tbuckley/cabot-search huggingface dataset:
First in human phase I trial of the PARP inhibitor AG-014699 with temozolomide (TMZ) in patients (pts) with advanced solid tumors
Authors: R. Plummer, M. Middleton, R. Wilson, C. Jones, J. Evans, L. Robson, H. Steinfeldt, R. Kaufman, S. Reich, A. H. Calvert
Journal: Journal of Clinical Oncology (2005)

3065 Background: AG-014699 inhibits poly(ADP-ribose) polymerase (PARP) is a key enzyme in DNA repair. AG-014699 sensitizes cancer cells to DNA damaging drugs such as TMZ. AG-014699 is the first PARP inhibitor to be evaluated in cancer patients. Methods: In part 1 of the study, pts with solid tumors received AG-014699 + TMZ daily x 5 every 28 days. TMZ dose was half of standard (100 mg/m2 po) and AG-014699 (30 min infusion) was escalated up to the PARP-inhibitory dose (PID) as determined by PARP activity in peripheral blood lymphocytes (PBLs). We defined PID as maximal (at least >50%) reduction in PARP activity 24 hr after AG-014699. In part 2, AG-014699 dose was fixed at PID and TMZ was escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma pts. Endpoints included safety, efficacy, PK and tumor PARP activity (obligatory in part 2). Overall objective based on xenograft data was to achieve > 40% PARP inhibition in tumor. Results: 27 pts enrolled, safety data available on first 18. In part 1, AG-014699 dose levels in 18 pts were 1, 2, 4, 8 and 12 mg/m2. No dose-limiting toxicity (DLT) was observed. All related events were grade (gr) 1/2, except 1 case each of gr 3 infection, fatigue, low phosphate and lymphopenia. PID was 12 mg/m2 based on 74 -97% inhibition of PBL PARP activity. PK evaluation for AG-014699 alone after 2 - 12 mg/m2 shows mean terminal T\(\frac{1}{2}\) = 7.4 - 11.7 hr, clearance = 25 L/hr, and linear dose proportionality for AUC and Cmax. AG-014699 did not affect TMZ PK compared to historical data. Two durable partial responses (15+, 9+ mo) occurred (GIST, melanoma). In part 2, no DLT was seen in 9 pts up to 200 mg/m2 TMZ. Median tumor PARP inhibition at 5 hours was 90% (range 50 - 98%). Conclusions: Doses up to 12 mg/m2 AG-014699 and 200 mg/m2 TMZ are safe and significantly inhibit PBL and tumor PARP. One further dose level (AG-014699 18 mg/m2, TMZ 200 mg/m2) will be tested to maximize tumor PARP inhibition. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer, Schering-Plough Pfizer Schering-Plough Pfizer, Schering-Plough Pfizer
A Prospective Controlled Trial on Effect of Percutaneous Transluminal Angioplasty on Functioning Arteriovenous Fistulae Survival
Authors: Nicola Tessitore, Giancarlo Mansueto, Valeria Bedogna, Giovanni Lipari, Albino Poli, Linda Gammaro, Elda Baggio, Giovanni Morana, Carmelo Loschiavo, Alessandro Laudon, Lamberto Oldrizzi, Giuseppe Maschio
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Balloon angioplasty (PTA) is an established treatment modality for stenosis in dysfunctional arteriovenous fistulae (AVF), although most studies showing efficacy have been retrospective, uncontrolled, and nonrandomized. In addition, it is unknown whether correction of stenosis not associated with significant hemodynamic, functional, and clinical abnormality may improve survival in AVF. This study was a prospective controlled open trial to evaluate whether prophylactic PTA of stenosis not associated with access dysfunction improves survival in native, virgin, radiocephalic forearm AVF. Sixty-two stenotic, functioning AVF, <i>i.e.</i>, able to provide adequate dialysis, were enrolled in the study: 30 were allocated to control and 32 to PTA. End points of the study were either AVF thrombosis or surgical revision due to reduction in delivered dialysis dose. Kaplan-Meier analysis showed that PTA improved AVF functional failure-free survival rates (<i>P</i> = 0.012) with a fourfold increase in median survival and a 2.87-fold decrease in risk of failure. Cox proportional hazard model identified PTA as the only variable associated with outcome (<i>P</i> = 0.012). PTA induced an increase in access blood flow rate (Qa) by 323 (236 to 445) ml/min (<i>P</i> &lt; 0.001), suggesting that improved AVF survival is the result of increased Qa. PTA was also associated with a significant decrease in access-related morbidity by approximately halving the risk of hospitalization, central venous catheterization, and thrombectomy (<i>P</i> &lt; 0.05). This study shows that prophylactic PTA of stenosis in functioning forearm AVF improves access survival and decreases access-related morbidity, supporting the usefulness of preventive correction of stenosis before the development of access dysfunction. It also strongly supports surveillance program for early detection of stenosis. E-mail: nicola.tessitore@mail.azosp.vr.it
Endocardial excision: a new surgical technique for the treatment of recurrent ventricular tachycardia.
Authors: M E Josephson, A H Harken, L N Horowitz
Journal: Circulation (1979)

Twelve patients with medically refractory ventricular tachycardia secondary to ischemic heart disease underwent surgery for cure of their arrhythmia. Preoperatively, the tachycardia could be reproducibly initiated and terminated in each patient by programmed stimulation. In all instances, intraoperative mapping localized the tachycardia to the border of the aneurysm, a site not routinely resected during aneurysmectomy. In nine instances, the area of origin involved the septum. During bypass the tachycardia could still be induced after standard aneurysmectomy or ventriculotomy in 11 of 12 patients. On the basis of intraoperative mapping, resection of endocardium in the area of origin (25--40% the circumference of the aneurysmectomy) up to normal muscle was performed. In one patient without a discrete aneurysm, endocardial excision alone through a ventriculotomy was performed. There was one operative death due to cardiogenic shock (preoperative ejection fraction 5%) and one late death due to rupture of a mycotic aneurysm in the pulmonary artery. Before discharge, all patients underwent a repeat relectrophysiologic study off antiarrhythmic agents and in none could ventricular tachycardia be initiated. Hemodynamic and angiographic catheterization showed improved hemodynamics and ejection fractions in all. The 10 survivors remained free of sustained ventricular tachycardia for 9--20 months, with one late nonarrhythmic death.
Gastrin activates nuclear factor kappaB (NFkappaB) through a protein kinase C dependent pathway involving NFkappaB inducing kinase, inhibitor kappaB (IkappaB) kinase, and tumour necrosis factor receptor associated factor 6 (TRAF6) in MKN-28 cells transfected with gastrin receptor
Authors: M Ogasa
Journal: Gut (2003)

<b>Background:</b> We previously reported that gastrin induces expression of CXC chemokines through activation of nuclear factor κB (NFκB) in gastric epithelial cells that express gastrin receptor. <b>Aims:</b> To clarify gastrin receptor mediated signals leading to activation of NFκB. <b>Methods:</b> MKGR26 cells were created by transfecting gastrin receptor cDNA into MKN-28 cells. Degradation of inhibitor κB (IκB) and phosphorylation of protein kinase C (PKC)-δ were both detected by western blot analysis. NFκB activation was determined by luciferase assay and electrophoretic mobility shift analysis. <b>Results:</b> Gastrin induced degradation of IκB-α and activation of NFκB, which was abolished by the selective gastrin receptor antagonist L-740,093 and the general PKC inhibitor GF109203X. Gastrin induced phosphorylation of PKC-δ, and its inhibitor rottlerin partially suppressed NFκB activation. However, the mitogen activated protein kinase (MAPK) kinase inhibitor PD98059, p38 MAPK inhibitor SB203580, and tyrphostin AG1478 had no effect on NFκB activation. Introduction of the dominant negative mutant of IκB kinase, of NFκB inducing kinase, and of tumour necrosis factor receptor associated factor 6 (TRAF6), but not that of TRAF2, inhibited gastrin induced activation of NFκB. <b>Conclusions:</b> Gastrin activates NFκB via a PKC dependent pathway which involves IκB kinase, NFκB inducing kinase, and TRAF6.
An Amphioxus Emx Homeobox Gene Reveals Duplication During Vertebrate Evolution
Authors: Nic A. Williams, Peter W. H. Holland
Journal: Molecular Biology and Evolution (2000)

Members of the Emx homeobox gene class are expressed during embryogenesis in the brain and/or other head structures of phylogenetically diverse phyla. Here, we describe sequence, genomic structure, and molecular phylogenetic analysis of a cephalochordate (amphioxus) Emx class gene termed AmphiEmxA. The genomic structure of AmphiEmxA is very similar to that of vertebrate Emx genes, with two conserved intron sites. The Drosophila homolog empty spiracles (ems) has just one intron, which may be shared with chordates; the other has been secondarily lost in this Drosophila gene and in a cnidarian Emx-related gene. We identify a highly conserved peptide motif close to the amino terminus of Emx proteins, demonstrate its similarity to a sequence found in a variety of transcription factors, and argue that it arose through convergent evolution in homeobox and forkhead genes. Finally, our molecular phylogenetic analysis strongly supports the presence of a single Emx gene in the ancestor of chordates and gene duplication along the vertebrate lineage.
Significance of precipitins and asymptomatic lymphocytic alveolitis: a 20‐yr follow-up
Authors: Y. Cormier, L. Létourneau, G. Racine
Journal: European Respiratory Journal (2004)

What is the significance of serum preciptins and lymphocytic alveolitis in a healthy subject exposed to antigens responsible for hypersensitivity pneumonitis (HP)? This study was done to evaluate the 20‐yr outcome of asymptomatic dairy farmers with or without precipitins or lymphocytic alveolitis in their bronchoalveolar lavage (BAL). Twenty-seven of the initial 43 farmers were restudied. Of the missing 16, 11 refused the follow-up, three had died and two could not be located. The restudied farmers had a clinical evaluation, lung function tests and a high resolution computed tomography (HRCT). Only one subject, an asthmatic, had dyspnoea, none described present or past symptoms suggestive of HP. Of those who were no longer on the farm, none had quit because of respiratory problems. Lung function changes were as expected with aging. The only difference was that farmers with positive precipitins had a statistically significant greater decrease in their forced expiratory volume in one second than the sero-negative farmers. Four HRCTs showed signs of minimal parenchymal abnormalities; these were not more prevalent for subjects with or without precipitins or BAL lymphocytosis. Serum precipitins and asymptomatic lymphocytic alveolitis in an asymptomatic, exposed dairy farmer have no clinically meaningful long-term consequences.
Prevalence of deliberate self harm and attempted suicide within contemporary Goth youth subculture: longitudinal cohort study
Authors: Robert Young, Helen Sweeting, Patrick West
Journal: BMJ (2006)

To investigate whether deliberate self harm is associated with contemporary Goth youth subculture.Longitudinal cohort study.School and community based study of young people living in the Central Clydeside Conurbation, Scotland.1258 people aged 19, surveyed in 2002-4 and followed-up since age 11 (1994).Lifetime prevalence of self harm and attempted suicide and their association with Goth youth subculture, before and after adjusting for confounders.Identification as belonging to the Goth subculture was strongly associated with lifetime self harm and attempted suicide, with a prevalence of 53% and 47%, respectively among the most highly identified group, and evidence for a dose-response relation. Adjusting for potential confounders did not significantly attenuate this association. Analysis of other youth subcultures showed that this effect was primarily associated with Goth subculture.Identification as belonging to the Goth subculture was the best predictor of self harm and attempted suicide. Although based on small numbers, additional longitudinal analysis suggests both selection and modelling mechanisms are involved, selection mechanisms possibly being more likely.
Pegylated liposomal doxorubicin (doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2
Authors: T. Safra, F. Muggia, S. Jeffers, D.D. Tsao-Wei, S. Groshen, O. Lyass, R. Henderson, G. Berry, A. Gabizon
Journal: Annals of Oncology (2000)
Prognostic Value of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Imaging in Patients With Advanced-Stage Non–Small-Cell Lung Carcinoma
Authors: Jenny K. Hoang, Luke F. Hoagland, R. Edward Coleman, April D. Coan, James E. Herndon, Edward F. Patz
Journal: Journal of Clinical Oncology (2008)

To determine whether the amount of fluorine-18 fluorodeoxyglucose (FDG) uptake in the primary lung cancer on positron emission tomography (PET) imaging at the time of presentation has prognostic significance in patients with advanced-stage non-small-cell lung cancer (NSCLC).A retrospective review identified 214 patients with advanced-stage NSCLC (stage IIIA, IIIB, and IV) who underwent FDG PET study at the time of diagnosis. Extensive clinical data, including tumor histologic cell type, pathologic stage at presentation, and treatment, were recorded. The maximum standardized uptake value (SUV(max)) in the primary tumor on FDG PET on survival was examined using Cox proportional hazards regression.One hundred fifty-eight (74%) of the 214 patients died and 56 patients were reported alive at 27 months (range, 3 to 140 months) after the diagnosis of NSCLC. Using the median SUV(max) of 11.1, the patient population was subdivided. The median survival of the 106 patients with the primary tumor having an SUV(max) less than 11.1 was 16 months (95% CI, 12 to 21 months), whereas the median survival of the 108 patients with the primary tumor having an SUV(max) > or = 11.1 was 12 months (95% CI, 10 to 15 months). Univariate and multivariate analysis did not provide evidence that survival for patient subgroups defined by the median SUV(max) were significantly different (univariate P = .11; multivariate P = .45).FDG uptake of the primary lesions in patients with a new diagnosis of advanced-stage NSCLC does not have a significant relationship with survival.
Hereditary Angioedema Without C1 Inhibitor Deficiency: Clinical Evaluation Of 67 Brazilian Patients
Authors: Elisabete Cordeiro, Camila Veronez, Christiane Stieber, Nathalia Cagini, Rosemeire Constantino-Silva, Rozana Gonçalves, Gustavo Fusaro, Neusa Wandalsen, Sven Cichon, Joao Bosco Pesquero, Anete S. Grumach
Journal: Journal of Allergy and Clinical Immunology (2014)
Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation
Authors: Salim Yusuf, Marcus Flather, Janice Pogue, David Hunt, John Varigos, Leopoldo Piegas, Alvaro Avezum, Jeffrey Anderson, Matyas Keltai, Andrzej Budaj, Keith Fox, Leszek Ceremuzynski
Journal: The Lancet (1998)
Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion
Authors: Che-Hung Shen, Hsin-Yi Chen, Ming-Shien Lin, Fang-Yen Li, Cheng-Chi Chang, Min-Liang Kuo, Jeffrey Settleman, Ruey-Hwa Chen
Journal: Cancer Research (2008)

Abstract Breast tumor kinase (Brk), an Src-like nonreceptor tyrosine kinase, is overexpressed in breast cancer and several other cancer types. Our previous study indicates that Brk promotes cell migration and tumor invasion by phosphorylating the focal adhesion protein paxillin. Here, we report the identification of p190RhoGAP-A (p190) as a Brk substrate. Brk phosphorylates p190 at the Y1105 residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120). As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively. In carcinoma cells expressing high levels of Brk, endogenous Brk functions as a key contributor to epidermal growth factor–induced p190 tyrosine phosphorylation. We present evidence showing that p190 phosphorylation plays essential roles in both migratory and proliferative effects of Brk. Furthermore, disruption of p190 phosphorylation–induced p190/p120 complex in breast cancer cells abolishes not only the abilities of Brk to regulate RhoA and Ras but also the stimulatory effects of Brk on proliferation, migration, invasion, transformation, and tumorigenicity. Together, our findings reveal a previously unknown function of Brk in regulating both RhoA and Ras by phosphorylating p190 and provide evidence for the crucial roles of this Brk-elicited signaling pathway in promoting breast malignancy. [Cancer Res 2008;68(19):7779–87]
NVP-BEZ235 as a New Therapeutic Option for Sarcomas
Authors: Maria C. Manara, Giordano Nicoletti, Diana Zambelli, Selena Ventura, Clara Guerzoni, Lorena Landuzzi, Pier-Luigi Lollini, Saveur-Michel Maira, Carlos García-Echeverría, Mario Mercuri, Piero Picci, Katia Scotlandi
Journal: Clinical Cancer Research (2010)

To evaluate the in vitro and in vivo effects of NVP-BEZ235, a dual pan-phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor in the three most common musculoskeletal tumors (osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma).Antiproliferative activity as well as the effects on migration and metastasis were evaluated in a panel of osteosarcoma, Ewing's sarcoma, as well as rhabdomyosarcoma cell lines. Moreover, simultaneous and sequential treatments were done in association with two of the most important conventional drugs in the treatment of sarcoma, doxorubicin and vincristine.NVPBEZ235 effectively blocked the pathway in in vitro and in vivo settings. Under the experimental conditions tested, the compound induced disease stasis, by arresting cells in G(1) phase of cell cycle, without remarkable effects on apoptosis. As a consequence, to obtain the maximum exploitation of its therapeutic potential, NVP-BEZ235 has been evaluated in combination with conventional cytotoxic agents, thus showing promising efficacy with either doxorubicin and vincristine. Inhibition of the phosphoinositide 3-kinase/mammalian target of rapamycin pathway increased activation of extracellular signal-regulated kinase 1/2, likely due to the presence of autocrine circuits shifting growth factor signaling toward the mitogen-activated protein kinase pathway. This supports the combined use of NVP-BEZ235 with other small signaling inhibitors. Here, we showed synergistic effects when the compound was associated with a anti-insulin-like growth factor-I receptor tyrosine kinase inhibitor. NVP-BEZ235 also inhibited cell migration and metastasis. Combination with vincristine further potentiated the antimetastatic effects.NVP-BEZ235 displays the features to be considered for sarcoma therapy to potentiate the activity of other anticancer agents. The drug is currently undergoing phase I/II clinical trials in advanced cancer patients.
Sacral stress fracture: an unusual cause of low back pain in an amateur tennis player
Authors: R T Silva, A De Bortoli, C F S Laurino, R J Abdalla, M Cohen
Journal: British Journal of Sports Medicine (2006)

Stress fractures are common in athletes, and their incidence in sport is estimated at 2–4%. A case is reported of a stress fracture of the sacrum in an amateur tennis player. The patient was treated with rest and physiotherapy, focusing on stretching programmes and analgesic treatments, followed by an educational programme of tennis training and muscle strengthening. This appears to be the first report of this pathology in a tennis player.
Cytochromes P450 Expression Systems
Authors: F J Gonzalez, K R Korzekwa
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Catalytically active cytochrome P450 enzymes have been successfully expressed in bacterial, yeast, and mammalian cells. A variety of expression vectors have been used, resulting in both transient and stable expression. The system of choice depends on the goals of a particular project. Factors such as expense, ease of use, and yields required should govern the decision whether to use bacterial, yeast, insect, or mammalian cDNA expression. High-level expression of mammalian P450s in bacteria usually requires modifications of the amino-terminal region of the enzyme. The Escherichia coli P450-OR fusion proteins may also come of age for use in fermentation-production processes for the chemical industry. Many cytochromes P450 have been expressed in yeast, with variable levels of expression. Baculovirus, albeit somewhat tedious in having to individualize expression conditions, can produce high levels of enzyme. The standard mammalian cell expression systems, both transient and stable, have been of tremendous value to drug metabolism and carcinogenesis research and will continue to play a role in these areas.
Randomized Controlled Trial of Weight Training and Lymphedema in Breast Cancer Survivors
Authors: Rehana L. Ahmed, William Thomas, Douglas Yee, Kathryn H. Schmitz
Journal: Journal of Clinical Oncology (2006)

Lymphedema is a common condition that breast cancer survivors face. Despite a lack of supporting evidence from prospective observational studies, occupational and leisure time physical activity are feared to be possible risk factors for lymphedema onset or exacerbation. We examined effects of supervised upper- and lower-body weight training on the incidence and symptoms of lymphedema in 45 breast cancer survivors who participated in the Weight Training for Breast Cancer Survivors study.Participants were on average 52 years old, 4 to 36 months post-treatment, and had axillary dissection as part of their treatment. Thirteen women had prevalent lymphedema at baseline. The intervention was twice-a-week weight training over a period of 6 months. Lymphedema was monitored at baseline and 6 months by measuring the circumference of each arm, and by self-report of symptoms and clinical diagnosis.None of the intervention-group participants experienced a change in arm circumferences > or = 2.0 cm after a 6-month exercise intervention. Self-reported incidence of a clinical diagnosis of lymphedema or symptom changes over 6 months did not vary by intervention status (P = .40 and P = .22, respectively).This is the largest randomized controlled trial to examine associations between exercise and lymphedema in breast cancer survivors. The results of this study support the hypotheses that a 6-month intervention of resistance exercise did not increase the risk for or exacerbate symptoms of lymphedema. These results herald the need to start reevaluating common clinical guidelines that breast cancer survivors avoid upper body resistance activity for fear of increasing risk of lymphedema.