tbuckley/cabot-search huggingface dataset:
Abstract #1751: MK-8033, a selective c-Met / Ron inhibitor, suppresses tumor cell growth in vitro and in vivo
Authors: Elizabeth Harrington, Grace Chan, Melissa Chenard, William Dahlberg, Lenora Davis, Sujal Deshmukh, Christopher Dinsmore, Clayton Efferson, Gaozhen Hang, Harold Hatch, Nancy Kohl, Kaiko Kunii, Wei Lu, Bart Lutterbach, Pradip Majumder, Alan Northrup, Xianlu Qu, John Reilly, Craig Rosenstein, Alexander Szewczak, Jennifer Tammam, Christopher Ware, Qinwen Zheng, Bo-Sheng Pan
Journal: Cancer Research (2009)

Aberrant c-Met activity has been implicated in the pathogenesis of a variety of human tumors and is therefore an attractive target for therapeutic intervention. We have identified MK-8033, a highly selective inhibitor of c-Met and Ron kinases. MK-8033 potently inhibits the kinase activity of c-Met (IC50 1.3 nM) and Ron (IC50 14 nM) while exhibiting no inhibitory activities against over 220 protein kinases when tested at 1\#956;M. The compound is a novel ATP-competitive inhibitor that is equally potent against wild type c-Met and naturally occurring oncogenic c-Met mutants, including activation loop mutants. MK-8033 inhibits both ligand stimulated and constitutive c-Met phosphosphorylation. As a result c-Met driven in vitro cell proliferation and scattering are inhibited by MK-8033. Genomic amplification and constitutive activation of c-Met are predictors of tumor cell line response to treatment in vitro. In a gastric cancer xenograft model driven by MET amplification, MK-8033 inhibits autophosphorylation of c-Met docking site tyrosine residues and suppresses downstream signaling events such as ERK1/2 and Akt phosphorylation. Tumor growth is inhibited at well tolerated oral doses of the compound in MET amplified gastric and NSCLC xenograft models. These preclinical data provide support for ongoing clinical evaluation of MK-8033 as a potential targeted therapy for patients with c-Met driven tumors.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1751.
STEM-18. THE c-Jun N-TERMINAL KINASE (JNK) IS A CRUCIAL COMPONENT OF MAINTENANCE IN GLIOBLASTOMA STEM-LIKE CELLS.
Authors: Arlet Maria Acanda de la Rocha, Monica Rodriguez-Silva, Sergio Gonzalez-Arias, Jeremy W. Chambers
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM)is the most common malignant primary brain tumors in adults, and despite established therapeutic approaches, the prognosis remains bleak. The cellular heterogeneity within GBM is one of the major causes of poor patient outcomes, whereby GBM cancer stem-like cells (GSC) drive therapeutic resistance. Compelling evidence suggests that GSCs play a major role in initiation, progression, and recurrence of GBM; therefore, there is an urgent need to identify novel therapeutic approaches that targets GSCs. c-Jun N-terminal Kinase (JNK) signaling is chronically altered in several tumors, including GBM. Therefore, defining the functional role of JNK in GSCs is critical to understanding GBM pathophysiology and developing efficacious therapies against this recalcitrant population. In this study, we examined the impact of our potent, brain-penetrant pan-JNK inhibitors (Kamenecka et al., 2010) on cell proliferation, viability, neurosphere formation and migration capacity of GSCs, and compared the novel JNK inhibitors to SP600125, a widely-used JNK inhibitor with poor brain penetrance and selectivity. Our results show that inhibition of JNK using these novel compounds decreased cell viability, proliferation, migration, and neurosphere formation capacity of GSCs to a greater extent than SP600125. The use of pan-JNK inhibitors compared to SP600125 decreased the levels of c-Jun and phospho-c-Jun, a JNK target, in GSCs, illustrating the potency of these novel inhibitors. Interestingly, inhibition of JNK with our novel compounds ultimately induced caspases 3 and 7 indicating that the compounds initiate apoptosis mechanism GSCs. Small molecule inhibitors with good brain penetrance that decrease cell proliferation, migration, and viability in GSCs, offers a novel therapeutic strategy to eliminate GSCs from tumors by primed them for apoptosis. Kamenecka T, et al. (2010) Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J Med Chem 53:419–31.
Pilot randomized trial of an electronic symptom monitoring intervention for hospitalized patients with cancer
Authors: R.D. Nipp, A. El-Jawahri, M. Ruddy, C. Fuh, B. Temel, S.M. D'Arpino, B.J. Cashavelly, V.A. Jackson, D.P. Ryan, E.P. Hochberg, J.A. Greer, J.S. Temel
Journal: Annals of Oncology (2018)

Hospitalized patients with cancer experience a high symptom burden, which is associated with poor health outcomes and increased health care utilization. However, studies investigating symptom monitoring interventions in this population are lacking. We conducted a pilot randomized trial to assess the feasibility and preliminary efficacy of a symptom monitoring intervention to improve symptom management in hospitalized patients with advanced cancer.
Abstract 16369: Usefulness of Quick Sepsis-Related Organ Failure Assessment Score for Predicting In-Hospital Adverse Outcomes in Patients With Infective Endocarditis
Authors: Yudai Tamura, Akihiro Nomura, Shohei Yoshida, Tetsuo Konno, Kenji Sakata, Kenshi Hayashi, Masaaki Kawashiri, Masakazu Yamagishi
Journal: Circulation (2017)

Introduction: Infective endocarditis (IE) is an infection of endocardium, usually of heart valves, and can be life-threating because of various adverse events during hospitalization. The quick Sepsis-related Organ Failure Assessment (qSOFA) score is easy and useful for predicting in-hospital mortality in non-ICU patients with any of suspected infections. However, there has been still unclear whether qSOFA could also predict adverse events in IE patients during hospitalization. Hypothesis: High qSOFA score is independently associated with adverse events in IE patients during hospitalization. Methods: We enrolled IE patients in Kanazawa University Hospital, Japan from January 2006 to February 2017. IE was diagnosed based on the modified Duke criteria. High qSOFA group was defined as those with qSOFA score ≥ 2. In-hospital adverse outcomes was defined as an occurrence of any following events during hospitalization: any death, embolism, bleeding, or abscess formation . Cox regression was used to estimate a ha...
Abstract 9781: Deletion of Prolyl Hydroxylase Domain Protein 2 in Myeloid Lineage suppressed Experimental Abdominal Aortic Aneurysm via NF-κB Inactivation
Authors: Tomotake Tokunou, Chikahiro Sankoda, Aya Watanabe, Yusuke Takahara, Hiroshi Kojima, Shiro Kitamoto, Toshihiro Ichiki, Kenji Sunagawa
Journal: Circulation (2015)

Background: Macrophage migration to the vessels is important for vascular inflammation and induces vascular degenerative diseases. Macrophages secrete matrix metalloprotainases (MMPs), which activate many cytokines and digest extracellular matrix of aorta. MMPs play an important role in the progression of aortic aneurysm. We previously reported that non-specific prolyl hydroxylase domain protein (PHD) inhibitor, Cobalt chloride (CoCl2), suppressed MMP-2 and -9 expression and attenuated experimental abdominal aortic aneurysm (AAA) formation in mice. In this report we investigated the myeloid specific PHD2 knockout effect on MMPs expression and aneurysm formation. Methods: Myeloid specific PHD2 conditional knockout (MyPHD2KO) mice were generated. Experimental AAA was induced by periaortic application of Calcium chloride (CaCl2) for 6 weeks. In vitro Lipopolysaccharide (LPS, 100ng/ml) was used to induce MMP-2 and MMP-9 expression with peritoneal macrophages. MMPs mRNA, protein expression and protein activity were analyzed by qRT-PCR, Western blot analysis and Zymography, respectively. ELISA-based NF-κB p65 Transcription Factor Assay was used to examine NF-κB p65 binding activity with consensus DNA binding site. Results: CaCl2-induced AAA was suppressed with MyPHD2KO mice (max diameter of aneurysm: 1.03mm±0.14mm in MyPHD2KO group, 1.63mm±0.34mm in Control AAA group, p&lt;0.01). In peritoneal macrophages CoCl2 reduced LPS-induced MMP-2 and MMP-9 mRNA and protein expression. PHD2 deletion in peritoneal macrophages from MyPHD2KO mice also suppressed LPS-induced MMP-2 and MMP-9 mRNA, protein expression and activity. PHD2 deletion suppressed LPS-induced NF-κB p65 phosphorylation via IκBα stabilization by Western blot analysis. NF-κB p65 binding activity was suppressed in MyPHD2KO macrophages (p&lt;0.01 vs control). Conclusion: Deletion of PHD2 in myeloid lineage attenuated MMPs expression by NF-κB inactivation and suppressed AAA formation. PHD2 in macrophage may be a novel target for cardiovascular disease treatment.
CHOEP-14 x 6 Followed by Systemic CNS Prophylaxis Cell Lymphoma (DLBCL)/Follicular Lymphoma (FL) Grade 3 with Age Adjusted IPI Score 2-3: Preliminary Results of a Nordic Lymphoma Group (NLG) Phase 2 Study Including 160 Patients Aged 18- 64 Years
Authors: Harald Holte, Sirpa M. Leppa, Magnus Bjorkholm, Oystein Fluge, Sirkku Jyrkkio, Jan Delabie, Christer Sundstrom, Marja-Liisa Karjalainen-Lindsberg, Martin Erlanson, Arne Kolstad, Alexander Fossa, Björn Östenstad, Eva Lofvenberg, Maria Nordström, Lars Møller Pedersen, Harald Anderson, Mats Jerkeman, Mikael Eriksson
Journal: Blood (2008)
Abstract 13162: Post-Cardiac Arrest Serum TNF-α Levels Are Associated With Short-Term Survival in a Swine Model of Ventricular Fibrillation
Authors: Scott Youngquist, Atman Shah, John Rosborough, James T Niemann
Journal: Circulation (2015)

Introduction: Most resuscitated victims of out-of-hospital cardiac arrest who survive to hospital expire due to the post-resuscitation syndrome. This syndrome is characterized by a sepsis-like pro-inflammatory state. Hypothesis: We hypothesized that a relationship exists between the rise of TNF-α, a pro-inflammatory cytokine, following return of spontaneous circulation (ROSC) and early post-arrest survival in a clinically relevant animal model of spontaneous VF. Methods: Mixed-breed Yorkshire swine (n=20), weighing 39 + 5 kg, were anesthetized and catheters placed in the right atrium and left ventricle/ascending aorta for continuous pressure monitoring. VF was induced by occluding the LAD with an angioplasty balloon. After 7 min of untreated VF, ALS resuscitation attempts were made for up to 20 min. Animals achieving ROSC were monitored for 3 hrs and fluid and pressor support was administered as needed. TNF-α levels were measured prior to VF and at 0, 15, and 30 min after ROSC using quantitative sandwich ELISA. Exact logistic regression and binomial proportions were used for analysis. Results: Twelve (60%) animals experienced early death, expiring during the 3-hour post-arrest period (9 PEA, 2 VF, and 1 asystole). The TNF-α level at 15 minutes post-ROSC was significantly associated with death within the first 3 hours post ROSC with a univariate odds ratio (OR) of 1.4 (95% confidence interval [CI] 1.05-2.2, p=0.01). Using a cutoff TNF-α level of 525 pg/mL at 15 min post ROSC had 100% negative predictive value (95% CI 0-37%) and 67% positive predictive value (95% CI 35-90%) for early death. Conclusions: The pro-inflammatory cytokine TNF-α increases shortly after ROSC and is predictive of early death. Early identification of resuscitated victims at greatest risk for hemodynamic collapse and recurrent arrest might facilitate the use of early hospital-based interventions to decrease the likelihood of a poor outcome.
SURG-23. CLINICAL RESULTS AFTER SURGICAL RESECTION OF PARASAGITTAL MENINGIOMAS IN PATIENTS USING A ND-YAG LASER IN THE DISTAL POSTOPERATIVE PERIOD
Authors: Aleksei Buzunov, Natalia Karneeva
Journal: Neuro-Oncology (2018)

Nowadays, the problem of surgical treatment of cerebral meningiomas of complex localization in the whole world remains relevant. First, it is associated with a high risk of relapse and continued growth. Secondly, subsequent re-surgeries often lead to the development of a persistent neurological deficit and disability of patients, thereby significantly reducing the quality of life. The use of a neodymium laser during the removal of the tumor node and the processing of the meningioma matrix leads to a statistically significant reduction in postoperative complications in the early postoperative period, and the number of patients with relapses and continued growth is statistically significantly reduced, which affects the quality of life in the remote postoperative period. In this article, we analyzed the dynamics of the neurological deficit, the frequency of relapse and continued growth, as well as the analysis of the dynamics of the functional state of the brain and cerebral hemodynamics in the distal postoperative period. This analysis was carried out in two statistically homogeneous groups of patients operated on for parasagittal meningiomas. In the first group, Nd-YAG laser radiation was used in parallel (study group). In the second group (control group) operated by conventional microsurgical techniques remove cerebral meningiomas. The distant period in the study group received the significant reduction of neurological deficiency, the number of recurrences, as well as marked improvement in functional status and cerebral hemodynamics and hence the highest quality life of the patients in this group.
Abstract 14667: Amiodarone is an Effective Treatment of PVC-Cardiomyopathy in the Veteran Population
Authors: Jose F Huizar, Susan G Fisher, Karoly Kaszala, Alex Y Tan, Hans Moore, Kenneth A Ellenbogen, Steven N Singh
Journal: Circulation (2017)

Introduction: PVC-cardiomyopathy (PVC-CM) is commonly treated with radiofrequency ablation (RFA). No randomized prospective clinical study has been performed to support the benefit of RFA or antiar...
MNGI-37. DMD GENOMIC DELETIONS CHARACTERIZE A SUBSET OF PROGRESSIVE/HIGHER-GRADE MENINGIOMAS WITH POOR OUTCOME
Authors: Tareq Juratli, Devin McCabe, Naema Nayyar, Erik Williams, Ian Silverman, Maria Martinez-Lage, Ganesh Shankar, Shilpa Tummala, Alexandria Fink, Julie Miller, Heather Ely, Jason Christiansen, Gabriele Schackert, Hiroaki Wakimoto, Miguel Rivera, John Iafrate, Scott Carter, Priscilla Brastianos, Daniel Cahill
Journal: Neuro-Oncology (2018)

Progressive meningiomas that have failed surgery and radiation have poor a prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from progressive/high-grade tumors, including matched primary and recurrent samples. We detected frequent alterations in genes residing on the X-chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n= 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n= 2, 8.3%), DDX3X, RBM10 and STAG2 (n= 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3–9.0) vs. median not reached (95% CI 2.9–not reached), p=0.006)]. We also assessed for TERT alterations, which have a known poor prognostic association, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n= 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p=0.033, HR=2.6, 95% CI 1.0–6.6) and TERT alterations (p= 0.005, HR= 3.8, 95% CI 1.5- 9.9) were mutually independent in predicting unfavorable outcomes. Thus, alterations of the mesodermal gene DMD identify a subset of progressive/high-grade meningiomas with worse outcomes.
How to make yourselves redundant
Authors: Fiona Godlee
Journal: BMJ (2018)

Books and blogs about management and leadership are full of exhortations to make yourself redundant: find aspects of your job that don’t need doing or that someone else could do; constantly innovate for smarter ways of working to release your time and energy; make it your aim to do yourself out of a job.

How does this advice translate to medicine? Two UK government announcements this week suggest some ideas. The first, from England’s health secretary, Matt Hancock, called for a greater focus …
CMET-05. ASSOCIATION BETWEEN TUMOR LOCATION AND TOXICITY OUTCOMES AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES
Authors: Boya Wang, Orit Kaidar-Person, Deanna Sasaki-Adams, Sivakumar Jaikumar, Matthew Ewend, Ronald Chen, Timothy Zagar, Joel Tepper, Lawrence Marks, Colette Shen
Journal: Neuro-Oncology (2018)

The toxicities associated with stereotactic radiosurgery (SRS) are important factors when considering treatment options and supportive management for patients with brain metastases. We assessed the association between brain metastasis location and rates of toxicity after SRS. We conducted a retrospective single-institution review of 170 patients treated with SRS for brain metastases from 2008–2016 with median follow-up of 8.6 months. Typical SRS doses were 18-20Gy in 1 fraction (lesions <2cm), 18-21Gy in 3 fractions (lesions 2-3cm), and 25-30Gy in 5 fractions (lesions > 3cm). Toxicity measures evaluated included radiation necrosis, seizure, and dexamethasone requirement. A total of 221 lesions were treated among frontal (29%), cerebellar (23%), parietal (16%), temporal (15%), occipital (14%), and other (brainstem, thalamus, basal ganglia) (4%) regions. The rate of SRS-related radionecrosis was 4% for all patients and significantly correlated with metastasis volume (increasing from 1% to 7% for lesions ≤1cm3 to > 3cm3) and prior whole brain radiotherapy (WBRT) but not with metastasis location or prior resection on multi-variable analysis (P<0.05). Post-SRS seizure occurred in 9% of all patients but was significantly higher after SRS to primary motor cortex and sensory cortex lesions, associated with 50% and 33% seizure rates, respectively (P<0.05). Of patients who initially presented with seizure and were on anti-epileptic medication during SRS, 62% had no further seizures, while 38% did have post-SRS seizures, nearly all with motor cortex lesions. Only 5% of patients had new-onset seizure after SRS, related to lesion hemorrhage or motor cortex location. Dexamethasone use > 3 months post-SRS was higher for motor strip lesions. Brain metastasis location in the primary motor cortex was associated with higher rates of post-SRS seizure, including new-onset seizures and breakthrough seizures on anti-epileptic medication during SRS. Rates of radionecrosis were associated with lesion volume and prior WBRT but not with metastasis location.
Impact of Physiologic Pacing Versus Right Ventricular Pacing Among Patients With Left Ventricular Ejection Fraction Greater Than 35%: A Systematic Review for the 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay
Authors: David J. Slotwiner, Merritt H. Raitt, Freddy Del-Carpio Munoz, Siva K. Mulpuru, Naseer Nasser, Pamela N. Peterson
Journal: Journal of the American College of Cardiology (2018)
TMIC-50. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ENTRAINED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA
Authors: Patricia Yee, Zhijun Liu, Yiju Wei, Melissa Gulley, Wei Li
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), the deadliest and most common primary CNS malignancy in adults, is highly heterogeneous with variable prognoses and treatment responses. The molecular underpinnings for such variability remain largely unclear. Mesenchymal (MES)-GBMs, associated with poorest prognosis and highest treatment resistance, exhibit hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ), the major effector of the Hippo tumor suppressive pathway. Additionally, the tumor microenvironment (TME) of MES-GBMs appears to be altered, containing more infiltrative tumor-associated macrophages and microglia than GBMs of other subtypes. Moreover, the Hippo pathway has recently been shown to be involved in suppressing tumor immunogenicity. Yet, it remains elusive whether TAZ dysregulation distorts the TME to contribute to MES transition and tumor progression of MES-GBMs. We suspected that such TME distortion facilitates tumor immune evasion, MES transition, and tumor progression, therefore worsening prognoses and treatment responses. To test this, we generated three GBM cell lines expressing various forms of TAZ: 1) GBM4SA expressing constitutively-active TAZ 2) GBM4SA-S51A expressing TAZ incapable of binding to its downstream effector, TEAD, and 3) GBMvector, vector control. We found mice orthotopically implanted with GBM4SA phenocopied MES-GBM patients and exhibited significantly shorter survival. Histopathology revealed that GBM4SA highly resembles human GBMs, with high cellular and nuclear anaplasia, microvascular proliferation, and pseudopalisading necrosis. Moreover, TME analyses from these GBMs suggested that GBM4SA contains significantly more infiltrative myeloid cells than GBM4SA-S51A or GBMvector, suggesting that hyperactivity of TAZ leads to an altered TME. While most infiltrative myeloid cells in the GBMvector or GBM4SA-S51A TME were of monocyte lineage, those in the GBM4SA TME were predominantly granulocytic, likely representing neutrophils. We will further delineate the roles of each myeloid cell type in the MES-GBM TME in driving tumor progression and treatment resistance, and we hope to draw implications for future GBM clinical management and novel TME-targeted anti-GBM therapies.