tbuckley/cabot-search huggingface dataset:
Abstract S4-5: Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer. The AZURE Trial (BIG 01/04)
Authors: RE Coleman, HC Thorpe, D Cameron, D Dodwell, R Burkinshaw, M Keane, M Gil, SJ Houston, RJ Grieve, PJ Barrett-Lee, D Ritchie, C Davies, R. Bell
Journal: Cancer Research (2010)

Abstract Background: The ABCSG XII trial demonstrated a 32% risk reduction in disease-free survival (DFS) events with Zoledronic acid (ZOL) use in a cohort of premenopausal women treated with endocrine therapy at 62 months median follow-up .[1,2] This strategy is increasingly being adopted in the wider breast cancer population. The AZURE trial is an academic study designed to determine whether treatment with ZOL added to standard adjuvant therapy improves DFS and bone metastasis-free survival (BMFS) in a broader range of patients with stage II/III breast cancer. Materials and methods: 3360 patients from 174 centres were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy (ET) +/− ZOL 4mg iv every 3-4 weeks for 6 doses, then 3 monthly x 8 and 6 monthly x 5 to complete 5 years treatment. The primary DFS endpoint was to be determined after 940 DFS events, providing 80% power to detect a 17% reduction in hazard rates (HR) for DFS events. The rate of events on study has been slower than expected, resulting in an estimated final analysis in 2012. In light of the clinical interest in the results of AZURE, the DMEC has agreed to a second interim analysis after 705 events with boundaries set by an independent statistician, unaware of results at the first interim analysis, for both efficacy (HR ∼0.82, alpha spend 1%) and lack of clinical benefit (HR ∼0.935 with a 5% risk of declaring a false negative result). Contingent on DMEC advice, efficacy results that breach either boundary will be presented. A DMEC recommendation not to release the results at the second interim analysis may indicate that the point HR estimate lies between these boundaries. Results: Patient characteristics including stage, number of positive axillary nodes, CT type, ER status, menopausal status and statin use were well balanced. 3208 patients (96%) received (neo) adjuvant CT (93% anthracyclines, 23% taxanes). 152 patients received ET alone. As of June 9th 2010, with a median follow up of 49 (IQR 42-56) months, there have been 695 DFS events. The safety population comprised 3340 patients (ZOL 1665; control 1675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. Serious adverse events (SAE) were similar in both treatment arms. To date 13 confirmed (0.83%; 95% CI 0.38%, 1.28%) and 12 possible (1.12%; 95% CI 0.39%, 1.85%) cases of osteonecrosis of the jaw (ONJ) in the ZOL arm have occurred. Discussion: AZURE is one of the largest phase III studies of adjuvant bisphosphonates, and the results from this study will help define the role of adjuvant ZOL in the management of early breast cancer. [1] Gnant M et al. NEJM 2009; 360(7):679-691 [2] Gnant M et al. ASCO 2010 Proceedings; abs #533. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-5.
His and Hers
Authors: Daniel D. Federman
Journal: New England Journal of Medicine (1974)

We tend to take evolution for granted, particularly these days when there is so much else to worry about. But, as one may say when looking back, things might have been different. Human sexual differentiation is a case in point. Granted the need for different genital anatomy in the male and female, there is no a priori reason why another solution than the familiar would not have worked. For example, female embryos could have had only the structural gene information for the development of female genitalia, and male embryos only for the male pattern. That is, the internal and external . . .
Association between myelodysplastic syndromes and inflammatory bowel diseases. Report of seven new cases and review of the literature
Authors: M Hebbar, D Kozlowski, E Wattel, S Mastrini, M Diévart, B Duclos, B Bonaz, H d’Almagne, J Belaiche, J-F Colombel, P Fenaux
Journal: Leukemia (1997)
ANTIDIURETIC PITUITARY SUBSTANCE IN BLOOD, WITH SPECIAL REFERENCE TO THE TOXEMIA OF PREGNANCY
Authors: K. I. Melville
Journal: The Journal of Experimental Medicine (1937)

A method is described for the quantitative extraction of posterior pituitary antidiuretic substance from blood with which it has been mixed in vitro and in vivo for experimental purposes. With this procedure, it is found that a similarly extractable active substance may be detected as a normal constituent of dog and human blood. The data obtained from the blood of normal pregnancies and several cases of early toxemia, do not indicate any causal relationship between the presence of this substance in the circulating blood and the early symptoms (hypertension, edema, albuminuria) of the toxemia of pregnancy.
Chronic eosinophilic leukemia presenting with autoimmune hemolytic anemia and erythrophagocytosis by eosinophils
Authors: J.S. Kuk, J.A. MacEachern, P. Soamboonsrup, A. McFarlane, A. Benger, W. Patterson, L. Yang, M.R. Trus
Journal: American Journal of Hematology (2006)

Eosinophils function primarily as secretory cells and phagocytosis by eosinophils is rarely seen. We describe a case of chronic eosinophilic leukemia (CEL) in a 72-year-old male with a history of previously treated non-Hodgkin's lymphoma (NHL) presenting with erythrophagocytosis by eosinophils and an associated autoimmune hemolytic anemia (AIHA). This patient did not show evidence of relapsed NHL. The patient's blood showed a markedly elevated eosinophil count of 16 × 109/L [normal 0–0.45 × 109/L] on a background of myelodysplasia and features of AIHA. Prominent erythrophagocytosis by eosinophils was visualized in the blood and in the bone marrow. Numerous Charcot–Leyden crystals were also seen in the bone marrow amid increased numbers of eosinophils and the presence of dysplastic granulopoiesis. AIHA is rarely described in the setting of CEL. More significantly, this represents the first case report to describe erythrophagocytosis by eosinophils. Am. J. Hematol. 81:458–461, 2006. © 2006 Wiley-Liss, Inc.
Preventing and exploiting the oncogenic potential of integrating gene vectors
Authors: Ute Modlich, Christopher Baum
Journal: Journal of Clinical Investigation (2009)

Gene therapy requires efficient gene delivery to cure or prevent disease by modifying the genome of somatic cells. However, gene vectors, which insert themselves into the host genome in order to achieve persistent protein expression, can trigger oncogenesis by upregulating cellular protooncogenes. This adverse event, known as insertional mutagenesis, has become a major hurdle in the field. Vectors developed on the basis of lentiviruses are considered to be less genotoxic than the hitherto used γ-retroviral vectors. For their report in this issue of the JCI, Montini et al. utilized a tumor-prone mouse model to identify the genetic determinants of insertional mutagenesis (see the related article beginning on page 964). They report that the lentiviral integration pattern and additional improvements in vector design reduce the genotoxic risk. These findings will inform future vector design with the goal of limiting genotoxicity for gene therapy or increasing genotoxicity for protooncogene discovery.
Gross and Microscopic Lesions in the Female SENCAR Mouse Skin and Lung in Tumor Initiation and Promotion Studies
Authors: Gary L. Knutsen, Robert M. Kovatch, Merrel Robinson
Journal: Environmental Health Perspectives (1986)

The skin and lung tissues from SENCAR mice used as part of the Environmental Protection Agency's (EPA's) Carcinogenesis Testing Matrix were examined. This study included SENCAR mice used in three different short-term bioassay protocols in which the skin papilloma assay was used to identify initiators, promoters, and complete carcinogens. Also included were the pathology findings from SENCAR mice used in the combined bioassay in which the skin assay and the lung adenoma assay were conducted simultaneously. The gross and microscopic features of treatment-associated and spontaneous lesions of the skin and lung of the SENCAR mouse used in these studies are defined and the lesions most commonly observed are described. Generally, gross observations and microscopic findings in both the skin and lung tissues were poorly correlated. Although there are several definite criteria on which gross interpretations of the various skin and lung lesions can be made, with the exception of pedunculated squamous cell papillomas and the classic squamous cell carcinomas, the various lesion types had a wide variety of clinical presentations that severely compromised the accuracy of gross diagnosis. Further, in the case of benign skin neoplasms, malignant transformation of these tumors most often occurred at the base of the lesion and was initially hidden from gross observation. As a result, approximately 50% of the neoplasms interpreted clinically as benign tumors (papillomas and keratoacanthomas) were actually malignant neoplasms. Moreover, many lesions determined grossly to be nontumorous were in fact found to be neoplastic when examined microscopically. The SENCAR mouse was found to be more responsive in the lung adenoma assay than other strains examined with exception of the Strain A. Although accurate interpretation of the lung lesions in the SENCAR was compromised by nonneoplastic treatment-associated and/or spontaneous lesions, the feasibility of using the SENCAR skin and lung as target tissues in two-stage combined carcinogenesis studies merits further consideration.
A PHYSIOLOGIC CONSIDERATION OF THE FOOD VALUE OF ALCOHOL, WITH ESPECIAL REFERENCE TO THE EXPERIMENTS OF PROFESSOR W. O. ATWATER, CONTAINED IN BULLETIN NO. 69 OF THE UNITED STATES DEPARTMENT OF AGRICULTURE.
Authors: FRANK WOODBURY
Journal: JAMA (1900)

had a duration of one hour.The pulse was 84-90, the respiration 30-42.The pupils were contracted, but sluggish; later, with a pulse of 84 and respiration 42, they were moderately dilated and inactive to the end.Case 35 had a duration of 40 minutes.The pulse was 90-120, respiration 30-36.The pupils were dilated and sluggish throughout.Case 95 gave a pulse of 90-102, respiration 30-42, pupils changeable, unequal and at times inactive.Case 92 had a duration of 2% hours.Pulse was 66-102, respiration 30-54, the pupils sluggish, then wide, inactive, later contracted and active.(Note Cases 72 and 73.)In some cases a moderately dilated pupil, with an active or sluggish reflex is due to an over- dose of the anesthetic, and then it contracts on with- drawal of the latter; in others it may be due to anemia, in which case the condition sets in early in the anesthesia and withdrawal of this produces no effect.The following case is very instructive, showing the rather loose connection between the pulse, respiration and pupil: Case 95 gave a pulse of 96,102,102,102, 90, 102, 96, 90, 96, 90, 90, 108, 96, and a respiration of 30.30,30,42,33,30,36,30,36,39,42,42,36.The pupils were contracted, active, then unequal and inactive, unequal, right active, left inactive, then both active, both inactive, then again both active, then both inactive.In 48 of the series gastric irritation was present, in 38 absent.In the rest no record was made.Although the degree of anesthesia has some bearing on the nausea and vomiting, incomplete anesthesia favoring it, it is often due to high irritability of the stomach of the indi- vidual.In Case 19, the patient, after being promptly anesthetized, was kept lightly under for some time on account of delay in the operation.Nausea persisted a week.Whether it was due to this fact alone I can not positively say, but I am inclined to think that this was the case.Complete anesthesia was secured in less than ten min- utes in 8 cases, in ten in 30, in fifteen in 20, in twenty in
Effects of metals in in vitro bioassays.
Authors: M A Sirover
Journal: Environmental Health Perspectives (1981)

The capacity of in vitro bioassays to detect the potential carcinogenicity of metal compounds is reviewed. The in vitro bioassays discussed include: bacterial reversion analysis to determine the capacity of metal salts to revert Salmonella typhimurium histidine auxotrophs or to revert Escherichia coli WP 2 tryp- to tryptophan prototrophy; examination of the ability of metal salts to preferentially inhibit cell growth in Bacillus subtilis cells deficient in DNA repair pathways; determination of the ability of metal salts to induce resistance to base analogs in mammalian cells; the capacity of metal salts to enhance viral transformation of mammalian cells or to transform cells in the absence of virus; and the ability of metal salts to induce chromosomal aberrations in mammalian cells. Using each of these in vitro bioassays, diverse metal compounds have been identified as potential carcinogens. Furthermore, the use of different compounds of a specific metal may allow a determination of the valence which may be required for carcinogenesis.
Evidence that serotonin receptors mediate the cutaneous vasoconstriction produced by 5-hydroxytryptamine in canine forelimbs.
Authors: D E Dobbins, S W Adamski, M F Lokhandwala, G J Grega
Journal: Circulation Research (1983)

The effects of local intra-arterial infusions of serotonin (5 or 25 micrograms base/min) or norepinephrine (1 or 5 micrograms base/min) on cutaneous (skin) and skeletal muscle vasculatures were investigated in canine forelimbs perfused at constant flow in dogs anesthetized with pentobarbital. Norepinephrine produced dose-related constriction of the skin and skeletal muscle vasculatures. In the cutaneous vascular circuit, norepinephrine produced large artery, small vessel, and large vein constriction. The increase in cutaneous vascular resistance was primarily due to an increase in small vessel resistance. Serotonin did not increase skeletal muscle vascular resistance but produced marked cutaneous vasoconstriction subsequent to large artery and large vein constriction. The small vessels, if anything, tended to dilate. The skin and skeletal muscle vascular responses to serotonin and norepinephrine were similar in innervated and acutely denervated forelimbs. Phentolamine pretreatment completely blocked all vascular actions of norepinephrine, and largely inhibited the cutaneous vasoconstriction produced by the infusion of the low dose of serotonin. However, the cutaneous large artery and large vein constriction produced by the infusion of the high dose of serotonin was not affected by phentolamine pretreatment. Cyproheptadine pretreatment blocked or largely inhibited the cutaneous vasoconstriction produced by serotonin only in doses which also inhibited norepinephrine and vasopressin cutaneous vasoconstriction. Pretreatment with methysergide blocked or largely inhibited the cutaneous large artery and large vein constriction produced by infusions of serotonin. Norepinephrine and vasopressin produced significant vasoconstriction in the presence of methysergide. These data suggest that the cutaneous large artery and large vein constriction produced by serotonin is not due to the activation of postjunctional alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies on a complex mechanism for the activation of plasminogen by kaolin and by chloroform: the participation of Hageman factor and additional cofactors
Authors: Derek Ogston, C. Marie Ogston, Oscar D. Ratnoff, Charles D. Forbes
Journal: Journal of Clinical Investigation (1969)

As demonstrated by others, fibrinolytic activity was generated in diluted, acidified normal plasma exposed to kaolin, a process requiring Hageman factor (Factor XII). Generation was impaired by adsorbing plasma with glass or similar agents under conditions which did not deplete its content of Hageman factor or plasminogen. The defect could be repaired by addition of a noneuglobulin fraction of plasma or an agent or agents eluted from diatomaceous earth which had been exposed to normal plasma. The restorative agent, tentatively called Hageman factor-cofactor, was partially purified by chromatography and had an apparent molecular weight of approximately 165,000. It could be distinguished from plasma thromboplastin antecedent (Factor XI) and plasma kallikrein, other substrates of Hageman factor, and from the streptokinase-activated pro-activator of plasminogen. Evidence is presented that an additional component may be needed for the generation of fibrinolytic activity in mixtures containing Hageman factor, HF-cofactor, and plasminogen.The long-recognized generation of plasmin activity in chloroform-treated euglobulin fractions of plasma was found to be dependent upon the presence of Hageman factor. Whether chloroform activation of plasminogen requires Hageman factor-cofactor was not determined, but glass-adsorbed plasma, containing Hageman factor and plasminogen, did not generate appreciable fibrinolytic or caseinolytic activity. These studies emphasize the complex nature of the mechanisms which lead to the generation of plasmin in human plasma.
608. Cytotoxic T Lymphocyte Response to AAV2- and AAV8-Mediated Human Factor IX Gene Therapy in Mice
Authors: Jian Chen, Hui-Chen Hsu, Alex Schlachterman, Katherine A. High, John D. Mountz
Journal: Molecular Therapy (2005)

Recombinant adeno-associated virus (AAV) gene therapy expressing coagulant factor IX (F.IX) under the control of a liver specific promoter results in a low immune response. However, F.IX gene expression in humans decreases over time and liver enzymes can be elevated. To determine if AAV-hF.IX treatment could induce specific cytototoxic T lymphocyte (CTL) responses in mice, we first produced CTL epitope peptides from human F.IX (hF.IX), AAV2 and AAV8 capsid proteins in the context of H2-Kd and H2-Db (Table 1). DBA/2 (D2), BALB/c (H2d) and C57BL/6 (B6; H2b) were iv injected with 2|[times]|1011vg of AAV2-hF.IX or AAV8-hF.IX, in which hF.IX expression is regulated by a liver-specific ApoE/hAAT promoter. To obtain the optimal immunization, the mice were boosted 30 days later with the same route and dose of vector. Blood samples were collected for analysis of ALT and hF.IX. The plasma ALT level was elevated by day 4 after administration and a second peak was observed 9 days after boost in all mice (p<0.05). There was no significant decrease in serum hF.IX levels up to 9 days after boost. To determine the specificity of CTLs in the liver, mononuclear cells (MNC) were analyzed 9 days after boost by an IFNg ELISPOT assay using epitope peptides specific for hF.IX, AAV2 or AAV8 capsid as shown inTable 1. An irrelevant flu peptide AA240(IYSTVASSL) restricted by H2-Kd was used as negative control. There was a significant increase in IFNg spot forming cells (SFC) specific for the hF.IX311 peptide in H2d mice and hF.IX254 in H2b mice respectively (Fig 1). The highest CTL response to hF.IX was observed in BALB/c mice receiving AAV8-hF.IX. There was also a significant increase in SFCs specific for the AAV2373 and AAV851 peptide in H2d mice, with the highest CTL response against AAV8 capsid in BALB/c mice receiving AAV8-hF.IX (Fig 1). The in vivo CTL assay was performed to confirm the function of hF.IX specific CTLs (Fig 2). These results indicated that AAV2- or AAV8-hF.IX gene transfer can induce both vector and transgene specific CTLs in the liver of both H2d and H2b mice. The use of specific peptides, ELISPOT and the in vivo killing assay provides sensitive methods to measure CTL response and will be useful in the design of effective and safe vectors and protocols for AAV-hF.IX gene therapy delivery.
Drug points: Severe ergotism associated with interaction between ritonavir and ergotamine
Authors: L. Liaudet
Journal: BMJ (1999)

Ergotism is a severe complication of chronic abuse or acute intoxication with ergot derivatives. Occasional cases have been reported in patients taking usual doses of ergot combined with drugs that interact with it. 1 2 We report a case of severe ergotism associated with the anti-HIV drug ritonavir.

A woman aged 28 who was positive for HIV infection was treated with anti-HIV tritherapy: stavudine (40 mg/12 h), didanosine (200 mg/12 h), and ritonavir (600 mg/12 h). …
microRNA-21 Negatively Regulates Cdc25A and Cell Cycle Progression in Colon Cancer Cells
Authors: Peng Wang, Fangdong Zou, Xiaodong Zhang, Hua Li, Austin Dulak, Robert J. Tomko, John S. Lazo, Zhenghe Wang, Lin Zhang, Jian Yu
Journal: Cancer Research (2009)

Abstract microRNAs (miRNA) are small noncoding RNAs that participate in diverse biological processes by suppressing target gene expression. Altered expression of miR-21 has been reported in cancer. To gain insights into its potential role in tumorigenesis, we generated miR-21 knockout colon cancer cells through gene targeting. Unbiased microarray analysis combined with bioinformatics identified cell cycle regulator Cdc25A as a miR-21 target. miR-21 suppressed Cdc25A expression through a defined sequence in its 3′-untranslated region. We found that miR-21 is induced by serum starvation and DNA damage, negatively regulates G1-S transition, and participates in DNA damage–induced G2-M checkpoint through down-regulation of Cdc25A. In contrast, miR-21 deficiency did not affect apoptosis induced by a variety of commonly used anticancer agents or cell proliferation under normal cell culture conditions. Furthermore, miR-21 was found to be underexpressed in a subset of Cdc25A-overexpressing colon cancers. Our data show a role of miR-21 in modulating cell cycle progression following stress, providing a novel mechanism of Cdc25A regulation and a potential explanation of miR-21 in tumorigenesis. [Cancer Res 2009;69(20):8157–65]
DIABETES MELLITUS AS AN INDEPENDENT PREDICTOR OF CAROTID ARTERIAL WALL INFLAMMATION IN PATIENTS WITH CORONARY ARTERY DISEASE
Authors: Maria I. Drakopoulou, Georgios Benetos, Konstantinos Toutouzas, Pavlos Bounas, George Latsios, Charalampia Nikolaou, Konstantinos Stathogiannis, Eleftherios Tsiamis, Elias Siores, Christodoulos Stefanadis
Journal: Journal of the American College of Cardiology (2014)
Effects of Chronic Heart Failure on the Capacity of Glucagon to Enhance Contractility and Adenyl Cyclase Activity of Human Papillary Muscles
Authors: ROBERT E. GOLDSTEIN, C. LYNN SKELTON, GERALD S. LEVEY, D. LUKE GLANCY, G. DAVID BEISER, STEPHEN E. EPSTEIN
Journal: Circulation (1971)

Glucagon has a positive inotropic effect in normal hearts but is ineffective in animals with chronic cardiac failure. To assess directly the influence of glucagon on the human myocardium, we measured contractility and activation of adenyl cyclase, the enzyme thought to mediate the inotropic action of glucagon, in left ventricular papillary muscles obtained from 12 patients at mitral valve replacement. On the basis of preoperative ventricular end-diastolic pressures and cardiac output (independent of papillary muscle data) patients were classified in three groups: normal, cardiac failure, and condition indeterminate. Concentration-response curves showed that glucagon caused a mean rise of 11% in peak papillary muscle tension and a rise of 12% in peak rate of tension development in the normal patients; myocardial adenyl cyclase activity from each normal patient rose after glucagon (average, 84%). In the papillary muscles of the patients with cardiac failure, glucagon did not augment either tension or adenyl cyclase activity. In contrast, contractility and adenyl cyclase activity increased after norepinephrine in both normal patients and those with cardiac failure. The indeterminate group had two patients whose papillary muscles responded to glucagon and two whose papillary muscles did not respond. Thus, direct study of human papillary muscles shows that chronic cardiac failure is uniformly associated with complete loss of the normal enhancement of contractility and associated activation of adenyl cyclase after glucagon. This perhaps explains the inefficacy of this drug in treating patients with chronic cardiac failure.