after NAC treatment, suggesting that nicotine-induced ROS, through regulation of AKT pathway, controls the EMT and stemness during early stages of carcinogenesis. In summary, to our knowledge, this is the first report showing that chronic exposure to nicotine induces malignant transformation in human kidney epithelial cells through ROS-mediated epigenetic modifications. Citation Format: Yuwei Chang, Kamaleshwar Singh. Nicotine-induced oxidative stress causes epigenetic alterations during malignant transformation of human kidney epithelial 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 879.
Abstract 888: Exploring the signaling and activity interactome between oncogenic RAS and the nucleotide pool-detoxifying enzyme MTH1
Authors: Govindi J. Samaranayake, Clara I. Troccoli, Christina Jayaraj, Brittany C. Durden, Nagaraj Nagathihalli, Nipun Merchant, Priyamvada Rai
Journal: Cancer Research (2019)

Abstract MutT Homolog 1 (MTH1) is a NUDIX pyrophosphorylase that hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, thus preventing their incorporation into DNA. Our prior work has shown that MTH1 is critical for the maintenance of multiple pro-tumorigenic phenotypes in oncogenic RAS-driven cancer cells, with its depletion leading to decreased tumor formation in vivo. Our subsequent analyses of TCGA patient datasets showed elevated MTH1 expression to be significantly associated with poorer disease-free survival in RAS-mutated cancers, such as that of the lung and pancreas. We found that MTH1 mRNA levels were positively correlated with KRAS levels even in early-stage non-small cell lung cancer patient tissues, and that the introduction of oncogenic KRAS was sufficient to upregulate MTH1 mRNA and protein levels. The aim of this study is to identify RAS-effector signaling intermediates affecting MTH1 expression and activity. Chemical inhibitors of the MAPK/ERK, PI3K/AKT and NOX pathways, plus oncogenic RASV12-effector domain mutants (RASV12- S35/ E38/ G37/ C40), were used to identify key signaling molecular mediators of MTH1 expression in the distinct RAS isoforms (H- and K-RAS). The dependencies of the different KRASG12-mutant polymorphisms (KRASG12- C/ D/ V) on MTH1 expression and activity, as well as candidate transcription factors regulating MTH1 expression, were evaluated. Our work shows MTH1 at the nexus of crosstalk between different effector pathways activated downstream of RAS. Dissecting these signaling intermediates are important in identifying alternate pathways of MTH1 regulation, which may manifest as resistance mechanisms to standard-of-care cancer treatments. Our work will also help understand how to best leverage MTH1 as a therapeutic target in oncogenic RAS-driven cancers driven by the different isoforms, and their respective mutant polymorphisms. Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Christina Jayaraj, Brittany C. Durden, Nagaraj Nagathihalli, Nipun Merchant, Priyamvada Rai. Exploring the signaling and activity interactome between oncogenic RAS and the nucleotide pool-detoxifying enzyme MTH1 [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 888.
Impact of high‐altitude therapy on type‐2 immune responses in asthma patients
Authors: Tadech Boonpiyathad, Gertruda Capova, Hans‐Werner Duchna, Andrew L. Croxford, Herve Farine, Anita Dreher, Martine Clozel, Juliane Schreiber, Petr Kubena, Nonhlanhla Lunjani, David Mirer, Beate Rückert, Pattraporn Satitsuksanoa, Ge Tan, Peter M. A. Groenen, Eugen Bersuch, Mübeccel Akdis, Daniel S. Strasser, Ellen D. Renner, Cezmi A. Akdis
Journal: Allergy (2019)

Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma.Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry.The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)-expressing CD4+ and CD8+ T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2+ Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4+ and CD8+ T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2+ Tregs which partially normalized during high-altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2+ Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels.Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions.
Abstract 205: Are All Codes the Same? House Staff Perceptions of Cardiopulmonary Resuscitation in the Cardiac Catheterization Laboratory
Authors: Janet Karol, Meredith Borak, David G Beiser, Dana Edelson, Nathan Deal, Sandeep Nathan, Jonathan Paul, Christine Babcock, Atman P Shah
Journal: Circulation (2012)

Background: Patients who are resuscitated after cardiac arrest (ROSC) are increasingly being taken to the cardiac catheterization laboratory (CCL) for diagnostic procedures and ventricular support. These critically ill patients may suffer a second arrest and need cardiopulmonary resuscitation (CPR) during their CCL procedure. The goal of this study was to assess housestaff perceptions of these codes and subsequent management. Methods: All codes at our institution are run by housestaff. Seventy-five internal medicine and emergency medicine residents at a single tertiary care university hospital were sent a web-based survey. Residents were asked their level of training, the quality of the CPR in the CCL compared to other clinical areas, and the top reason why they felt quality CPR was hindered in the CCL. The identities of the respondents were anonymous, but the respondents self-identified training program was recorded. Results: Fifty of the residents responded (66.7%). Compared to codes in the ICU, 40% felt that the CPR in the CCL was worse while 46% reported that it was the same and 14% felt that the codes were better. Compared to codes in the Emergency Department, 28% felt that the CPR was worse while 44% felt it was the same and 28% felt it was better. The top three reasons that CPR was felt to be compromised was the physical interference of the imaging equipment, the need for frequent stops of CPR, and the fear of radiation exposure (Table 1). Conclusions: This study identified perceived obstacles to resusitative efforts in the CCL. Standardization of care, identification of obstacles and removing these barriers are key to effective CPR and patient survival.
Abstract 16107: Cardioprotection of Omega-3 Fatty Acids is Lost With Free Fatty Acid Receptor 4 Polymorphisms in the Framingham Heart Study Offspring Cohort
Authors: Gregory C Shearer, Jenna Veenstra, Nathan Tintle, Timothy D O’Connell
Journal: Circulation (2018)

Introduction: We demonstrated that dietary eicosapentaenoic acid (EPA), but not docosahexaenoic acid (DHA), prevents fibrosis and contractile dysfunction in a mouse model of heart failure, but EPA ...
Abstract 4427: LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast cancer
Authors: Muhammed Hamidur Rahaman, Yinghui Zhang, Md Saiful Islam, Gary Heinemann, Abel Tesfaye Anshabo, Hugo Albrecht, Robert Milne, Shudong Wang
Journal: Cancer Research (2019)

Abstract Treatment of breast cancer represents a major therapeutic challenge, and thus identification of new targeted therapy is of paramount importance. Anti-apoptotic proteins, BCL2 and MCL1, and oncoprotein c-MYC are implicated in evasion of apoptosis and resistance to chemotherapy in both triple-negative breast cancer (TNBC) and estrogen receptor-positive breast cancer (ER+ BC). Transcription of these oncogenic factors requires cyclin dependent kinase 9 (CDK9). CDK9 phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAPII) and acts as a rate-limiting step of transcription. Thus, targeting CDK9 can reduce the expression of these proteins effectively and simultaneously, presenting a promising therapeutic strategy for breast cancer. Utilizing extensive medicinal chemistry and biochemical assays, we previously identified and developed LS007 as an orally bioavailable (F = 56% in cynomolgus monkey at 4 mg/kg), and nanomolar inhibitor of CDK9 (Ki = 4 nM). In vitro, inhibition of CDK9-mediated phosphorylation of RNAPII (pRNAPIIS2) by LS007 resulted in downregulation of BCL2, MCL1 and c-MYC and activation of PARP cleavage indicating apoptosis in breast cancer cells (TNBC: MDA-MB-231, Hs578T and ER+ BC: MCF-7, T47D). In vivo, LS007 was well tolerated in mice after oral administration (MTD = 50 mg/kg QD and 100 mg/kg Q3D). In MDA-MB-231 TNBC xenograft, by daily oral dosing at 25 mg/kg and 50 mg/kg LS007 significantly reduced tumor growth (p &amp;lt; 0.001) with T/C of 53 % and 35 %, respectively, on day 21, when compared to the vehicle dosed group. Similarly, in MCF-7 ER+ BC xenograft model, oral dosing of LS007 at 25 mg/kg QD, 50 mg/kg Q2D and 75 mg/kg Q3D showed significant tumor growth inhibition with T/C of 50 %, 60 % and 47 %, respectively, and increased in animal survival (p &amp;lt; 0.001) compared to vehicle control. It was safe in the xenograft models as there was no significant body weight loss or other overt toxicities. In addition, histological analysis of major organs (liver, kidney, heart, bone marrow and intestine) of the mice receiving LS007 showed no drug related toxicities. These results support for development of LS007 towards the clinical trials for the treatment of TNBC and ER+ BC. Citation Format: Muhammed Hamidur Rahaman, Yinghui Zhang, Md Saiful Islam, Gary Heinemann, Abel Tesfaye Anshabo, Hugo Albrecht, Robert Milne, Shudong Wang. LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast 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 4427.
Long-term follow-up of previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) treated with ofatumumab (OFA) and chlorambucil (CHL): Final analysis of the phase 3 COMPLEMENT 1 trial.
Authors: Fritz Offner, Tadeusz Robak, Ann Janssens, Govind Babu Kanakasetty, Janusz Kloczko, Sebastian Grosicki, Jiri Mayer, Panagiotis Panagiotidis, Anna Schuh, Andrew Pettitt, Marco Montillo, Olena Werner, Ghislaine Vincent, Sadhvi Khanna, Peter Hillmen
Journal: Journal of Clinical Oncology (2019)

7528 Background: Previously in the COMPLEMENT 1 study, treatment with OFA and CHL in pts with untreated CLL had shown a significant improvement in the progression-free survival (PFS) compared with CHL alone, and was well tolerated. Here, we report the final overall survival (OS) analysis of the 5-year (y) follow-up, updated investigator-assessed PFS and safety from the study. Methods: Untreated pts, not fit for fludarabine-based therapy (due to advanced age or co-morbidities) were randomized 1:1 to OFA+CHL or CHL alone. Pts in OFA+CHL arm received OFA (Cycle 1: 300 mg day (d) 1, 1000 mg d8; subsequent cycles: 1000 mg d1) in addition to CHL (10 mg/m 2 , d1-7) for 3 to 12 cycles of 28 d each. Pts in CHL arm received CHL only. Results: Overall, 447 pts were randomized to OFA+CHL (n = 221) or CHL (n = 226); 168 (76%) and 164 (73%) pts completed the scheduled treatments, respectively. Baseline characteristics were similar in both arms. The investigator-assessed median PFS was 23.4 months (mos) in the OFA+CHL arm and 14.7 mos in the CHL arm (HR: 0.61 [95% CI 0.49, 0.76], p &lt; 0.001). Median OS could not be estimated for the OFA+CHL arm and was 84.7 mos for the CHL arm (HR: 0.88 [95% CI 0.65, 1.17], p = 0.363). Estimated OS rate (95% CI) at 5 y was 68.5% (61.5%, 74.5%) in the OFA+CHL arm, and 65.7% (58.6%, 71.9%) in the CHL arm. Post-treatment anti-cancer therapy after discontinuation was received by a greater proportion of pts in the CHL (66%) vs. OFA+CHL (56%), and started earlier in the CHL arm (486 d) vs. OFA+CHL (743 d) arm. Overall, 84 (39%) pts in the OFA+CHL, and 99 (44%) pts in the CHL arms died during the study with 5 on-treatment deaths in each group. Grade ≥3 adverse events were seen in 64% and 48% of pts in the OFA+CHL vs. CHL arms, respectively, most common being (≥5% in either arm) neutropenia (26% vs. 15%), thrombocytopenia (5% vs. 10%), pneumonia (9% vs. 5%), and anemia (5% vs. 5%). Conclusions: This 5-y survival follow-up analysis supported the results from primary analysis with an estimated 12% (not significant) and 39% risk reduction in OS and PFS, respectively, in the OFA+CHL arm compared with the CHL arm. No new safety concerns were observed in the OFA+CHL arm. Clinical trial information: NCT00748189.
Abstract 21304: Calmodulin Modulates the Functional Effects of cMyBP-C on the Thin Filament
Authors: Yuanzhang Yang, Vahid Azimi, Elaine Hoye, Betty Belknap, Howard D White, Samantha P Harris
Journal: Circulation (2017)

Introduction: Cardiac myosin binding protein-C (cMyBP-C) is an essential regulator of heart muscle function that is necessary for both normal contraction and for increased contractility in response to inotropic signals. Effects of cMyBP-C on contraction are complex and attributable to dynamic interactions with both actin and myosin. For instance, cMyBP-C binding to actin can exert either activating or inhibitory effects on contraction by shifting tropomyosin on the thin filament or by blocking myosin heads, respectively. Recently, calmodulin (Ca 2+ /CaM) was also shown to bind cMyBP-C at a unique sequence within the regulatory M-domain of cMyBP-C (Lu et al, JBC 287:31596, 2012). Importantly, the binding site for CaM overlaps with a conserved actin binding site that we found was important for mediating the activating and inhibitory effects of cMyBP-C on the thin filament (Bezold et al. JBC 288: 21496, 2013). Hypothesis: Here we hypothesized that CaM competes with actin for cMyBP-C binding and thus influences the functional effects of cMyBP-C that are mediated through the thin filament. Methods: Recombinant N’-terminal domains of cMyBP-C were used in co-sedimentation binding assays, pull-down assays, and actomyosin ATPase assays to determine effects of CaM binding on cMyBP-C function. Results: We found that CaM binds to N’-terminal domains of cMyBP-C in the presence of Ca 2+ (Ca 2+ /CaM) with an affinity comparable to cMyBP-C binding to actin (3-10 UM). We further show that Ca 2+ /CaM reduces apparent binding affinity of cMyBP-C for actin, consistent with Ca 2+ /CaM competing with actin for binding to cMyBP-C. Also consistent with reduced binding of cMyBP-C to actin, Ca 2+ /CaM reversed the inhibitory effects of cMyBP-C N’-terminal domains on actin activated myosin ATPase rates. However, apo-CaM showed reduced binding affinity for cMyBP-C, did not compete with actin, and did not reverse the activating effects of cMyBP-C on the thin filament at low Ca 2+ . Conclusions: These data suggest that Ca 2+ /CaM is a novel modulator of cMyBP-C function that can temporally tune the complex effects of cMyBP-C on contraction, potentially as Ca 2+ rises and falls during a single heartbeat.
Abstract LB-029: Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow
Authors: Haiyan Xu, Eric S. Muise, Sarah Javaid, Lan Chen, Razvan Cristescu, My Sam Mansueto, Nicole Follmer, Jennifer Cho, Kimberley Kerr, Rachel Altura, Michelle Machacek, Benjamin Nicholson, George Addona, Ilona Kariv, Hongmin Chen
Journal: Cancer Research (2019)

Abstract Acute myeloid leukemia (AML) is a malignancy with complex genetics, poor survival rates and high rates of chemotherapy resistance. This study reports the establishment of a novel bone marrow mononuclear cell 3D-culture model and the application of this model to define sensitivity and resistance biomarkers as evident by DNA and RNA expression signatures in response to standard Cytarabine (Ara-C) chemotherapy. By simulating the bone marrow microenvironment, we optimized the growth conditions using frozen bone marrow mononuclear cells (BMMC) derived from healthy donors. We validated our platform by demonstrating that healthy BMMCs are capable of differentiating into all hematopoietic lineages and various types of stromal cells. Using this platform, we then characterized BMMC samples from 47 AML patients. Sixty percent of AML samples were capable of proliferating and 23 samples demonstrated robust growth. RNA sequencing was performed for 3D and 2D cultures to determine which conditions are superior at maintaining original gene expression signatures as compared to the uncultured bone marrow, To elucidate specific genetic mutations and/or gene expression signatures associated with the ability of ex vivo growth of these AML donors, whole exosome sequencing and RNA Sequencing were performed. The model identified unique gene expression signatures that correlated with sensitive as well as resistant donors in response to Ara-C treatment. These data demonstrate the translational value of our platform which should be widely applicable to evaluate other therapies in AML. Citation Format: Haiyan Xu, Eric S. Muise, Sarah Javaid, Lan Chen, Razvan Cristescu, My Sam Mansueto, Nicole Follmer, Jennifer Cho, Kimberley Kerr, Rachel Altura, Michelle Machacek, Benjamin Nicholson, George Addona, Ilona Kariv, Hongmin Chen. Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow [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 LB-029.
Smart start: Final results of rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma.
Authors: Jason Westin, Loretta J. Nastoupil, Luis Fayad, Fredrick B. Hagemeister, Yasuhiro Oki, Francesco Turturro, Sairah Ahmed, Maria Alma Rodriguez, Hun Ju Lee, Raphael Steiner, Ranjit Nair, Simrit Parmar, Ken H Young, Timothy McDonnell, Hubert Chuang, Michael Richard Green, Sattva Swarup Neelapu, Richard Eric Davis
Journal: Journal of Clinical Oncology (2019)

7508 Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes from standard immuno-chemotherapy. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We report the final results of RLI prior to chemotherapy in newly diagnosed non-GCB DLBCL patients, an investigator initiated, single-arm, open-label, phase 2 study. Methods: Adult patients with non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were ≥ 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of ≥ 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids and RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI was 84.6% (n=44), and the CRR was 38.5% (n=20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free 18 months later. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Additional studies evaluating more cycles of RLI with less chemotherapy consolidation are planned. Clinical trial information: NCT02636322.