tbuckley/cabot-search huggingface dataset:
Relationship between tumor biomarkers (BM) and efficacy in TH3RESA, a phase 3 study of trastuzumab emtansine (T-DM1) versus treatment of physician’s choice (TPC) in HER2-positive advanced breast cancer (BC) previously treated with trastuzumab and lapatinib.
Authors: Sung-Bae Kim, Hans Wildiers, Ian E. Krop, Abraham C.F. Leung, Caroline Trudeau, Ron Yu, Sanne de Haas, Antonio Gonzalez-Martin
Journal: Journal of Clinical Oncology (2014)

605 Background: T-DM1, an antibody–drug conjugate comprising trastuzumab, DM1 (microtubule inhibitor), and a stable linker, is approved for patients (pts) with HER2-positive metastatic BC previously treated with trastuzumab and a taxane. In two phase 3 studies, T-DM1 prolonged progression-free survival (PFS; EMILIA, TH3RESA) and overall survival (EMILIA) v control arms. Here we examine the relationship between tissue BM related to the HER2 pathway and PFS in TH3RESA (NCT01419197). Methods: Pts had prior taxane therapy and ≥2 HER2-directed regimens, including trastuzumab and lapatinib, and were randomized 2:1 to T-DM1 (3.6 mg/kg q3w) v TPC. qRT-PCR for HER2, HER3, and G6PDH (ref) mRNA was performed with available pt tumor tissue. Analyses of tumor DNA for PIK3CA mutations (exons 1, 4, 7, 9, 20) and cytoplasmic PTEN expression by IHC were performed as optional research. PFS was analyzed for each BM subgroup using the Kaplan-Meier method and a Cox regression model. Results: Overall, median HER2 mRNA, HER3 mRNA, and PTEN levels and PIK3CA mutation status were consistent across arms and with previous results. For all BM subgroups, median PFS was longer with T-DM1 v TPC (Table). Relative risk reduction for PFS was numerically greater for T-DM1 v TPC for >median HER2 mRNA levels than ≤median levels but similar within HER3 mRNA, PIK3CA, and PTEN (not shown) subgroups. Conclusions: Similar to previous results, T-DM1 prolonged PFS in all BM subgroups analyzed with a greater benefit observed for pts with tumors expressing >median HER2 mRNA levels. Although PIK3CA mutation status was not associated with decreased PFS in the control arm, benefit was seen with T-DM1 regardless of mutation status. Clinical trial information: NCT01419197. T-DM1 TPC HR 95% CI n Median PFS (mo) n Median PFS (mo) All pts 404 6.2 198 3.3 0.52 0.42–0.65 HER2 mRNA ≤Median >Median 164 177 5.5 7.2 89 75 3.9 3.4 0.68 0.40 0.49–0.92 0.28–0.59 HER3 mRNA ≤Median >Median 166 176 6.0 6.8 90 73 3.3 4.1 0.52 0.55 0.37–0.71 0.38–0.79 PIK3CA mutation status Mutated Wild-type Unknown 65 187 33 6.2 6.8 5.9 37 78 10 3.1 3.4 3.6 0.44 0.47 0.56 0.26–0.73 0.33–0.67 0.22–1.45
Association Between Thrombolytic Treatment and the Prognosis of Hemodynamically Stable Patients With Major Pulmonary Embolism
Authors: StavrosKonstantinides, AnnetteGeibel, ManfredOlschewski, FritzHeinrich, KlausGrosser, KlausRauber, SteinIversen, MatthiasRedecker, JoachimKienast, HanjörgJust, WolfgangKasper
Journal: Circulation (1997)

Background Thrombolytic treatment has been shown to accelerate resolution of major pulmonary embolism and lead to a rapid improvement of right-side hemodynamics. However, the association between these favorable effects and the clinical outcome of patients who have no severe hemodynamic compromise at presentation remains unknown. Methods and Results The present multicenter registry included 719 consecutive patients with major pulmonary embolism according to clinical, echocardiographic, scintigraphic, and cardiac catheterization criteria. Symptom onset was acute (<48 hours) in 63% of patients. All patients were hemodynamically stable (ie, without evidence of cardiogenic shock) at presentation. Primary thrombolytic treatment (within 24 hours of diagnosis) was given to 169 patients (23.5%), whereas the remaining 550 patients were initially treated with heparin alone. Overall 30-day mortality was significantly lower in the patients who received thrombolytic agents (4.7 versus 11.1%, P=.016). Clinical factors a...
Regulation of the Ca2+ Gradient Across the Sarcoplasmic Reticulum in Perfused Rabbit Heart
Authors: WeinaChen, RobertLondon, ElizabethMurphy, CharlesSteenbergen
Journal: Circulation Research (1998)

Abstract—Myocardial contractility depends on Ca2+ release from and uptake into the sarcoplasmic reticulum (SR). The Ca2+ gradient between the SR matrix and the cytosol (SR Ca2+ gradient) is maintained by the SR Ca2+-ATPase using the free energy available from hydrolysis of ATP. The activity of the SR Ca2+-ATPase is not only dependent on the energy state of the cell but is also kinetically regulated by SR proteins such as phospholamban. To evaluate the importance of thermodynamic and kinetic regulation of the SR Ca2+ gradient, we examined the relationship between the energy available from ATP hydrolysis (ΔGATP) and the energy required for maintenance of the SR Ca2+ gradient (ΔGCa2+SR) during physiological and pathological manipulations that alter ΔGATP and the phosphorylation state of phospholamban. We used our previously developed 19F nuclear magnetic resonance method to measure the ionized [Ca2+] in the SR of Langendorff-perfused rabbit hearts. We found that addition of either pyruvate or isoproterenol r...
Abstract 9690: Does Testosterone Therapy Increase Risk of Cardiovascular Event Among Men? A Meta-Analysis
Authors: nadermakki, WassefKarrowni
Journal: Circulation (2014)

Background: Testosterone therapy has been increasingly promoted and prescribed over the past decade. However, there is rising concern about its safety, and randomized data adequately powered to assess its effect on cardiovascular outcomes is not available. Aim: We conducted a meta-analysis and systematic review of published randomized and observational studies to examine the overall risk of cardiovascular events associated with testosterone therapy. Methods: We searched Medline (1966-2014), Embase (1966-2014), and Cochrane central (2000-2014). Data was collected and analyzed using random and fixed effect model, as appropriate, with inverse variance weighting. Results: Of 2,800 studies identified, 34 were eligible including 76,270 patients with a mean follow up of 11.7 months. Testosterone therapy was associated with increased risk of cardiovascular events (adjusted HR=1.41, 95% CI = 1.18-1.70, p<0.05), all-cause mortality (adjusted HR=1.51, 95% CI = 1.05-2.18, p<0.05), and ischemic heart disease (adjusted...
Right or Left Ventricular Pacing in Young Minipigs With Chronic Atrioventricular Block
Authors: AidaSalameh, StefanDhein, KatjaBlanke, ArdawanRastan, BahiHiyasat, AnnaDietze, AxelSobiraij, IngoDähnert, JanJanousek
Journal: Circulation (2012)

Background—Left ventricular (LV) dyssynchrony may occur as a result of right ventricular (RV) pacing and is a known risk factor for the development of heart failure. In children with complete atrioventricular block, pacing-induced dyssynchrony lasting for decades might be especially deleterious for LV function. To determine the hemodynamic and ultrastructural remodeling after either RV free wall or LV apical pacing, we used a chronic minipig model. Methods and Results—Fourteen piglets 8 weeks of age underwent atrioventricular node ablation and were paced from either the RV free wall or the LV apex at 120 bpm for 1 year (7 age-matched minipigs served as controls with spontaneous heart rates of 104±5 bpm). Echocardiographic examinations, pressure-volume loops, patch-clamp investigations, and examinations of connexin43, calcium-handling proteins, and histomorphology were carried out. RV free wall–paced minipigs exhibited significantly more LV dyssynchrony than LV apex–paced animals, which was accompanied by ...
Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure
Authors: YoshitakaIwanaga, YasukiKihara, KoichiInagaki, YokoOnozawa, TakeshiYoneda, KazuakiKataoka, ShigetakeSasayama
Journal: Circulation (2001)

Background In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental. Methods and Results In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6- and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3- and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shorten...
Failing Grade for Shared Decision Making for Lung Cancer Screening
Authors: Rita F. Redberg
Journal: JAMA Internal Medicine (2018)

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Abstract 4382: Complement system mutational landscape reveals <i>C4BPA</i> mutations enhance apoptosis in an immune-independent manner
Authors: Monica M. Olcina, Nikolas G. Balanis, Ryan K. Kim, Michael J. Thompson, Thomas G. Graeber, Amato J. Giaccia
Journal: Cancer Research (2018)

Abstract The complement system is an important pathway in immunity. When dysregulated in the tumor microenvironment, complement is associated with suppression of antitumor immunity and tumorigenesis promotion. While complement has been reported to have important intracellular functions in immune cells, the role of intracellular complement in cancer has remained poorly understood to date. In this study we investigated the prevalence and significance of pathway-wide complement mutations as well as their role with respect to intracellular complement in cancer. We describe mutations in both individual genes as well as within functional groups that are significantly associated with altered survival outcomes. Analyzing mutations occurring across multiple TCGA cancer types highlighted the potential clinical significance of certain mutations that would otherwise not have surfaced at a single cancer level. As an example, we test the significance of mutations in complement regulator C4BPA in vitro and in vivo in a single cancer type. This approach allowed us to uncover a new immune-independent biologic function of the complement system with potential clinical implications for colorectal cancer patients. Specifically, we find that colorectal cancer cells with specific C4BPA mutations display increased oxaliplatin-induced intracellular C4BPA stabilization. By studying the mechanistic basis of this association we report novel crosstalk between intracellular complement and apoptosis signaling, occurring in an NFκB/RelA-dependent manner. Based on both experimental and patient outcome data, we therefore propose that assessing complement mutation status might facilitate patient stratification. In the case of C4BPA mutations, this would be particularly relevant to improve accuracy of prognosis assessment in stage II colorectal patients where TNM staging alone does not accurately predict outcome in patients who might benefit from adjuvant chemotherapy. Citation Format: Monica M. Olcina, Nikolas G. Balanis, Ryan K. Kim, Michael J. Thompson, Thomas G. Graeber, Amato J. Giaccia. Complement system mutational landscape reveals C4BPA mutations enhance apoptosis in an immune-independent manner [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 4382.
Abstract 4917: Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models
Authors: Linda Kessler, Catherine Scholz, Antonio Gualberto, Yi Liu, Francis Burrows
Journal: Cancer Research (2018)

Abstract Genomic profiling of squamous tumors has revealed important similarities between lung squamous cell carcinoma (LSCC) and head and neck squamous cell carcinoma (HNSCC). For instance, HRAS is the most commonly mutated RAS species in both LSCC and HNSCC, observed in approximately 2% and 5% of cases, respectively (TCGA, Nature 2013). Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FT) that catalyzes the post-translational attachment of farnesyl groups to proteins that require localization to the inner cell membrane. Although all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. With limited treatment options, LSCC and HNSCC remain a significant unmet medical need. Recent evidence supports the clinical utility of tipifarnib for treatment of patients with HRAS-mutant HNSCC, and we present herein data supporting a potential utility of tipifarnib in the treatment of HRAS-mutant LSCC. We have characterized the antitumor activity of tipifarnib in CDX and PDX models of squamous cell carcinoma with activating HRAS mutations. Tipifarnib displayed robust antitumor activity in the majority of these models, including lung and head and neck tumors. Six of seven HRAS-mutant lung SCC PDX models responded to tipifarnib treatment with the majority either fully growth-inhibited or undergoing partial or complete regression. Importantly, even LSCC PDX tumors resistant to chemotherapy responded to tipifarnib, suggesting tipifarnib has the potential to offer clinical benefit in patients relapsed or refractory to standard therapies. The activity of tipifarnib in LSCC models is quite similar to that seen in HNSCC PDX models, where tipifarnib also induced regressions consistent with those observed in patients enrolled in the ongoing Phase 2 study in HRAS-mutant SCCHN patients (NCT02383927), including patients refractory to chemotherapy, cetuximab and/or immunotherapy. These data demonstrate that HRAS is a targetable mutation in lung SCC as well as in HNSCC and illustrate the potential for tipifarnib in the treatment of additional HRAS-mutant squamous cell carcinomas. Citation Format: Linda Kessler, Catherine Scholz, Antonio Gualberto, Yi Liu, Francis Burrows. Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models [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 4917.
Abstract 11223: Valve Repair Improves the Outcome of Surgery for Chronic Severe Aortic Regurgitation. A Propensity Score Analysis
Authors: Christophede Meester, SophiePierard, StéphanieSeldrum, BernhardGerber, DavidVancraeynest, Anne-CatherinePouleur, PhilippeNoirhomme, AgnèsPasquet, GébrineEl Khoury, Jean-LouisVanoverschelde
Journal: Circulation (2012)

Background. For patients with aortic regurgitation (AR), aortic valve (AV) repair represents as an attractive alternative to AV replacement (R), as it does not expose the patients to the risk of prosthetic valve complications. Although the durability of AV repair has been documented, its superiority to prosthetic AVR has not yet been established. Methods. We examined the outcome of 317 consecutive patients who underwent surgical correction of severe AR between 1995 and 2010, of whom 264 underwent AV repair and 53 AVR. Results. Operative mortality was similar in the AV repair and AVR groups (1% vs 4%, p=0.19). Kaplan Meier survival analysis indicated a significantly better overall 6-year survival after AV repair than after AVR (88% vs 69%, log rank p=0.0002). These differences persisted after age adjustment. Cox's proportional survival analysis demonstrated that the choice of treatment was an independent predictor of post-operative survival. To reduce the effect of selection bias, we matched 49 pairs of pa...
Abstract LB-277: A small molecule compound targets mutant Ras driven cancers via changes in mitochondrial morphology and mTOR-dependent execution
Authors: Jonathan C. Foo, Kartini B. Iskandar, Shazib Pervaiz
Journal: Cancer Research (2018)

Abstract In a recent report, we presented evidence that a small molecule compound selectively induces autophagy-associated execution of mutant RAS driven cancer cells via Akt-dependent mitochondrial ROS production (Iskandar, K. et al. Antiox. Redox Sig., 2016). During our efforts to explore the underlying mechanism of RAS dependent execution, we unraveled a novel mechanism of action involving changes in proteins responsible for maintaining mitochondrial morphology, Drp-1 and Opa-1. Exposure of cells to the small molecule, C1, results in specific phosphorylation of Drp-1 (serine 616) associated with mitochondrial fission as well as cleavage of the fusion associated protein Opa-1. Gene knockdown of KRAS significantly abrogated drug-induced phosphorylation of Drp-1 and rescued mitochondrial morphology. Interestingly, siKRAS also resulted in the complete inhibition of mitophagy induced upon exposure to the small molecule compound; mitophagy in this model is driven by the activation of Drp-1. We also provide evidence that KRAS is recruited to the mitochondria, upstream of Drp-1 activation and mitophagy induction in response to drug treatment. Furthermore, as Akt activation was linked to an increase in ROS production and knockout of Akt1/2 salvaged cells from the death inducing activity of C1, we studied the mechanism of Akt activation in this model. We present evidence that Akt activation might be downstream of Torin-sensitive but not Rapamycin-sensitive mTOR activation. Furthermore, a priori treatment with Torin completely blocked the effect of C1 on tumor colony forming ability. These data provide an interesting insight into the molecular mechanism(s) of a small molecule compound that triggers RAS dependent execution with potential therapeutic implications. Citation Format: Jonathan C. Foo, Kartini B. Iskandar, Shazib Pervaiz. A small molecule compound targets mutant Ras driven cancers via changes in mitochondrial morphology and mTOR-dependent execution [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 LB-277.
Abstract 12557: INTERMACS Profiles and Clinical Outcomes Among Ambulatory Patients With Systolic Heart Failure
Authors: Ayman S Tahhan, Alanna A Morris, Jeffrey S Hedley, Andrew A McCue, Mariyah Yazdani, Raghda Al-Anbari, Javed Butler, Vasiliki V Georgiopoulou, Andreas Kalogeropoulos
Journal: Circulation (2015)

Introduction: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles are used to classify patients with heart failure (HF) considered for mechanical circulatory support (MCS). Limited data exist on the prognostic value of INTERMACS profiles in the general ambulatory HF population. Hypothesis: INTERMACS profiles identify systolic HF outpatients with distinct disease trajectories. Methods: We evaluated INTERMACS profiles, mortality, and healthcare resources utilization in 474 HF outpatients with left ventricular ejection fraction ≤40% who received care during a 3-month period in 2012 and were not on advanced therapies (MCS, heart transplant, or palliative inotropes). Patients whose HF severity did not meet any INTERMACS profile were classified as stage C. Results: Table 1 presents the distribution of patient characteristics across INTERMACS profiles. After a median follow-up of 3.1 years (interquartile range 1.6, 3.3), 95 patients died (3-year mortality 21.4%); 24 patients received MCS; and 11 received heart transplant (combined 3-year mortality, MCS, and transplant: 29.3%). Compared to stage C patients, mortality and hospitalization rates were higher in all INTERMACS profiles, Table 2 . Patients with profiles 4-5 demonstrated mortality and hospitalization rates similar to those with profiles 2-3, despite a higher use of advanced therapies in the latter. Conclusions: In ambulatory HF patients, all INTERMACS profiles are associated with significantly higher mortality and hospitalization rates compared to stage C patients. Outcomes in patients with profiles 2-3 are similar to those with the theoretically more benign profiles 4-5.