tbuckley/cabot-search huggingface dataset:
Phase I study evaluating the safety, tolerability, and pharmacokinetics (PK) of HGS1029, a small-molecule inhibitor of apoptosis protein (IAP), in patients (pts) with advanced solid tumors.
Authors: S. G. Eckhardt, G. Gallant, B. I. Sikic, D. R. Camidge, H. A. Burris, H. A. Wakelee, W. A. Messersmith, S. F. Jones, A. D. Colevas, J. R. Infante
Journal: Journal of Clinical Oncology (2010)

2580 Background: Overexpression of IAPs confers protection against a number of proapoptotic stimuli in a variety of tumors. XIAP, the best characterized IAP family member, binds to and inhibits the activation of caspase 9, so targeting caspase activation through the inhibition of IAP function may be an anticancer strategy. HGS1029 is an IAP inhibitor designed to directly kill tumor cells. XIAP inhibition by small molecules has been associated with loss of cIAP-1, a potential pharmacodynamic (PD) marker. Methods: To evaluate the safety, tolerability, and PK profile of HGS1029, given as a 15 min IV infusion on days 1, 8, and 15 of a 28-day cycle, in pts with relapsed or refractory advanced solid malignancies. Results: 27 pts (12 females, 15 males) with a median age of 63 years (range: 42-79 years) have been enrolled in 7 cohorts (0.1, 0.2, 0.4, 0.6, 0.9, 1.4, and 2.1 mg/m2). At 1.4 mg/m2, 1 pt experienced DLTs of grade (Gr) 3 AST, Gr3 amylase, Gr4 lipase, and Gr3 fatigue after receiving the first dose of HGS1029. All events recovered quickly without clinical sequelae and no further DLTs were observed. The most frequent Gr1 to Gr2 adverse events (AEs), judged to be at least possibly related to HGS1029, include nausea (37%), diarrhea (22%), anorexia (19%), vomiting (19%), fatigue (15%), and pyrexia (7%). HGS1029 produced a dose-dependent short-lived lymphocytopenia and possibly a transient neutrophilia. In addition to the DLTs described above, 2 Gr3 AEs were considered to be at least possibly related to HGS1029: elevated INR and supraventricular tachycardia. Preliminary PK analysis indicates that PK are linear over the dose range tested with a similar profile between single vs. multiple dosing. At 1.4 mg/m2, the elimination of HGS1029 follows a three-compartment model with a terminal half life of 4.8 hrs and no apparent accumulation of HGS1029 in the plasma between the doses. cIAP-1 loss in PBMC's occurred rapidly at each dose level. The decrease in cIAP-1 levels was related to the dose. Conclusions: The administration of HGS1029 has been well tolerated in pts with advanced malignancies and the MTD has not been reached. Accrual to this study continues. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences Human Genome Sciences Human Genome Sciences
Elevated Blood Pressure, Pulse Rate and Serum Creatinine in Negro Males Deficient in Glucose-6-Phosphate Dehydrogenase
Authors: Stephen L. Wiesenfeld, Nicholas L. Petrakis, Bruce J. Sams, Morris F. Collen, John L. Cutler
Journal: New England Journal of Medicine (1970)

Elevated diastolic and systolic casual blood pressures, pulse rates and serum creatinine levels were found in G-6-PD-deficient Negro men as compared with nondeficient age-matched controls. There is thus a possible role of G-6-PD in the metabolic systems concerned with regulation of blood pressure.
Abstract 4017: DLC1 and α-catenin protein interaction enhances DLC1 antioncogenic activity by stabilizing adherens junctions and suppressing NFκB signaling
Authors: Veenu Tripathi, Drazen B. Zimonjic, Nicholas C. Popescu
Journal: Cancer Research (2011)

Abstract Adherens junctions (AJs), which are cell-cell adhesion complexes closely associated with actin cytoskeleton, play an important role in maintaining epithelial tissue homeostasis. Both malignant transformation, and tumor progression to metastasis are often associated with major changes in cytoskeletal organization, the cell-cell adhesion, and aberrant adhesion-mediated signaling. The tumor suppressor gene DLC1 (Deleted in Liver Cancer 1) encodes a RhoGTPase activating protein (GAP) that acts as a negative regulator of the Rho family of small GTPases, which are implicated in cytoskeleton organization and regulation of AJs. A yeast two-hybrid screening identified α-catenin, a component of AJs, as a potential DLC1's binding partner. We relied on this finding and investigated the role of DLC1 in the regulation of AJs and in adhesion-mediated signaling. Using human embryonic kidney (HEK 293) cells we demonstrated that DLC1 interacted with α-catenin and associated with E-cadherin and β-catenin, both constitutive AJs proteins. Co-immunoprecipitation using various deletion constructs of DLC1 and of α-catenin established that the N-terminal (340-435 aa) of DLC1 interacted with the N-terminal (39-161 aa) of α-catenin. Immuno-fluorescence staining and western blot of cellular membrane and cytoplasmic fractions, demonstrated that binding of DLC1 to α-catenin recruited α-catenin to the plasma membrane and required DLC1 GAP activity. In contrast, the DLC1 GAP mutant (R718E) failed to produce the same effect. Fluorescence Recovery After Photobleaching (FRAP) analysis demonstrated that DLC1-α-catenin interaction increased the GFP-E-cadherin mobility at cell-cell junctions, whereas phalloidin staining showed intact actin cable formation around the cell periphery, resulting in the stabilization of AJs. The DLC1-α-catenin interaction is instrumental for a maximal oncosuppressive effects of DLC1 (i.e., by inhibiting proliferation and abolishing colony formation of prostate carcinoma cells); DLC1 mutant defective for α-catenin binding failed to reproduce such an effect. Loss of α-catenin is usually accompanied by an increase in the activation of NFkB, which is associated with increased cell proliferation and resistance to apoptosis. We demonstrated that, by immobilizing NFkB to the AJ complex, DLC1-α-catenin interaction effectively inhibited NFkB phosphorylation and, therefore, its activation. Together, these results unravel a new mechanism through which DLC1 exerts its oncosuppressive function by stabilizing AJs and suppressing NFkB signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4017. doi:10.1158/1538-7445.AM2011-4017
CARDIAC BETA-ARRESTIN2 GENE TRANSFER STIMULATES CARDIAC FUNCTION IN HEART FAILURE VIA SERCA2A POTENTIATION
Authors: Anastasios Lymperopoulos, Katie A. McCrink, Angela Vu, Malika Jafferjee, Thairy Reyes Valero, Christine Marrero, Ava Brill, Xuipei Huang
Journal: Journal of the American College of Cardiology (2016)
MS2-2: Environmental Exposures, Epigenetics, and Epidemiology: Influence of Environmental Factors on Pubertal Maturation and Breast Cancer Etiology.
Authors: RA Hiatt
Journal: Cancer Research (2011)

Abstract Although much of breast cancer etiology can be explained on the basis of reproductive and family histories, there remains concern among both the public and scientific communities about the possible role of environmental factors. Several well-established observations suggest a role of external environmental factors including the 5-fold international differences in incidence rates and the rapid inter-generational increases in incidence with migration from low to high incidence countries. Although epidemiologic studies in adult populations have generally failed to discover a strong role for environmental factors in breast cancer etiology, emerging data suggests that relevant exposures may have effects in early life during so-called “windows of susceptibility” and be missed by attempted measurement in adulthood. Exposures to ionizing radiation and to diethylstilbestrol during pubertal development and in utero, respectively, are two examples. Recently, more attention has been directed to other environmental exposures, especially endocrine disrupting chemicals (EDCs) during early development and the pubertal period in particular. Many EDCs can now be measured in biospecimens from young prepubertal girls and in pregnant women, and animal studies suggest that some of these may cause changes in reproductive systems. Early menarche is a well-established risk factor for breast cancer and increases risk approximately 2-fold compared to later menarche. The average age at menarche has also dramatically decreased in developed countries over the last 100 years, likely as the result of environmental factors including diet. However, the relevant exposures and their mode and timing of action are not well understood. An on-going epidemiologic cohort study of 1239 pre-pubertal girls from diverse race/ethnic and socioeconomic backgrounds has documented still earlier ages of pubertal onset and is offering insights into the potential role of EDCs and other chemicals, diet, physical activity, psychosocial and genetic factors on pubertal onset, the age of menarche and other markers of early development. This research on early environmental exposures in humans is proving both exciting and challenging and requires consideration of the complex nature of breast cancer etiology. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS2-2.
Evaluation des capacités de détection et de discrimination des adénomes au cours de la coloscopie dans le programme national de dépistage organisé du cancer colorectal par Hemoccult®
Authors: B Denis, EA Sauleau, I Gendre, C Piette, JF Bretagne, P Perrin
Journal: Endoscopy (2011)

Introduction: En termes de coût-efficacité et de bénéfice-risque, le meilleur coloscopiste est celui qui détecte tous les adénomes et ne résèque que ceux ci. A ce jour, un indicateur unique est utilisé pour évaluer ces 2 qualités, détection et discrimination: le taux de détection des adénomes (TDA) (nombre de coloscopies avec ≥1 adénome/nombre de coloscopies). Le but de ce travail était de définir l' (es) indicateur(s) le(s) plus approprié(s) pour évaluer les capacités de détection et de discrimination des adénomes en pratique courante.
Psychosocial Processes and Health: A Reader
Authors: A. Furnham
Journal: BMJ (1995)

Ed Andrew Steptoe, Jane Wardle Cambridge University Press, pounds sterling24.95, pp 525 ISBN 0 521 42618 9

Edited collections of papers are often something of a curate's egg either because of the occasional incompetence of the contributors or because of the indolence of the editors. This is less likely in a book that consists of already published papers from leading specialist journals. The particular selection criteria for papers, however, need to be clearly spelt out.

The dust jacket of Psychosocial Processes and Health claims that the book “makes available within a single volume some …
Sudden Death in Hypertrophic Cardiomyopathy
Authors: Hugh Watkins
Journal: New England Journal of Medicine (2000)

Few problems are harder for physicians and patients alike than having the ability to predict, but not to avert, adverse events; few adverse events are harder to deal with than sudden death in young people. Thus, familial hypertrophic cardiomyopathy presents an extreme problem in medical management. Recent insights into the genetic basis of hypertrophic cardiomyopathy have not yet led to new, rationally designed treatments, so our diagnostic capabilities have outpaced the therapeutic options. The article by Maron and colleagues1 in this issue of the Journal shows the value of an empirical approach to the prevention of sudden death in patients . . .
THE CLINICAL USEFULNESS OF PERFORMING SAME-DAY SEQUENTIAL 18FDG AND COMBINED 18F-/18FDG REGIONAL ONCOLOGIC PET
Authors: C. Y.O. Wong, M. V. Bleza, P. Bohdiewicz, H. Dworkin
Journal: Clinical Nuclear Medicine (1999)

Scientific Abstracts: Central Chapter, Society Of Nuclear Medicine, April 9-11, 1999, Cleveland Sheraton City Center Cleveland, Oh
Case 64-1962
Authors: Irving P. Ackerman, Benjamin Castleman
Journal: New England Journal of Medicine (1962)

Presentation of CaseA thirty-six-year-old woman entered the hospital because of weakness.Four days previously the patient had the onset of a "viral illness" characterized by malaise, coryza, sore throat, slight cough and elevations of the temperature to 100°F. Penicillin and novobiocin were given orally for the next two days. On the day before admission she became bedridden because of extreme weakness. She experienced increased weakness with vertigo in the upright position and had one episode of momentary loss of consciousness while trying to get out of bed. No shaking chills, melena or chest pain occurred. Two weeks before entry . . .
Abstract 2519: A class of biometallo-organic compounds that target human topoisomerase IIa
Authors: Alexander M. Fagenson, Matthew P. Akerman, Orde Munro, Mark T. Muller
Journal: Cancer Research (2011)

Abstract Topoisomerase IIa (topo II) is a nuclear enzyme that changes the topological state of DNA by breaking and rejoining the phosphodiester backbone of DNA. It is an important target for anticancer therapy and a number of agents are known to influence its action in vivo. These agents operate by either disrupting the cleavage-resealing cycle (interfacial poisons) or by simply blocking catalytic action of topo II (catalytic inhibitors). A new class of metallo-drugs is described that is unique in acting by both mechanisms. These are a series of fully characterized crystalline d8 coordination compounds with tetradentate ligands that we have evaluated for their targeting potential with topo II. These compounds are quite toxic to cells in culture with inhibitory values in low micromolar range. Mechanistic in vitro data with purified enzyme reveal these compounds to act as both catalytic inhibitors and as interfacial poisons over the same range of drug concentration. For example, CC50 values (drug concentrations yield 50% maximum DNA cleavage) were 3.47 µM for the prototype metallo-agent (compared to 5.47 µM for etoposide). Acting as catalytic inhibitors, the IC50 value was 3.17 µM. In sum, these compounds exhibit dual mechanisms in vitro, by stabilizing the covalent cleavage complex as well as blocking catalytic function. Analysis of endogenous topo II activity in HeLa cells confirms that the compounds target endogenous topo II by stabilizing the covalent cleavage complex and therefore acting as a poison in a cellular context. Endogenous topo I was not affected by the drug showing that these novel metallo-agents are type II specific. The dual mechanism of targeting of topo II suggests significant anti-tumor potential, and further studies are being conducted to evaluate clinical potential. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2519. doi:10.1158/1538-7445.AM2011-2519
THU0144 Induction of remission and inhibition of joint damage in patients with rheumatoid arthritis treated with mono- or combination therapy using non-biological DMARDS in routine clinical practice
Authors: K. Katayama, T. Okubo, T. Sato
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Recently, a tight control strategy with treat to target (T2T) is this worldwide to achieve remission, and to inhibit joint damage, in rheumatoid arthritis (RA) patients. However, little is known about the rate of remission or the inhibitory effect on joint damage with non-biological DMARDs (non-Bio) in routine clinical practice. <h3>Objectives</h3> To investigate the rate of remission and the inhibitory effect on joint damage by non-Bio mono- or combination therapy for RA in routine clinical practice. <h3>Methods</h3> In 555 patients with newly registered RA during 3.5 years, the outcome of induction of remission by mono- or combination therapy with non-Bio was analyzed retrospectively. Patients were treated initially with non-Bio monotherapy, including methotrexate (MTX), and changed to MTX combination therapy if monotherapy was not effective. They were evaluated clinically by DAS28 (ESR) approximately every 3–4 months, and designated as in remission when they satisfied DAS &lt;2.6 on two successive occasions. We excluded patients who were in remission before therapy. The inhibition of joint damage was assessed radiographically using the total Sharp/van der Heijde scoring (SHS). <h3>Results</h3> Among 538 RA patients, remission was achieved in 89 (58 cases of monotherapy, 31 cases of MTX combination therapy. Following monotherapy, the DAS28 improved from 4.54 to 1.87 (mean age, 58 years; mean duration of disease, 32 months; mean time to remission, 17.8 months). As well as MTX (n=18), the drugs used were salazosulfapyridine (SSZ: n=20), bucillamine (BUC: n=19), and leflunomide (LEF: n=1). The remission rates were 7.1% (20/282) for SSZ, 11.9% (17/142) for BUC, and 23.9% (17/71) for MTX. The SHS/year changed from 6.3 to 0.04 (P&lt;0.10), from 33.6 to 0.49 (P&lt;0.01), and from 6.51 to 2.06 (P&lt;0.05), respectively. Following combination therapy, the DAS28 improved from 4.70 to 1.89 (mean age, 52.6 years; mean duration of disease, 38 months; mean time to remission, 15.0 months). The drugs used in combination with MTX were BUC (n=14), LEF (n=8), tacrolimus (TAC: n=8) and SSZ (n=1). The remission rates were 6.8% (14/204) for MTX+BUC, 23.5% (8/34) for MTX+LEF, and 10.7% (8/75) for MTX+TAC. SHS/year changed from 12.8 to 1.39 (P&lt;0.10), from 15.7 to –1.64 (P&lt;0.20), and from 7.1 to 0.31 (P&lt;0.10), respectively. <h3>Conclusions</h3> Satisfactory inhibition of joint destruction was seen in RA patients with remission using non-BIO mono- or MTX combination therapy in routine clinical practice. We can anticipate that use of the T2T strategy will lead to improved remission rates and inhibition of joint destruction in RA. <h3>Disclosure of Interest</h3> None Declared
False-Positive Tc-99m Sestamibi Examination for Parathyroid Adenoma in a Case of Asymmetrical Salivary Gland Enlargement
Authors: RICHARD J. CAMPEAU, WARREN L. REUTHER, JAMES WAYNE
Journal: Clinical Nuclear Medicine (1999)

A 50-year-old African American man with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome had a Tc-99m sestamibi scan as part of an evaluation for parathyroid adenoma-hyperplasia. His history was positive for multiple gastric and duodenal ulcers. Biochemical parameters for hyperparathyroidism were equivocal; borderline parathyroid hormone elevation was present with low phosphate but normal calcium levels. An abnormal focus of radioactivity was evident in the right neck region in the area of the carotid bifurcation. A CT scan was obtained before contemplated neck exploration. Marked asymmetry of the right submandibular gland, corresponding to the focus of tracer uptake, was present with virtual absence of the left gland. The patient subsequently died of pulmonary embolism on the 25th day after surgery for pancreatic and duodenal neuroendocrine tumors. Post mortem examination confirmed an enlarged right submandibular gland with normal thyroid and parathyroid glands.
AB0934 Clinical Features and Prognosis of Adult-Onset Still's Disease: S Single Center Study in Japan: Table 1.
Authors: R. Motohashi, H. Ikeuchi, K. Kayakabe, N. Sakurai, Y. Kaneko, A. Maeshima, K. Hiromura, Y. Nojima
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Adult-onset Still9s disease (AOSD) is an inflammatory diseases characterized by spiking fever, arthritis and evanescent rash. Although AOSD is considered as a benign disease, relapses are common and life-threatening severe complications occur in some patients. <h3>Objectives</h3> In this study, we reviewed the clinical features and outcomes of AOSD patients to seek out risk factors for unfavorable outcomes. <h3>Methods</h3> We retrospectively reviewed medical charts of AOSD patients who were admitted to our department between 1997 and 2013. For the statistical analyses, Mann Whitney U test and Fisher9s exact test were carried out. Multivariate logistic analysis was used to identify factors independently associated with death. It was considered statistically significant if p value was less than 0.05. <h3>Results</h3> A total of 27 patients (8 male and 19 female) were available to analysis. The median age was 33 years (range, 15-64) and the median follow-up period was 2.2 years (range, 0.1-9.1). Corticosteroids and immunosuppressants were used in 92.6% and 33.3% of the patients, respectively. Methylprednisolone pulse therapy was applied in 18.5% of the patients and the median initial dose of steroids was 50 mg/day (range, 30-70; equivalent dose of prednisolone, excluding the dose of pulse therapy). All patients responded to the initial therapy, including 2 patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Twelve patients (44.4%) continued remission, whereas 15 patients (55.6%) had at least one relapse (median 2 times; range, 1-6). Five patients (18.5%) died from multiple organ failure in 3, sepsis in 1 and respiratory failure in 1 patient. The comparison of baseline characteristics between dead and alive patients was shown in Table. The complications of hemophagocytic syndrome (HPS) and disseminated intravascular coagulation (DIC) were significantly more frequent, and the hemoglobin level was significantly lower in dead patients than patients who survived. Multivariate logistic analysis showed a presence of DIC was an independent risk factor for death (OR 20.0, 95%CI 1.613-247.981, p=0.020). <h3>Conclusions</h3> Relapse rate was relatively high and death occurred not rarely in our cohort. The complication of DIC at the initial presentation was associated with death. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4939