tbuckley/cabot-search huggingface dataset:
Abstract 905: RICTOR modulation regulates cisplatin sensitivity in lung cancer
Authors: Haiying Cheng, Ni Fan, Alain Borczu, Huijie Liu, Aditi Singh, Feng Wang, Balazs Halmos, Roman Perez-Soler
Journal: Cancer Research (2018)

Abstract Background: Despite treatment advances, most lung cancer patient will still receive platinum-based chemotherapy and platinum resistance remains a serious clinical problem. RICTOR is a key component of the mTOR complex 2. Activation of RICTOR signaling has been suggested to play critical roles in regulating cancer cell migration, invasion and metastasis. A recent study indicates that RICTOR contributes to cisplatin resistance in human ovarian cancer cells. We hypothesize that activation of RICTOR signaling is associated with platinum resistance in lung cancer. Thus, we tested platinum sensitivities in lung cancer cells and xenograft mouse models with different RICTOR levels. Results: RICTOR expression was found in 79% (99/125) of primary lung tumors and 67% (24/36) lung cancer cells by immunohistochemistry. The expression of RICTOR was significantly higher in squamous cell lung cancer in comparison to lung adenocarcinoma (P&amp;lt;0.05). Overexpression of RICTOR in the Ba/F3 cells resulted in significant cisplatin resistance, whereas down-regulation of RICTOR in H23, HCC827 and H1703 lung cancer cells led to significantly improved cisplatin sensitivity. In addition, the combination of cisplatin and RICTOR knockdown significantly promoted more apoptosis than single treatment. To test the in vivo effects of RICTOR on platinum sensitivity, we performed HCC827 xenograft mouse experiments. Cisplatin alone and RICTOR knockdown alone significantly inhibited tumor growth. Moreover, RICTOR knockdown significantly increased the sensitivities to cisplatin in the xenografts and the combination led to more pronounced tumor reduction than either alone (P&amp;lt;0.05). Conclusion: Our study provides a novel resistance mechanism to platinum treatment in lung cancer and may serve as basis to target RICTOR to overcome platinum resistance. Citation Format: Haiying Cheng, Ni Fan, Alain Borczu, Huijie Liu, Aditi Singh, Feng Wang, Balazs Halmos, Roman Perez-Soler. RICTOR modulation regulates cisplatin sensitivity in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 905.
Association of Compensation From the Surgical and Medical Device Industry to Physicians and Self-declared Conflict of Interest
Authors: Kasra Ziai, Alessio Pigazzi, Brian R. Smith, Roxana Nouri-Nikbakht, Helene Nepomuceno, Joseph C. Carmichael, Steven Mills, Michael J. Stamos, Mehraneh D. Jafari
Journal: JAMA Surgery (2018)

Surgical and medical device manufacturers have a cooperative relationship with clinicians. When evaluating published works, one should assess the integrity and academic credentials of the authors, who serve as putative experts. A relationship with a relevant manufacturer may increase the potential risk for bias in relevant studies.To characterize the association of industrial payments by device manufacturers, self-declared conflict of interest (COI), and relevance of publications among physicians receiving the highest compensation.This population-based bibliometric analysis identified 10 surgical and medical device manufacturing companies and the 10 physicians receiving the highest compensation from each company using the 2015 Open Payments Database (OPD) general payments data. For each of the 100 physicians, the total amount of general payments, number of payments, institution type, and academic rank were recorded. Royalty or license payments were excluded. A search of PubMed identified articles published by each physician from January 1 through December 31, 2016, and their associated COI declaration. Scopus was used to identify bibliometric data reported as the h index (number of papers by a researcher with at least h citations each).Discrepancy between self-declared COI and industry payments.The 100 physicians included in the sample population (88% men) were paid a total of $12 446 969, with a median payment of $95 993. Fifty physicians (50.0%) were faculty at academic institutions. The mean (SD) h index was 18 (18; range, 0-75) for the authors. In 2016, 412 articles were published by these physicians, with a mean (SD) of 4 (6) publications (range, 0-25) and median of 1 (36 physicians had no publications). Of these articles, 225 (54.6%) were relevant to the general payments received by the authors. Only in 84 of the 225 relevant publications (37.3%) was the potential COI declared by the authors.A high level of inconsistency was found between self-declared COI and the OPD among the physicians receiving the highest industry payments. Therefore, a policy of full disclosure for all publications, regardless of relevance, is proposed. No statistically significant association was demonstrated between academic rank or productivity and industrial payments.
Aldosterone Induces Angiotensin-Converting-Enzyme Gene Expression in Cultured Neonatal Rat Cardiocytes
Authors: EisakuHarada, MichihiroYoshimura, HirofumiYasue, OsamuNakagawa, MasayoNakagawa, MasakiHarada, YujiMizuno, MasafumiNakayama, YukioShimasaki, TeruhikoIto, ShotaNakamura, KoichiroKuwahara, YoshihikoSaito, KazuwaNakao, HisaoOgawa
Journal: Circulation (2001)

Background— The cardiac renin-angiotensin-aldosterone system is activated in failing hearts in proportion to the severity of the disease. We hypothesized that a positive feedback mechanism might exist within this system and contribute to the progression of the heart failure. Methods and Results— To test this hypothesis, we examined whether angiotensin II or aldosterone induces the expression of angiotensin-converting-enzyme (ACE) mRNA in cultured neonatal rat ventricular cardiocytes. Expression of ACE mRNA was detected and quantified using real-time reverse transcription-polymerase chain reaction. Exposure to angiotensin II (10−5 mol/L) for 24 hours had no significant effect on the expression of ACE mRNA (0.7±0.5-fold versus control, P=NS), but similar treatment with aldosterone (10−5 mol/L) induced a 23.3±7.9-fold increase (P<0.01) in ACE mRNA expression. The effect of aldosterone was both time- (maximal effect, 24 hours) and dose-dependent (EC50, 4×10−7 mol/L), and it was significantly (P<0.01) inhibite...
Abstract 14922: Prognostic Value of Baseline BNP and NT-ProBNP and its Interaction With Spironolactone in Patients With Heart Failure and Preserved Ejection Fraction in the TOPCAT Trial
Authors: Inder S Anand, Scott D Solomon, Brian Claggett, Sanjiv J Shah, Eileen O’Meara, Robin Boineau, Jerome L Fleg, Marc A Pfeffer, Bertram Pitt
Journal: Circulation (2015)

Background: Plasma natriuretic peptides (NP) are helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) and predict adverse outcomes. Levels of NP beyond a certain cut-off level are often used as inclusion criteria in clinical trials to ensure that the patients have HF, and to select patients at higher risk. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. In the I-Preserve trial a benefit of irbesartan on all outcomes was only seen in HFpEF patients with low but not high NP levels. We hypothesized that in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, spironolactone might have a greater benefit in patients with lower NP levels. Methods and Results: BNP (n=468) or NT-proBNP (n=400) levels were available at baseline in 868 patients with HFpEF enrolled in the natriuretic peptide stratum (BNP ≥100 pg/mL or an NT- proBNP ≥360 pg/mL) of the TOPCAT trial. In a multi-variable Cox regression model, that included age, gender, region (Americas vs. Russia/Georgia), atrial fibrillation, diabetes, eGFR, BMI and heart rate, higher BNP or NT-proBNP as a continuous, standardized log-transformed variable or grouped by terciles (see Figure for BNP &amp; NT-proBNP tercile values) was independently associated with an increased risk of the primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for heart failure (Figure-1). There was a significant interaction between the effect of spironolactone and baseline BNP or NT-proBNP terciles for the primary outcome (P=0.02, Figure-2), with greater benefit of the drug in the lower compared to higher NP terciles. Conclusions: The benefit of spironolactone in lower risk HFpEF patients may indicate effects of the drug on early, but not late higher-risk stage of the disease. These findings question the strategy of using elevated NP as a patient selection criterion in HFpEF trials.
Delayed Postconditioning in the Mouse Heart In Vivo
Authors: FrançoisRoubille, AliciaFranck-Miclo, AurélieCovinhes, ChrystelLafont, FrédéricCransac, StéphaneCombes, AnneVincent, PierreFontanaud, CatherineSportouch-Dukhan, ChristelleRedt-Clouet, JoëlNargeot, ChristophePiot, StéphanieBarrère-Lemaire
Journal: Circulation (2011)

Background—Reperfusion during acute myocardial infarction remains the best treatment for reducing infarct size. Postconditioning, applied at the onset of reperfusion, reduces myocardial infarction both in animals and humans. The objective of this study was to identify the time delay to apply postconditioning at reperfusion, allowing preservation of cardioprotection in the mouse myocardium. This is a major issue in the management of acute myocardial infarction patients. Methods and Results—Mice were subjected to 40 minutes of ischemia and 60 minutes of reperfusion (IR60′). Postconditioning protocols corresponding to repetitive ischemia (3 cycles of 1 minute of ischemia and 1 minute of reperfusion) were applied during early reperfusion at various time durations (Δt) after reopening of the coronary artery (Δt=10 seconds, 1, 5, 10, 15, 20, 30, and 45 minutes; PostCΔt). Infarct size/area at risk was reduced by 71% in PostCΔ1 compared with IR60′ mice (P=5×10−6). There was a linear correlation (r2=0.91) between ...
Abstract 78: p38 kinase is a negative regulator of tumorigenesis and recurrence after surgery in a mammary carcinoma model
Authors: Carla S. Capobianco, Johanna E. Sidabra, Maria F. Gottardo, Julio A. Aguirre-Ghiso, Daniel F. Alonso, Hernan G. Farina
Journal: Cancer Research (2018)

Abstract The mitogen activated protein kinase (MAPK) p38 is a kinase involved in the response to different external stimuli, extremely diverse such as oxidative stress or growth factors. Its activation triggers different responses which include from promoting cell apoptosis or cell cycle arrest, to cell differentiation and the activation of survival pathways. Although the role of p38 in cancer is a well studied field, there are still multiple unanswered questions, given the large amount of evidence supporting both a tumorigenic but also a tumor suppressor function for p38 in cancer development and progression. In this study, the effects produced by p38 negative modulation using the chemical inhibitor SB203580 in different aspects of tumor biology are analyzed in vitro and in vivo. As a study model, F3II cell line was used, which is an aggressive murine mammary carcinoma. We found that p38 inhibition provokes contradictory effects in our mammary carcinoma model. On one hand, p38 inhibition provoked the reduction of cell viability and colony formation. On the other hand, SB203580 treatment increased cell adhesion and proliferation in matrix coated surfaces. In vivo we found that SB203580 treatment increases tumor aggressiveness. The shortened latency times, higher number of lung metastasis and larger local recurrences are a reflection of the aforementioned effect. Taking together, the results presented in this work position p38 as a tumor suppressor kinase, in the context of cells adapting to a new environment and developing the first stages of growth. P38 inhibition represented an advantage for cells newly inoculated in vivo. We consider that this phenotypic adaptation is probably a consequence of ERK activation and integrin α5 increased expression. Data presented here is of importance to show how determinant is the microenvironment in the responses elicited by the modulation of p38 kinase. We propose a differential role according to the environment conditions, which reflects the complexity of the pathway and the importance of the extracellular stimuli when evaluating the implications of treatment with p38 MAP kinase inhibitors. Citation Format: Carla S. Capobianco, Johanna E. Sidabra, Maria F. Gottardo, Julio A. Aguirre-Ghiso, Daniel F. Alonso, Hernan G. Farina. p38 kinase is a negative regulator of tumorigenesis and recurrence after surgery in a mammary carcinoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 78.
Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias
Authors: Roberta Russo, Immacolata Andolfo, Francesco Manna, Antonella Gambale, Roberta Marra, Barbara Eleni Rosato, Paola Caforio, Valeria Pinto, Piero Pignataro, Kottayam Radhakrishnan, Sule Unal, Giovanna Tomaiuolo, Gian Luca Forni, Achille Iolascon
Journal: American Journal of Hematology (2018)

Abstract Mutations in more than 70 genes cause hereditary anemias (HA), a highly heterogeneous group of rare/low frequency disorders in which we included: hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA) and Diamond‐Blackfan anemia; hemolytic anemias due to erythrocyte membrane defects, as hereditary spherocytosis and stomatocytosis; hemolytic anemias due to enzymatic defects. The study describes the diagnostic workflow for HA, based on the development of two consecutive versions of a targeted‐NGS panel, including 34 and 71 genes, respectively. Seventy‐four probands from 62 unrelated families were investigated. Our study includes the most comprehensive gene set for these anemias and the largest cohort of patients described so far. We obtained an overall diagnostic yield of 64.9%. Despite 54.2% of cases showed conclusive diagnosis fitting well to the clinical suspicion, the multi‐gene analysis modified the original clinical diagnosis in 45.8% of patients (nonmatched phenotype‐genotype). Of note, 81.8% of nonmatched patients were clinically suspected to suffer from CDA. Particularly, 45.5% of the probands originally classified as CDA exhibited a conclusive diagnosis of chronic anemia due to enzymatic defects, mainly due to mutations in PKLR gene. Interestingly, we also identified a syndromic CDA patient with mild anemia and epilepsy, showing a homozygous mutation in CAD gene, recently associated to early infantile epileptic encephalopathy‐50 and CDA‐like anemia. Finally, we described a patient showing marked iron overload due to the coinheritance of PIEZO1 and SEC23B mutations, demonstrating that the multi‐gene approach is valuable not only for achieving a correct and definitive diagnosis, but also for guiding treatment.
Hurricane Maria and Puerto Rico: A Physician Looks Back at the Storm
Authors: Jennifer Abbasi
Journal: JAMA (2018)

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Abstract 4298: Targeting the DNA damage checkpoint kinase Chk1 induces multiple pathways of cytotoxicity
Authors: Nicholas Warren, Jennifer Ditano, Alan Eastman
Journal: Cancer Research (2018)

Abstract DNA damaging agents are standard therapies for many cancers, but result in limited long-term clinical benefit. DNA damage checkpoints arrest DNA synthesis and provide time for repair and recovery. Using DNA checkpoint inhibitors to sensitize cancer cells to traditional chemotherapeutics is an emerging strategy. However, clinical trials involving Checkpoint Kinase 1 inhibitors (Chk1i) plus DNA-damaging chemotherapies have shown little clinical benefit. This may be due to sub-optimal scheduling of combinations. We have published that delaying Chk1i until 18 h after gemcitabine confers the greatest sensitization of cancer cells. We have now characterized the mechanisms by which the Chk1i, MK-8776, sensitizes human cancer cells to gemcitabine and SN38. SN38, the active metabolite of irinotecan, traps topoisomerase I on DNA resulting in S phase arrest. Chk1i re-activates replication and drives cells into mitosis before the damage from SN38 is repaired. Co-incubation with a CDK1/2 inhibitor surprisingly failed to prevent S phase progression, but did block mitotic entry and prevented further DNA damage. Conversely, the replication-associated kinase, CDC7, is essential for Chk1i-mediated S phase abrogation. CDC7 is presumably required to activate dormant origins of replication. Gemcitabine inhibits ribonucleotide reductase, thus preventing production of deoxyribonucleotides. Addition of Chk1i 18 h following gemcitabine causes aberrant activation of DNA helicases, but without deoxyribonucleotides, this results in excessive single-stranded DNA. Eventually, the level of single-stranded DNA exceeds cellular stores of the protective protein, RPA, which leads to nucleolytic cleavage and double-strand DNA breaks. Chk1i-mediated helicase activation is again dependent on CDC7, but insensitive to a CDK1/2 inhibitor. Concurrent incubation with gemcitabine plus MK8776 does not activate DNA helicases. These data provide a rationale for a delayed administration of Chk1i when patients are receiving gemcitabine. These investigations have detailed how Chk1i elicits distinct mechanisms of cytotoxicity depending on the context of DNA damage. Understanding of these mechanisms may help identify biomarkers to predict patient response. Furthermore, the clinical development of several Chk1i have been terminated due to unfavorable toxicity, but the cause of toxicity remains unknown. The work described here may help the clinical development by determining whether the observed toxicities are due to on- or off-targets. Citation Format: Nicholas Warren, Jennifer Ditano, Alan Eastman. Targeting the DNA damage checkpoint kinase Chk1 induces multiple pathways of cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4298.
Abstract 1825: PIK3CA E542K mutation in bladder cancer confers resistance to PI3K targeted therapy but synergy with BET inhibition
Authors: May Faek Elbanna, Nur Damayanti, Sreenivasulu Chintala, Roberto Pili
Journal: Cancer Research (2018)

Abstract Background: We have previously reported that two bladder cancer PDX models that carry distinct PIK3CA helical domain (HD) mutations respond differently to dual PI3K/mTOR inhibitor (LY3023414), where one model is sensitive (RP-B-02, PIK3CA E545K MUT) while the other is resistant (PIK3CA, E542K MUT) (Wei L et al Oncotarget 2016). Thus, we transduced these mutations in isogeneic cells to determine whether each mutation is indeed associated with a distinct oncogenic potential, as well as differential therapeutic response. Subsequently, we tested rational drug combinations capable of overriding resistance to PI3K targeted therapy (i.e. bromodomain inhibitor). Methods: Isogeneic HEK cells and urothelial cells (SV-HUC) were transduced with plasmids carrying either wild type (WT) or mutant PIK3CA (E545K and E542K mutants). Proliferation and growth were compared both in 2D and 3D culture respectively. We tested the therapeutic response to LY3023414 in 2D and 3D culture. Western blotting was used to test target modulation in the PI3K/mTOR pathway in response to treatment. JQ1 and LY3023414 combination studies were done in vitro. Calcusyn™ was used to determine whether synergy between the two agents exists in the context of either mutation. Results: PIK3CA E542K mutation has a growth advantage compared to the E545K mutation. This observation was more significant in 3D culture, which more faithfully represents the complexity of the tumor microenvironment. Isogeneic HEK cells expressing the E542K mutation were significantly more resistant to LY3023414 treatment both in 3D and 2D. This resonates with the resistance we initially reported in the bladder cancer PDX models carrying the E542K mutation. Interestingly, LY3023414+JQ1 combination was synergistic in the RP-B-01 (E542K MUT, but not in the RP-B-02 cell line (E545K MUT). Conclusion: PIK3CA mutation status is predictive of response to PI3K targeted therapy in bladder cancer, where PIK3CA E542K mutation confers resistance to PI3K targeted therapy. The synergistic combination of LY3023414 and the bromodomain inhibitor JQ1 can override resistance to PI3K targeted therapy. This drug combination may be of clinical significance in the context of PIK3CA E542K, but not E545K mutation. Citation Format: May Faek Elbanna, Nur Damayanti, Sreenivasulu Chintala, Roberto Pili. PIK3CA E542K mutation in bladder cancer confers resistance to PI3K targeted therapy but synergy with BET inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1825.
Abstract 5520: Oncogenic RTK signaling inhibits Spred1/NF1 to sustain constitutive Ras/MAPK signaling
Authors: Evan Markegard, Ellen L. Mercado, Pau Castel, Jillian Silva, Jacqueline Galeas, Kathy Li, Anatoly Urisman, Frank McCormick
Journal: Cancer Research (2018)

Abstract Spred proteins negatively regulate Ras/MAPK signaling following growth factor stimulation. Inhibition of Ras primary occurs through Spreds ability to bind and localize NF1, a RasGAP and major tumor suppressor, to the plasma membrane. Spred1 and NF1 loss-of-function mutations occur across multiple cancer types including non-small cell lung carcinoma, glioblastoma, melanoma, stomach carcinoma, and uterine carcinosarcoma. Here we demonstrate that oncogenic RTK signaling leads to phosphorylation of Spred1(S105) in the EVH domain, which disrupts Spred1-NF1 binding and function. Phosphomimetic Spred1 is unable to suppress Ras-GTP following growth factor stimulation and cancer cell proliferation. The Spred1(S105) kinase is likely to be a CDK based on in vitro kinase and in vivo cell line assays. Our findings provide one potential mechanism by which oncogenic RTK signaling disrupts negative feedback to sustain constitutive Ras signaling. Furthermore, this work may elucidate a novel therapeutic target for restoring NF1-mediated inhibition of Ras. Citation Format: Evan Markegard, Ellen L. Mercado, Pau Castel, Jillian Silva, Jacqueline Galeas, Kathy Li, Anatoly Urisman, Frank McCormick. Oncogenic RTK signaling inhibits Spred1/NF1 to sustain constitutive Ras/MAPK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5520.