tbuckley/cabot-search huggingface dataset:
Abstract 16115: Rapamycin Protects Diabetic Heart Against Ischemia-reperfusion Injury by Inhibiting JNK and STAT4
Authors: Fadi N Salloum, Rakesh C Kukreja, Anindita Das
Journal: Circulation (2015)

Background: Persistent activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and plays a critical role in myocardial injury following ischemia/reperfusion. Recently we reported that mTOR inhibition with rapamycin improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress and alteration of antioxidants and contractile protein expression. Since increased JNK and STAT4 activities have been strongly associated with T2D-induced cardiovascular complications, we hypothesized that rapamycin would reduce myocardial infarction (MI) in T2D mice through inhibition of JNK and STAT4. Methods and Results: Adult male wild type (C57) or db/db T2D mice were treated daily for 28 days with rapamycin (0.25 mg/kg, i.p.). Following treatment, the hearts were subjected to global I (30 min) and R (60 min) in Langendorff mode. In addition, cardiomyocytes were isolated from treated mice and subjected to 40 min simulated ischemia (SI) and 1 hr or 18 hr reoxygenation (RO) to assess necrosis (by trypan blue staining) or apoptosis (by TUNEL assay), respectively. Diabetes exacerbated ischemic infarct size (measured by tetrazolium chloride staining) in db/db mice as compared to C57 mice (Fig. A), and also enhanced cardiomyocyte necrosis (Fig. B) and apoptosis (Fig. C). Rapamycin treatment reduced infarct size following I/R and protected adult cardiomyocytes against necrosis and apoptosis following SI/RO. Rapamycin also improved post-ischemic contractile function in db/db mice (Fig. D). Western blot analysis revealed a marked increase in phosphorylation of JNK and STAT4 in diabetic hearts, which were reduced in rapamycin-treated diabetic hearts (Fig. E). Conclusion: Rapamycin treatment reduces MI possibly by inhibiting JNK and STAT4 in T2D heart. We propose that inhibition of JNK and STAT4 with rapamycin therapy may be an attractive strategy to improve prognosis in diabetics following MI.
Abstract #3698: Efficacy of MEK inhibitor AS703026 in various primary tumor explants.
Authors: Andreas Machl, Janet Ogden, Angela Romanelli
Journal: Cancer Research (2009)

The Raf/MEK/ERK cascade is a major survival signaling pathway regulating cell proliferation, differentiation and apoptosis. This pathway is known to be deregulated in multiple malignancies including pancreatic, melanoma, and colon cancer as a result of pathway-activating mutations (ie: Ras, Raf, EGFR). AS703026 is a novel and selective small molecule inhibitor of the protein kinase MEK and is currently in Phase I clinical trials. The aim of this study was to profile the anti-tumor activity of AS703026 on a panel of human primary tumor explants, in vitro, using soft agar assays, to evaluate tumor potency and sensitivity to MAPK pathway inhibition and possibly determine potential molecular factors responsible for sensitivity in these tumor types. AS703026 was initially evaluated in vitro using a clonogenic assay on a large panel of human tumor xenografts including colorectal, melanoma, pancreatic, hepatocellular, hematologic, non-small cell lung, small-cell lung, breast, and ovarian cancer. A dose-dependent inhibition of anchorage-independent growth was observed in most of the tumor types tested with a mean IC70 value of 0.47uM for the sensitive tumors. The anti-tumor potency of AS703026 was in the range of or better than several cytotoxic standard chemotherapeutic agents tested in the same tumor panel.The anti-tumor activity of AS703026 was profiled further in an additional \#8220;blinded\#8221; panel of human non-small cell lung, acute myelogenous leukemia (AML), and hepatocellular primary tumor explants, in vitro, using soft agar assays, to evaluate the relationship of EGFR over-expression, K-Ras/B-Raf/EGFR activating mutations, or tumor stage/grade/sub-type with tumor sensitivity to MEK inhibition. This study showed no correlation between tumor stage, grade or tumor subtype and potency of AS703026 in any of the cancers evaluated. A correlation between EGFR expression and sensitivity to AS703026 was seen to a small extent in hepatocellular carcinoma explants. Lastly, a majority of the tumors bearing Ras and Raf mutations, albeit very few, were characterized as some of the most sensitive to growth inhibition with AS703026. Future evaluations on these samples will address whether correlations exist between sensitivity or resistance to AS703026 and PI3K/AKT or STAT pathway activation as well as expression/amplification of various receptor tyrosine kinases.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3698.
Fully human Anti-HER3 monoclonal antibodies (mAbs) have unique in vitro and in vivo functional and antitumor activities versus other HER family inhibitors
Authors: Daniel Freeman, Selam Ogbagabriel, Mike Rothe, Robert Radinsky, Martin Treder
Journal: Cancer Research (2008)

LB-21  Background:  HER3 is a member of the Human Epidermal Growth Factor Receptor (HER) family. HER3 is an essential partner for HER family driven tumorgenesis and recently has been implicated in mediating resistance to EGFR and HER2 inhibitors. Though HER3 lacks intrinsic kinase activity, it contains 6 docking sites for the p85 regulatory subunit of PI3K making it a scaffold for PI3K/AKT signaling for the HER family via heterodimeric interactions. We report uniqueactivities of the first fully human anti-HER3 mAbs vs. current HER family inhibitors. Combinations of HER family inhibitors were also explored.  Methods:  To determine the inhibition of HER3 ligand-induced phosphorylation, MDA MB 453 breast and A549 NSCLC cells were treated with 10 ug/ml of anti-HER3, C225 (anti-EGFR), c2C4 (anti-HER2) or control mAbs 1 hour prior to heregulin-beta (HRG) stimulation. To determine the activity of the anti-HER3 mAbs on anchorage-independent growth, MDA MB 453 cells were treated with 10 μg/ml anti-HER3 or isotype control mAbs in serum containing medium. Colonies were quantified using a Scanalyzer HTS imaging system. To evaluate the effect on HER3 internalization, MDA MB 453 and A549 cells were treated at 4oC with 10 μg/ml of an anti-HER3, anti-EGFR, anti-HER2 or control mAbs prior to incubation for 1 hour at 37oC. HER3 internalization was measured by confocal microscopy. To determine in vivo efficacy, mice bearing ~200 mm3 A549 NSCLC xenografts were treated twice per week with anti-HER family or control Abs. Since HER3 is a critical heterodimerization partner for other HER family members, the anti-tumor effects of single vs. combination mAbs in the Calu-3 and H1975 NSCLC xenograft models were tested.  Results:  Anti-HER3 mAbs inhibited ligand-induced pHER3 of both MDA MB 453 and A549 cells vs other HER family inhibitors. Treatment with anti-HER3 mAbs resulted in > 80% inhibition of MDA MB 453 colony formation; other HER inhibitors had little effect (p  90% reduction of HER3 cell surface expression on MDA MB 453 cells vs other HER family inhibitors or control mAbs. Administration of anti-HER3 mAbs resulted in tumor stasis in the A549 NSCLC xenograft model vs control mAbs, C225 or c2C4. Treatment of Calu-3 and H1975 xenografts with anti-HER3 plus anti-EGFR mAbs resulted in tumor inhibition that was greater than either single agent alone at the doses and schedule used (p
Sequence variants in the alcohol dehydrogenase (ADH) gene family and the risk of upper aerodigestive tract cancers in Central Europe
Authors: Mia Hashibe, James McKay, Paolo Boffetta, David Zaridze, Neonila Szeszenia-Dabrowska, Dana Mates, Vladimir Janout, Eleonora Fabianova, Vladimir Bencko, Rayjean Hung, Paul Brennan
Journal: Cancer Research (2007)

2614  Introduction. Previous studies on alcohol-related cancers have focused on several sequence variants in the ADH gene family such as ADH1B Arg48His and ADH1C Ile350Val. While we have previously reported associations on these polymorphisms and the risk of head and neck cancer, we further investigated whether the other genes in the ADH family may also play a role in cancer susceptibility.  Methods. A case-control study was conducted from 2000 to 2002 in 6 centers from 5 Central European countries: Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT at designated hospitals were recruited (n=775: 156 oral, 109 pharynx, 315 larynx, 169 esophagus). Controls with a recent diagnosis of diseases unrelated to tobacco and alcohol were included (n=1014). Genomic DNA was extracted from blood samples and genotyping was performed by the Taqman assay for tag SNPs in the ADH4, ADH5, ADH6 and ADH7 genes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the risks of UADT cancer overall and for the 4 specific sites (oral, pharynx, larynx, esophagus) for the SNPs. For overall UADT cancer risk, we further stratified by age, smoking status, and alcohol drinking status.  Results. A strong association was observed for ADH7 Ala92Gly (rs1573496), with ORs of 0.56 (95%CI=0.41-0.76) for heterozygotes and 0.10 (95%CI=0.03-0.42) for homozygotes (p for trend  Conclusion. Our results suggest that sequence variants in ADH4-ADH7 also play an important role in head and neck cancer susceptibility. As a next step, we plan to investigate our positive findings in other large-scale multicenter studies on UADT cancers in Western Europe and South America.
Molecular features of hormone-refractory prostate cancer cells by genome-wide gene-expression profiles and identification of novel molecular targets for prostate cancer treatment
Authors: Hidewaki Nakagawa, Kenji Tamura, Su-youn Chung, Motohide Uemura, Mutsuo Furihata, Shingo Ashida, Wataru Obara, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Konaka, Mikio Namiki, Keiichi Tozawa, Kenjiro Kohri, Nozomu Tanji, Masayoshi Yokoyama, Toru Shimai, Hideyuki Akaza, Yoichi Mizutani, Tsuneharu Miki, Tomoaki Fujioka, Taro Shuin, Yusuke Nakamura
Journal: Cancer Research (2007)

1484  One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen-dependent and responds well to androgen ablation therapy. However, at a certain stage they eventually acquire androgen-independent phenotype and show very poor response to any anti-cancer therapies that are presently available. To characterize the molecular features of clinical HRPCs and to identify novel molecular targets for HRPC treatment, we analyzed gene-expression profiles of 25 clinical HRPCs and 10 hormone-sensitive or naive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdisection. An unsupervised clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from individual patients were closely clustered regardless to metastatic organs. A supervised clustering analysis identified 36 up-regulated genes and 70 down-regulated genes in HRPCs, compared with HSPCs (P   1.5). We observed over-expression of AR, ANLN, and SNRPE, and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. Such genes were considered to be related to the androgen-independent and more aggressive phenotype of HRPCs. Furthermore, northern blot or immunohistochemistry validated the expression pattern of several over-expression genes in HRPC cells, and we investigated for their functional significance on cancer cell viability by siRNA. They are promising molecular targets for HRPC treatment, including a kinase and several enzymes. Our precise microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression as well as to identify molecular targets for development of treatment of HRPCs.
Novel Machine Learning Approach to Identify Preoperative Risk Factors Associated With Super-Utilization of Medicare Expenditure Following Surgery
Authors: J. Madison Hyer, Aslam Ejaz, Diamantis I. Tsilimigras, Anghela Z. Paredes, Rittal Mehta, Timothy M. Pawlik
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Typically defined as the top 5% of health care users,<i>super-utilizers</i>are responsible for an estimated 40% to 55% of all health care costs. Little is known about which factors may be associated with increased risk of long-term postoperative super-utilization. <h3>Objective</h3> To identify clusters of patients with distinct constellations of clinical and comorbid patterns who may be associated with an elevated risk of super-utilization in the year following elective surgery. <h3>Design, Setting, and Participants</h3> A retrospective longitudinal cohort study of 1 049 160 patients who underwent abdominal aortic aneurysm repair, coronary artery bypass graft, colectomy, total hip arthroplasty, total knee arthroplasty, or lung resection were identified from the 100% Medicare inpatient and outpatient Standard Analytic Files at all inpatient facilities performing 1 or more of the evaluated surgical procedures from 2013 to 2015. Data from 2012 to 2016 were used to evaluate expenditures in the year preceding and following surgery. Using a machine learning approach known as Logic Forest, comorbidities and interactions of comorbidities that put patients at an increased chance of becoming a super-utilizer were identified. All comorbidities, as defined by the Charlson (range, 0-24) and Elixhauser (range, 0-29) comorbidity indices, were used in the analysis. Higher scores indicated higher comorbidity burden. Data analysis was completed on November 16, 2018. <h3>Main Outcome and Measures</h3> Super-utilization of health care in the year following surgery. <h3>Results</h3> In total, 1 049 160 patients met inclusion criteria and were included in the analytic cohort. Their median (interquartile range) age was 73 (69-78) years, and approximately 40% were male. Super-utilizers comprised 4.8% of the overall cohort (n = 79 746) yet incurred 31.7% of the expenditures. Although the difference in overall expenditures per person between super-utilizers ($4049) and low users ($2148) was relatively modest prior to surgery, the difference in expenditures between super-utilizers ($79 698) vs low users ($2977) was marked in the year following surgery. Risk factors associated with super-utilization of health care included hemiplegia/paraplegia (odds ratio, 5.2; 95% CI, 4.4-6.2), weight loss (odds ratio, 3.5; 95% CI, 2.9-4.2), and congestive heart failure with chronic kidney disease stages I to IV (odds ratio, 3.4; 95% CI, 3.0-3.9). <h3>Conclusions and Relevance</h3> Super-utilizers comprised only a small fraction of the surgical population yet were responsible for a disproportionate amount of Medicare expenditure. Certain subpopulations were associated with super-utilization of health care following surgical intervention despite having lower overall use in the preoperative period.
Mouse Models of Nemaline Myopathy Display Structural and Functional Abnormalities of Mitochondria
Authors: Jennifer Tinklenberg, Rebecca Slick, Mark Mark Vanden Avond, Michael Grzybowski, Emily Siebers, Hui Meng, Margaret Beatka, James Heisner, Jacob Ross, Julien Ochala, Kristen Nowak, Liwen Zhang, Aron Geurts, David Stowe, Federica Montanaro, Michael W. Lawlor
Journal: Molecular Therapy (2019)
Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis
Authors: Hidemi Nakagawa, Osamu Nemoto, Atsuyuki Igarashi, Hidehisa Saeki, Manabu Oda, Kenji Kabashima, Takeshi Nagata
Journal: Journal of Allergy and Clinical Immunology (2019)

Topical delgocitinib (JTE-052), a novel Janus kinase inhibitor, had been shown to be clinically effective in adults with atopic dermatitis (AD). However, the efficacy of topical delgocitinib in pediatric patients with AD remained unclear.We sought to evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.In this phase 2 clinical study (JapicCTI-173553) Japanese patients aged 2 through 15 years with AD were randomized in a 1:1:1 ratio to receive 0.25% or 0.5% delgocitinib ointment or vehicle ointment twice daily for 4 weeks. The primary efficacy end point was the percentage change from baseline in the modified Eczema Area and Severity Index score at the end of treatment (EOT).At EOT, modified Eczema Area and Severity Index scores in both delgocitinib groups were significantly reduced compared with that in the vehicle group. The least-squares mean percentage change from baseline was -54.2% in the 0.25% group and -61.8% in the 0.5% group versus -4.8% in the vehicle group (P < .001 for both comparisons). Similarly, all other efficacy parameters, including Investigator's Global Assessment and pruritus scores, in both delgocitinib groups were significantly improved compared with those in the vehicle group at EOT. Adverse events in both delgocitinib groups were mild in severity, and no serious adverse events were reported.Delgocitinib ointment improved clinical signs and symptoms in pediatric patients with AD and was well tolerated. These study results indicate that delgocitinib ointment can be a promising therapeutic option for pediatric patients with AD.
A phase I trial using patupilone (epothilone B) and concurrent radiotherapy for CNS malignancies
Authors: S. E. Fogh, M. Machtay, M. Werner-Wasik, W. Curran, R. Bonanni, G. Mallon, R. Axelrod, D. Andrews, A. Dicker
Journal: Journal of Clinical Oncology (2009)

e14504 Background: Based on pre-clinical data indicating the radiosensitizing potential of Epothilone B, this study was designed to evaluate the toxicity and response rate of patupilone (EPO906), an anti-microtubule stabilizing agent, with concurrent radiotherapy in the treatment of patients with CNS malignancies. Methods: This phase I study evaluated the toxicities associated with patupilone in combination with radiotherapy for the treatment of CNS malignancies in order to establish maximum tolerated dose (MTD). Eligible patients had recurrent gliomas (10), primary (5), or metastatic (17) brain tumors. Dose escalation occurred if no dose limiting toxicities (DLT) defined as any Grade 4–5 toxicity or Grade 3 toxicity requiring hospitalization or interruption of radiation therapy. Results: A total of 32 patients were enrolled. Five patients were treated with weekly patupilone at 1.5 mg/m 2 , 4 patients at 2.0 mg/m 2 , 4 patients at 2.5 mg/m 2 and one patient at 4mg/m 2 . Based on sponsor recommendations, the protocol was changed to a q-3 week dosing schedule with a starting dose of 6 mg/m 2 . Seven patients were treated in the 6 mg/m 2 group, 6 patients in the 8 mg/m 2 cohort and 5 patients in the 10 mg/m 2 group. Radiation treatment was determined by the patient's diagnosis. Primary CNS malignancies received a median dose of 60 Gy in 1.8–2.0 Gy fractions. CNS metastases received whole brain radiation with a median dose of 37.4 Gy in 1.8–2.5 Gy fractions and patients with recurrent gliomas received stereotactic radiotherapy with a median dose of 37.5 Gy in 2.0–3.5 Gy fractions. No DLTs were observed in patients who received weekly patupilone or in the 6 mg/m 2 q3wk cohort. One DLT (pneumonia/infection without neutropenia) was observed at the 8 mg/m 2 q3wk group. In the subsequent dose level (10 mg/m 2 ), two grade 4 DLTs occurred (renal failure and pulmonary hemorrhage) making 8 mg/m 2 q3wk the MTD and recommended phase II dose. Median overall survival was 12 months for recurrent gliomas, 15 months for primary brain tumors and 4 months for CNS metastasis. Conclusions: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone is well tolerated and safe with a MTD of 8 mg/m 2 q3wk. A phase II study to characterize efficacy should be considered. No significant financial relationships to disclose.
Prediction of Coronary Revascularization in Stable Angina
Authors: Niels Peter Rønnow Sand, Louise Nissen, Simon Winther, Steffen E. Petersen, Jelmer Westra, Evald H. Christiansen, Pia Larsen, Niels R. Holm, Christin Isaksen, Grazina Urbonaviciene, Lone Deibjerg, Majed Husain, Kristian K. Thomsen, Allan Rohold, Hans Erik Bøtker, Morten Bøttcher
Journal: JACC. Cardiovascular imaging (2019)

This study was designed to compare head-to-head fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) (FFRCT) and cardiac magnetic resonance (CMR) stress perfusion imaging for prediction of standard-of-care-guided coronary revascularization in patients with stable chest pain and obstructive coronary artery disease by coronary CTA.FFRCT is a novel modality for noninvasive functional testing. The clinical utility of FFRCT compared to CMR stress perfusion imaging in symptomatic patients with coronary artery disease is unknown.Prospective study of patients (n = 110) with stable angina pectoris and 1 or more coronary stenosis ≥50% by coronary CTA. All patients underwent invasive coronary angiography. Revascularization was FFR-guided in stenoses ranging from 30% to 90%. FFRCT ≤0.80 in 1 or more coronary artery or a reversible perfusion defect (≥2 segments) by CMR categorized patients with ischemia. FFRCT and CMR were analyzed by core laboratories blinded for patient management.A total of 38 patients (35%) underwent revascularization. Per-patient diagnostic performance for identifying standard-of-care-guided revascularization, (95% confidence interval) yielded a sensitivity of 97% (86% to 100%) for FFRCT versus 47% (31% to 64%) for CMR, p < 0.001; corresponding specificity was 42% (30% to 54%) versus 88% (78% to 94%), p < 0.001; negative predictive value of 97% (91% to 100%) versus 76% (67% to 85%), p < 0.05; positive predictive value of 47% (36% to 58%) versus 67% (49% to 84%), p < 0.05; and accuracy of 61% (51% to 70%) versus 74% (64% to 82%), p > 0.05, respectively.In patients with stable chest pain referred to invasive coronary angiography based on coronary CTA, FFRCT and CMR yielded similar overall diagnostic accuracy. Sensitivity for prediction of revascularization was highest for FFRCT, whereas specificity was highest for CMR.