tbuckley/cabot-search huggingface dataset:
Abstract 83: β1 Vs β2 Adrenergic Signaling Differentially Regulates Mitochondrial Dynamics Through Alterations In Calcineurin And Drp1
Authors: Michael Coronado, Giovanni Fajardo, Mingming Zhao, Dongquing Hu, Aleksandr Stotland, Sushma Reddy, Roberta Gottlieb, Daniel Bernstein
Journal: Circulation Research (2014)

Signal transduction through β1 and β2-adrenergic receptors (ARs) is considered a primary mechanism for regulating cardiovascular function and remodeling. Upon β-AR activation (i.e., physical activity, cardiac pathology) inotropy and chonotropy increase and mitochondria must quickly meet increased energy demand. This suggests that βARs and mitochondria are coupled mechanistically to rapidly respond to the functional and energetic needs of the heart. To investigate the role of β1 vs. β2-AR signaling on mitochondrial dynamics, we compared β1-/- and β2-/- to WT controls. β2-/- had increased mitochondrial fragmentation (increased number and decreased size) by electron microscopy vs. both WT and β1-/-. β2-/- showed altered regulation of mitochondrial fission: increased Drp1 translocation to the mitochondria vs. WT, whereas β1-/- had lower Drp1 translocation. These data suggest differential regulation of fission by βAR signaling, β1 activating and β2 suppressing fission. Since Ca2+-dependent calcineurin is known to activate Drp1 and [Ca2+]i is differentially regulated by β-AR signaling, we examined calcineurin as the bridge between β-AR signaling and Drp1 activation. In β2-/-, both Ca2+ transients and calcineurin activity were increased, suggesting β1-AR/Ca2+/calcinurin-mediated fission. To quantify mitochondrial fragmentation and biogenesis, mitotimer-transfected C2C12 cells were treated with the non-specific β-AR agonist isoproterenol resulting in mitochondrial fragmentation that was inhibited by the β1-antagonist CGP 12177 but not by the ß2-antagonist ICI 118551. Taken together, our data indicate that β1 and β2-AR signaling differentially regulate mitochondrial dynamics in the heart through alterations in [Ca2+]i, leading to calcineurin-induced translocation of Drp1.
Safety and Efficacy of Panitumumab (Pmab) Monotherapy in Recurrent or Progressive Metastatic Colorectal Cancer (Mcrc): Results from a Non-Interventional Study (Vectis)
Authors: R. Lakomy, W. Rogowski, B. Pikó, Z. Mihaylova, E. Pritzova, L. Kvocekova
Journal: Annals of Oncology (2014)
Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention
Authors: Michelle L. O’Donoghue, Deepak L. Bhatt, Gregg W. Stone, Ph. Gabriel Steg, C. Michael Gibson, Christian W. Hamm, Matthew J. Price, Jayne Prats, Tiepu Liu, Efthymios N. Deliargyris, Kenneth W. Mahaffey, Harvey D. White, Robert A. Harrington
Journal: Circulation (2016)

Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed.The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26).In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.
Single agent oral vinorelbine (NVB) in advanced non-small cell lung cancer (NSCLC) in the elderly: Patient benefit improvement by weekly schedule
Authors: P. Mali, F. De Marinis, C. Manegold, O. Castelnau, M. Pless, J.-C. Pouget, D. Aubert, J.-P. Burillon, C. Gridelli
Journal: Journal of Clinical Oncology (2004)

7120 Background:Single agent IV NVB has proven its effectiveness in elderly NSCLC pts with reduced toxicity. IV and oral NVB formulation have proven comparable bioavailability. This phase II was conducted with oral NVB to evaluate efficacy/tolerability. Methods:Pts to be recruited were ≥70y with unresectable localised or metastatic NSCLC. Oral NVB was given weekly 60mg/m2x3 weeks/1 cy and then escalated to 80mg/m2 if no G4 or no more than 2 G3 neutropenia during 1stcy. At 80mg/m2, if 1 G4 or 2 consecutive G3 neutropenia occurred, dose was reduced to 60mg/m2.Treatment given up to progression. Primary endpoint was response rate (OR) with secondary endpoints being time dependant parameters and clinical benefit evaluation taking into account 6 lung cancer symptoms evaluation by visual analogic scales, weight and PS changes. Results:56 pts were recruited in 11 European centres. Median age was 74y (70–82), 75% were male with a KPS of 80 in 48%, others being 90/100. 43 pts (76.8%) were metastatic at inclusion. Co-morbidities were present in 87.5% of pts with 18% having ≥3. Median dose intensity (DI) was 46.5mg/m2/w with RDI of 65%. 66.7% pts receiving 2d cy were escalated to 80mg/m2. In ITT/evaluable pts, 6 PR (10.7/12.8%) and 25 SD (disease control=55.4/66%) were reported. Response duration was 5.2m, PFS 3.7m and MS 8.2m. 92 doses (73%) were skipped due to haematological toxicity, mostly G3/4 neutropenia in 61cy (30.8%) and leucopenia in 43cy (21.5%); 2 febrile neutropenia were recorded in 1 patient. G3 non-haematological toxicities were fatigue (4%cy), nausea (2.5%cy), diarrhea (1.5%cy). 1 pt had a G4 thrombosis (0.5%). Regarding clinical benefit, improvement was clear for chest pain, cough and dyspnea. Fatigue, appetite and hemoptysis remained stable or slightly decreased. Weight remained stable. On 32 evaluable pts, the clinical benefit response rate was 31.25%. Conclusions:Oral NVB given as a weekly monotherapy was easy to administer and well tolerated, offering an optimal disease control in this elderly NSCLC population leading to a favorable activity /toxicity ratio associated with a clinical benefit. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre Glaxo Institut de Recherche Pierre Fabre
Using the American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria to determine the diagnosis of systemic lupus erythematosus (SLE) in patients with subacute cutaneous lupus erythematosus (SCLE)
Authors: Janice Tiao, Rui Feng, Kasey Carr, Joyce Okawa, Victoria P. Werth
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 10604: Diastolic Function in Normal Sinus Rhythm vs. Chronic Atrial Fibrillation: Quantitative Comparison by Fractionation of E-wave Deceleration Time into Stiffness and Relaxation Components
Authors: Sina Mossahebi, Sandor Kovacs
Journal: Circulation (2013)

Atrial fibrillation (AF) is the most common pathologic cardiac arrhythmia. Although the electro-physiologic mechanism of AF has been characterized, the diastolic function (DF) consequences of AF in...
Cell Killing and Kinetic Effects of Diglycolaldehyde on Dividing and Nondividing Mammalian Cells In Vitro2
Authors: S. C. Barranco, D. R. Flournoy, W. E. Bolton, M. S. Oka
Journal: JNCI Journal of the National Cancer Institute (1978)

The effects of the anticancer drug diglycolaldehyde (NSC-118994) were studied on Chinese hamster ovary cells growing in vitro. Dividing cells, specifically those in S-phase, were more sensitive to the drug than were nondividing cells, although a large fraction of nondividing cells was also killed by doses up to 800 μg/ml. Dose-dependent effects on cell progression kinetics were observed In all phases of the cell cycle except In mitosis, during which treated cells progressed at control rates Into G1-phase. The Inhibition of cell progression from G1- into S-phase (most sensitive phase of the cell cycle) put self-limiting restrictions on the cell killing effects of the drug.
Abstract 17580: Reduced Fibrin Clot Permeability During Acute Phase of Myocardial Infarction is Associated with Increased Area of Microvascular Obstruction
Authors: Jaroslaw Zalewski, Anetta Undas, Piotr Lech, Monika Durak, Jadwiga Nessler, Krzysztof Zmudka
Journal: Circulation (2012)

Background: The epicardial pro-thrombotic environment and myocardial edema are primary reasons of perfusion deterioration during acute phase of ST-segment elevation myocardial infarction (STEMI) bu...
The effect of anastrozole on bone mineral density during the first 5 years of adjuvant treatment in postmenopausal women with early breast cancer.
Authors: Hiroaki Inoue, Akira Hirano, Kaoru Ogura, Akinori Hattori, Mari Kamimura, Fumie Okubo, Jun Kinoshita, Kiyomi Kimura, Tadao Shimizu
Journal: Journal of Clinical Oncology (2013)

e11604 Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. We assessed changes in bone mineral density (BMD) from baseline to 60 months of treatment in patients receiving anastrozole (ANA) as initial adjuvant therapy with/without oral bisphosphonates (Bis). Methods: Postmenopausal women with endocrine responsive breast cancer receiving ANA as adjuvant therapy at our hospital since 2004 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48 and 60 months. Oral Bis (risedronate or alendronate) treatment was initiated when patients were diagnosed as having osteoporosis with a T-score of -2.5 or lower. Results: Fifty-seven patients were enrolled in the study between 2004 and 2011. Patients’ median age was 65 years (range 50~85) and the median follow-up period was 46.3 months (9.6~83.8). Thirty-five patients were administered Bis (risedronate in 27 patients, alendronate in 8 patients). Within 6 months of hormone therapy, BMD decreased by 0.3% from baseline at the lumbar spine and BMD decreased by 1.2% at the femoral neck. However, BMD increased by 2.8% at the lumbar spine and BMD decreased 0.5% at the femoral neck for 60 months of treatment. In patients treated with upfront Bis (n=24), 4.9% BMD increase from baseline was noted at the lumbar spine whereas in those without Bis (n=20) BMD decreased by 4.6% from baseline within 24 months (p=0.0002). Fractures were observed in 4 patients (7.0%), and 1 patient (1.8%) had fragility fracture. Conclusions: Oral Bis prevented ANA-induced bone loss, and upfront treatment of Bis significantly increased BMD at the lumber spine.
Efficacy, effectiveness and safety of fumaric acid esters in the treatment of psoriasis: a systematic review of randomized and observational studies
Authors: D.M.W. Balak, S. Fallah Arani, E. Hajdarbegovic, C.A.F. Hagemans, W.M. Bramer, H.B. Thio, H.A.M. Neumann
Journal: British Journal of Dermatology (2016)

Fumaric acid esters (FAEs) are increasingly used as a systemic treatment for psoriasis, but there are still uncertainties regarding their suitability. The objective of this systematic review was to assess the evidence for the efficacy and safety of FAEs in psoriasis treatment. A systematic literature search was performed in seven databases up to 17 August 2015. Inclusion criteria were studies that reported clinical effects of FAEs in patients with psoriasis without restrictions in study design, language or publication date. Methodological quality of randomized controlled trials (RCTs) and overall level of quality were assessed using the Cochrane risk of bias tool and the Grading of Recommendation, Assessment, Development and Evaluation approach, respectively. A total of 68 articles were included. There were seven RCTs (total 449 patients) that had an unclear risk of bias and were too clinically heterogeneous to allow a meta‐analysis. Overall, mean Psoriasis Area and Severity Index decreased by 42–65% following 12–16 weeks of treatment. There were 37 observational studies (a total of 3457 patients) that supported the RCT findings, but most were uncontrolled with a high risk of bias. Commonly reported adverse events included gastrointestinal complaints and flushing, leading to treatment withdrawal in 6–40% of patients. Several case‐reports described rare adverse events, such as renal Fanconi syndrome and progressive multifocal leukoencephalopathy. There was a lack of studies focusing on long‐term use and comparisons with other treatments. This review concluded that there is low‐quality evidence to recommend the use of oral FAEs to treat plaque psoriasis in adult patients. Studies focusing on long‐term safety and comparison with systemic psoriasis treatments could lead to a better understanding of the role of FAEs as a treatment for psoriasis.
Gene Duplication of Zebrafish JAK2 Homologs Is Accompanied by Divergent Embryonic Expression Patterns: Only jak2a Is Expressed During Erythropoiesis
Authors: Andrew C. Oates, Alison Brownlie, Stephen J. Pratt, Danielle V. Irvine, Eric C. Liao, Barry H. Paw, Kristen J. Dorian, Stephen L. Johnson, John H. Postlethwait, Leonard I. Zon, Andrew F. Wilks
Journal: Blood (1999)
Screening for Lung Cancer: No Longer a Taboo Subject
Authors: James R. Jett
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.8.1959 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11956250 Screening for Lung Cancer: No Longer a Taboo Subject James R. JettxJames R. JettSearch for articles by this author Show More Mayo Clinic, Rochester, MN https://doi.org/10.1200/JCO.2002.20.8.1959 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for solid tumors
Authors: S. Alici, O. Alici, M. Izmirli, H. Tunahan, F. Gercik, H. Begenik
Journal: Journal of Clinical Oncology (2007)

19611 Background: Hepatitis virus infection through virus reactivation has a high risk of mortality in patients with solid malignancies receiving chemotherapy. Methods: We examined the incidence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and severe liver dysfunction (alanine aminotransferase &gt;ten times the normal upper limit and total bilirubin &gt;5 mg/dl) during chemotherapy in 171 patients with solid tumor. Results: Six patients (3.5%) were infected with HCV and 17 patients (9.9%) were infected with HBV. One patients (0.5%) were infected with both HCV and HCV. There were severe liver dysfunction in 29 (16.9%) all patients. HCV- or HBV-infected patients showed severe liver dysfunction at a significantly higher incidence than non-infected patients (7/22 (31%) vs. 18/149 (12%), p&lt;0.047). Furthermore, the incidence of severe liver dysfunction in HCV-infected patients was significantly higher than in HBV- infected patients (6/8 (75.0%) vs. 18/149 (18.2%), p&lt;0.01). Three of eight HBV infected patients were initially negative for hepatitis B surface antigen (HBsAg) by latex agglutination and became positive for HBsAg during chemotherapy. Furthermore, all three patients developed severe liver dysfunction and two developed fatal fulminant hepatitis. From an examination of the original stock of serum samples before chemotherapy, two patients were found to be positive for HBV-DNA by polymerase chain reaction (PCR). Although post-transfusion HBV infection was suspected in the one remaining patient, the cause of HBV infection could not be clarified due to the impossibility of examination in blood donors. Conclusions: Since HBV-infected patients develop severe liver dysfunction at a higher incidence than either patients not infected with virus or HCV-infected patients before chemotherapy for hematological malignancies, it is recommended that HBV- DNA should be tested by PCR to detect HBV marker-negative carriers and liver function tests should be carefully monitored. No significant financial relationships to disclose.
Patient-derived bladder cancer xenografts as a platform for drug development in bladder cancer.
Authors: Amy Wang Pan, Hongyong Zhang, Tzu-yin Lin, Yuanpei Li, Tianhong Li, James Keck, Clifford Tepper, Susan D. Airhart, Edison T. Liu, Chong-xian Pan, Ralph de Vere White, Kit S. Lam
Journal: Journal of Clinical Oncology (2015)

e15528 Background: The goal of this project is to develop and characterize a bladder cancer patient-derived xenograft (PDX) platform, and use this platform to determine the efficacy of bladder cancer-specific targeting PLZ4-nanotheranostics (PNT) in targeted chemotherapy, photodynamic diagnosis and therapy. Methods: Bladder cancer PDXs were developed through direct inoculation of patient cancer specimens subcutaneously in immunodeficient NSG mice. Morphological examination, exome and transcriptome sequencing were performed to molecularly characterize PDXs. PNT was synthesized through conjugating nanotheranostic particles with a bladder cancer-targeting ligand named PLZ4 on the surface, and loaded with therapeutic and/or imaging agents in the core. Results: Twenty-two bladder cancer PDXs have been established with annotated clinical information. PDXs maintained morphological fidelity and over 90% of genetic alterations of parental patient cancers. After intravenous administration, PNT could deliver the drug load specifically to the bladder cancer PDXs, but not to lung cancer xenografts in the same mice. PNT loaded with paclitaxel allowed administration of three times the therapeutic dose without increasing the toxicity, could overcame cisplatin resistance and prolong the overall survival of mice carrying PDXs from 27 days with free paclitaxel to 76 days (p < 0.001). Porphyrin-based PNT could specifically target bladder cancer cells for photodynamic diagnosis more than 30 times than that to adjacent normal urothelial cells in an orthotopic PDX model (p < 0.001), compared to only 2-3 time with the historical control of 5-aminolevulinic acid (5-ALA). Photodynamic therapy with porphyrin-PNT was more than 100 times more potent than 5-ALA (P < 0.001), and could eliminate bladder cancer in an orthotopic PDX bladder cancer model (p < 0.001). Conclusions: PNT can potentially be used for targeted delivery of chemotherapy, photodynamic diagnosis and therapy in bladder cancer. A Phase I trial of PNT loaded with paclitaxel for intravesical instillation to treat BCG-refractory bladder cancer; and a clinical trial of porphyrin-PNT for photodynamic diagnosis and therapy in dog bladder cancer have both been funded.
Biomarker changes associated with the development of resistance to aromatase inhibitors (AIs) in ER-positive breast cancer.
Authors: M. Arnedos, S. Drury, M. Afentakis, M. Hills, J. Salter, I. E. Smith, M. Dowsett
Journal: Journal of Clinical Oncology (2010)

1034 Background: Development of resistance to third-generation AIs is an important problem in ER+ve breast cancer. Several mechanisms have been identified in vitro (e.g., loss of ER expression, activation of signaling pathways independent of ER and acquisition of ER hypersensitivity), but there are no clinical data to support these. The aim of this study was to determine changes in key biomarkers expression (ER, PgR, HER2, and Ki67) in patients who had developed resistance to an AI treatment for ER+ve breast cancer. Methods: Patients with ER+ve breast cancer who had relapsed or progressed while on an AI for whom pathological material was available pre- and post- treatment were identified from the Royal Marsden Hospital database. IHC for ER, PgR, HER2, and Ki67 was performed. ER and PgR were scored by histoscore, Ki67 as % of cells positive and HER2 was scored following CAP/ASCO guidelines (HER2-positive if IHC=3+ ± FISH ratio ≥ 2.20). Results: 43 paired samples were identified. 56% patients received AI in the advanced setting; 44% relapsed on adjuvant AI. Median treatment duration was 21 months (1 to 102). There was no significant change in ER H-score, although 6 patients (14%) became ER-ve at progression on AI. PgR score decreased significantly (p=0.0016). 28 (65%) and 15 (35%) were PgR+ve pretreatment and at progression respectively. PgR+ve recurrences suggest re-establishment of estrogen signaling despite continued AI. In 6 (14%) cases PgR showed increased expression suggesting a possible acquisition of hypersensitivity. Ki67 levels were higher at progression (mean 10.4 vs. 16.7%, p<0.005) and inversely associated with ER levels (p<0.005). This association was due to high Ki67 of ER-ve lesions. Post-AI Ki67 levels were associated with time to treatment failure (p<0.05). No significant changes were observed in HER2 status. Conclusions: Most, but not all, tumors retain ER expression on acquisition of AI resistance. PgR positivity suggests persistent activation of ER pathways. Recurrent ER-ve tumors have a worse prognosis. Investigations are underway to identify potential driver mechanisms. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Novartis, Pfizer Novartis