tbuckley/cabot-search huggingface dataset:
The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST.
Authors: H Eidtmann, NJ Bundred, R DeBoer, A Llombart, N Davidson, P Neven, G von Minckwitz, J Miller, N Schenk, R Coleman
Journal: Cancer Research (2009)

Abstract Abstract #44 Background: Aromatase inhibitors (AI) administered alone or sequentially following tamoxifen are the preferred treatments for hormone-receptor-positive (HRP) early breast cancer (EBC) in postmenopausal women (PMW). As a class effect, long term AI use is associated with an increased loss of bone loss. The primary analysis at 12 months of the Z-FAST and ZO-FAST studies demonstrated that the loss of bone mineral density (BMD) can effectively be prevented by zoledronic acid (ZA). Also, the ABCSG-12 study recently demonstrated a positive impact by ZA on disease recurrence in pre-menopausal women. This 36-months (mo) follow-up for ZO-FAST provides an insight into these issues and longer term safety data as pre-planned secondary endpoints.&amp;#x2028; Materials and Methods: ZO-FAST has 1064 PMW with HRP EBC receiving Let (2.5 mg qd x 5 yrs). Pts with a BMD T-score &amp;gt;-2 were randomized to immediate ZA arm (IMZA) vs delayed ZA arm (DZA). DZA pts receive ZA when either the post baseline T-score decreases to &amp;lt; -2.0 or if a non-traumatic fracture occurs. All patients underwent a spine x-ray at baseline and at 36-mo to assess for asymptomatic fractures.&amp;#x2028; Results: The updated primary endpoint continues to demonstrate the benefit of IMZA vs. DZA, with a treatment difference of 9.29(p&amp;lt;0.0001) at the lumbar spine and 5.41(p&amp;lt;0.0001) at the hip. 110 pts (20.5%) in the DZA have started ZA as per protocol at a median of 11.8 mo (range 0.03-38.3). The majority of these (82 pts) for T-score &amp;lt; –2.0. There were 24(4.6%) pts who experienced clinical fractures in the IMZA and 26(4.9%) in DZA (Fisher's exact test:p value=0.88). A total of 676 pts (335 IMZA and 341 DZA) had both baseline and 36-mo spine x-ray reviewed centrally. The log rank test for disease recurrence (22 events-IMZA vs 37-DZA) has a p value of 0.0423. The log rank test for disease free survival (26 vs 43) has a p value of 0.0336. The median duration of Let is 43.3 vs 43.4 mo. Adverse events remain as previously reported, and are consistent with the known safety profile of the study drugs.&amp;#x2028; Conclusion: The 36-month data continues to demonstrate the efficacy of ZA in preventing BMD loss. The trends in disease events are significant though preliminary at this 36 month analysis. Further follow up is needed to confirm these promising results. These benefits are observed in the context of a favorable safety profile. To date in this relatively small sample size, the rates of fracture are low and similar. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 44.
Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function.
Authors: R Bhatia, E A Wayner, P B McGlave, C M Verfaillie
Journal: Journal of Clinical Investigation (1994)

Treatment of chronic myelogenous leukemia (CML) with interferon-a frequently results in normalization of periph- eral blood counts and, in up to 20% of patients, reestablish- ment of normal hematopoiesis.We hypothesize that interfer- on-ar may restore normal adhesive interactions between CML progenitors and the bone marrow microenvironment and restore normal growth regulatory effects resulting from these progenitor-stroma interactions.We demonstrate that treatment with interferon-a induces a significant, dose-de- pendent increase in the adhesion of primitive long-term cul- ture initiating cells and committed colony-forming cells (CFC) from CML bone marrow to normal stroma.Adhe- sion of CFC seen after interferon-a treatment could be in- hibited by blocking antibodies directed at the a4, a5, and ,B1 integrins and vascular cell adhesion molecule, but not CD44 or intracellular adhesion molecule, suggesting that interferon-a induces normalization of progenitor-stroma in- teractions in CML.Because FACS® analysis showed that the level of a4, a5, and fl1 integrin expression after interferon-a treatment is unchanged, this suggests that interferon-a may restore normal f81 integrin function.Normalization of inter- actions between CML progenitors and the bone marrow microenvironment may then result in the restoration of nor- mal regulation of CML progenitor proliferation, and ex- plain, at least in part, the therapeutic efficacy of interferon- at in CML. (
The Oxygen Sensor Factor-Inhibiting Hypoxia-Inducible Factor-1 Controls Expression of Distinct Genes through the Bifunctional Transcriptional Character of Hypoxia-Inducible Factor-1α
Authors: Frédéric Dayan, Danièle Roux, M. Christiane Brahimi-Horn, Jacques Pouyssegur, Nathalie M. Mazure
Journal: Cancer Research (2006)

Abstract The function of the hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in cellular adaptation to hypoxia, is restricted to low oxygen tension (pO2). As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1α subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1α possesses two transcriptional activation domains [TAD; NH2-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1α that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygen-sensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO2. (Cancer Res 2006; 66(7): 3688-98)
Effect of myocardial fiber direction on epicardial potentials.
Authors: B Taccardi, E Macchi, R L Lux, P R Ershler, S Spaggiari, S Baruffi, Y Vyhmeister
Journal: Circulation (1994)

BACKGROUND Understanding the relations between the architecture of myocardial fibers, the spread of excitation, and the associated ECG signals is necessary for addressing the forward problem of electrocardiography, that is, predicting intracardiac and extracardiac ECGs from known intracardiac activity. So far, these relations have been studied experimentally only in small myocardial areas. In this study, we tested the hypothesis that potential distributions measured over extensive epicardial regions during paced beats reflect the direction of superficial and intramural fibers through which excitation is spreading in both the initial and later stages of ventricular excitation. We also tried to establish whether the features of the epicardial potential distribution that correlate with fiber direction vary as a function of pacing site, intramural pacing depth, and time elapsed after the stimulus. An additional purpose was to compare measured epicardial potentials with recently published numerical simulations depicting the three-dimensional spread of excitation in the heart muscle and the associated potential fields. METHODS AND RESULTS The hearts of 18 mongrel dogs were exposed and 182 to 744 unipolar electrograms were recorded from epicardial electrode arrays (2.3 x 3.0 to 6.5 x 6.5 cm). Hearts were paced at various intramural depths through an intramural needle. The overall number of pacing sites in 18 dogs was 241. Epicardial potential distributions, electrographic waveforms, and excitation time maps were displayed, and fiber directions in the ventricular wall underlying the electrodes were determined histologically. During the early stages of ventricular excitation, the position of the epicardial maxima and minima revealed the orientation of myocardial fibers near the pacing site in all cases of epicardial and intramural pacing and in 60% of cases of endocardial or subendocardial pacing. During later stages of propagation, the rotation and expansion of the positive areas correlated with the helical spread of excitation through intramurally rotating fibers. Marked asymmetry of potential patterns probably reflected epicardial-endocardial obliqueness of intramural fibers. Multiple maxima appeared in the expanding positive areas. CONCLUSIONS For 93% of pacing sites, results verified our hypothesis that epicardial potential patterns elicited by ventricular pacing reflect the direction of fibers through which excitation is spreading during both the initial and later stages of propagation. Epicardial potential distributions provided information on the site of origin and subsequent helical spread of excitation in an epicardial-endocardial, endocardial-epicardial, or double direction. Results were in agreement with previously published numerical simulations except for the asymmetry and fragmentation of the positive areas.
Hazards from Plastics Sterilized by Ethylene Oxide
Authors: A. C. Cunliffe, F. Wesley
Journal: BMJ (1967)

ments.Shortly after Toennies et al. ' showed that the bulk of folates in human blood was present in the red cells we introduced the L. casei assay for the determination of folate activity in whole blood.' The value of this assay has also been established in anaemia of pregnancy, and it was found that in severe megaloblastic anaemia the red cells were almost completely depleted of folates.' ' In cases of severe deficiency administration of as little as 100 ,ug. of folate (pteroylglutamate (P.G.A.)) daily resulted in an excellent clinical and haematological response.However, even as much as 1,000 jug.daily given intramuscularly for 20 days was insufficient to raise the blood folate activity to normal levels, when assays were done 7 to 10 days after cessation of treatment.Under similar conditions at least 5 mg.daily of folic acid was needed to replenish body stores and to raise the blood folate level to normal.'In recent unpublished experiments rises in serum folate without concomitant increases in liver and red-cell folates have occurred in folatedeficient rats kept on a diet low in P.G.A.(1 mg.P.G.A./1 kg.food).This rise in serum folate nmay reflect immediate intake of P.G.A. and its transport rather than the con- cfition of tissue stores.-Weare, etc.,
Social Catastrophe: Orphaned by AIDS
Authors: Robert P. Robinson
Journal: JAMA (1993)

<h3>To the Editor.</h3> —We would like to express our gratitude to Michaels and Levine<sup>1</sup>for documenting the problem of AIDS orphans in the United States. As service providers to HIV-infected parents, we are also pleased with the editorial comments<sup>2</sup>on the need for action at the state and local level. Two years ago the Family AIDS Advocacy Task Force of the Families' and Children's AIDS Network convened to address this problem in Chicago. As a result, the Second Family Program of Lutheran Social Services of Illinois was recently implemented to facilitate permanency planning for HIV-affected families. The program will reduce the potential burden on the state child welfare system by recruiting adoptive parents or intervening with extended family members who might be appropriate parents or guardians. The Illinois Department of Children and Family Services supports our efforts and has taken part in program development. The objectives of
Nifedipine and Ureteral Colic
Authors: LYNE COPPENS
Journal: Annals of Internal Medicine (1986)

Letters and Corrections1 December 1986Nifedipine and Ureteral ColicLYNE COPPENS, M.D., FRANÇOIS LUSTMAN, M.D.LYNE COPPENS, M.D., FRANÇOIS LUSTMAN, M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-105-6-967_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: We were most interested in Carrol's (1) experiment concerning the favorable effect of nifedipine administered orally in two patients with nephritic colic. Our experience with this treatment in patients who responded favorably led us to undertake, as suggested by Carrol, a prospective randomized study comparing our standard therapy with nifedipine.Our usual treatment consists of an intravenous perfusion of sorbitol and procaine with papaverine and an antispasmodic, Baralgin (noramidopyrine methanesulfone, fenpiverinium bromide, pipethoxyphenone hydrochloride; Hoechst, Frankfurt, West Germany). Nifedipine was administered at the rate of one 10-mg capsule sublingually to be repeated after 10 minutes if pain...References1. CARROL W. Nifedipine and ureteral colic [Letter]. Ann Intern Med. 1985;102:864. LinkGoogle Scholar2. VISKINKAVERGREENSTEINHASSNER SIAA. Nifedipine and ureteral colic [Letter]. Ann Intern Med. 1986; 105:142. LinkGoogle Scholar3. BAGGIOGAMBAROMARCHINICICERELLOBORSATTI BGFEA. Effect of nifedipine on urinary calcium and oxalate excretion in renal stone formers. Nephron. 1986;43:234-5. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: LYNE COPPENS, M.D.; FRANÇOIS LUSTMAN, M.D.Affiliations: Hôpital de Saint-Gilles 1180 Brussels Belgium PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byA Systematic Review of Medical Therapy to Facilitate Passage of Ureteral CalculiRole of adjunctive medical therapy with nifedipine and deflazacort after extracorporeal shock wave lithotripsy of ureteral stonesEffectiveness of nifedipine and deflazacort in the management of distal ureter stonesNifedipine and Methylprednisolone in Facilitating Ureteral Stone Passage: A Randomized, Double-Blind, Placebo-Controlled StudySchmerztherapie der akuten NierenkolikNifedipine for the relief of renal colic: A double-blind, placebo-controlled clinical trial 1 December 1986Volume 105, Issue 6Page: 967-967KeywordsPatientsProspective studies ePublished: 1 December 2008 Issue Published: 1 December 1986 PDF downloadLoading ...
Alterations of skeletal muscle in chronic heart failure.
Authors: H Drexler, U Riede, T Münzel, H König, E Funke, H Just
Journal: Circulation (1992)

The present study was designed to define the prevalence and characteristics of skeletal muscle alterations in patients with chronic heart failure (CHF) and their relation to exercise capacity.The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry in 57 patients with CHF and 18 healthy controls. The volume density of mitochondria (Vvm) and the surface density (Svmc) of mitochondrial cristae were evaluated as a structural correlate of oxidative capacity of skeletal muscle. Vvm and Svmc were reduced by approximately 20% in patients with severe CHF irrespective of age and etiology. The cytochrome oxidase activity in mitochondria as determined by cytochemistry and subsequent morphometry in a subset of patients (n = 10) was significantly decreased in heart failure (p less than 0.01). The capillary length density of skeletal muscle was reduced in CHF (n = 12, p less than 0.05), and the fiber type distribution was shifted to type II fibers (n = 15, p less than 0.05). Vvm and Svmc were significantly related to peak exercise VO2 (r = 0.56, p less than 0.001, n = 60) and to VO2 at anaerobic threshold (r = 0.535, p less than 0.0001, n = 60). In 16 patients with severe heart failure, Vvm was inversely related to the duration of heart failure (r = 0.545, p less than 0.03). In 11 patients who underwent repeat biopsies after 4 months, a correlation was observed between the change in Vvm and the change in peak exercise VO2 (r = 0.89, p less than 0.001).These findings indicate that patients with CHF develop significant ultrastructural abnormalities of skeletal muscle reflecting a depressed oxidative capacity of working muscle. It appears that these alterations of skeletal muscle contribute to the decreased exercise capacity of these patients but are, in principle, reversible by an effective treatment regimen.
Abstract P6-10-01: Evaluation of post-progression survival (PPS) in advanced breast cancer (ABC) according to treatment line: Correlation with PFS and OS in an unselected population
Authors: M Ciccarese, R Forcignanò, L Petrucelli, A Fabi, VE Chiuri, G Cairo, L Lupo, A Gambino, V Saracino, G Ronzino, A Licchetta, D Giannarelli
Journal: Cancer Research (2013)

Abstract Background: MBC remains an incurable disease with a median survival of 2-3 years despite the use of new drugs. The validation of PPS as surrogate endpoint and its correlation to PFS and OS is matter of debate. Methods: From 2006-2012 we analyzed retrospectively consecutive 192 pts treated for MBC outside of clinical trials, 103 with at least 3 lines CT, in order to evaluate post-progression survival (PPS) according to treatment line and its relation to PFS and OS. Moreover we evaluated the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy. Results: Median age at M+ diagnosis was 59 years (30-89), median site of disease was 2 (1-6), 67% visceral, HER-2 + pts 32%, median number of anti-Her-2 treatment was 2 (0-6); median number of treatment was 3 (1-8). Median OS for all pts was 45.6 (95% CI: 36.5-54.7). Median OS for CT &amp;gt; = 3 vs CT &amp;lt; 3 was respectively 52.5 (95% CI: 43.3-61.7) and 32.3 (95% CI: 23.6-41.2) P = 0.007. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive versus negative p&amp;lt;0.0001) number of lines (&amp;gt;3 vs ≤3) p = 0.001 and number of metastatic sites (&amp;gt;2 vs ≤2) p&amp;lt;0.0001. We evaluated the relation between PFS and OS and between PPS and OS until the 6th line of therapy with a linear regression model. Median PFS (95% c.i.)Median PPS (95% c.i.)Median OS from M+ diagnosisCorrelation OS-PPSCorrelation OS-PFS1st line11.0 (9.5-12.5)29.9 (18.2-41.6)Not reachedP&amp;lt;0.0001 OS-PPS1P&amp;lt;0.0001 OS-PFS12nd line7.0 (5.8-8.2)20.9 (11.7-30.0)29.1 (17.5-40.7)P&amp;lt;0.0001 OS-PPS2P&amp;lt;0.0001 OS-PFS23rd line5.6 (4.5-6.7)19.5 (14.9-24.1)41.9 (15.5-68.2)P&amp;lt;0.0001 OS-PPS3P&amp;lt;0.0001 OS-PFS34th line5.7 (4.0-7.4)15.3 (13.4-17.2)50.4 (27.4-73.4)P&amp;lt;0.0001 OS-PPS4P&amp;lt;0.0001 OS-PFS45th line3.9 (3.1-4.7)11.2 (7.8-14.5)65.9 (20.8-112.2)P = 0.004 OS-PPS5P&amp;lt;0.0001 OS-PFS56th line3.3 (2.6-4.0)8.2 (2.2-14.2)56.8 (48.7-64.9)P = 0.36 OS- PPS6P = 0.002 OS-PFS6 Conclusion: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until the 6th line of treatment. The utility of PPS as surrogate endpoint of OS is a valid hypothesis that could be evaluated in prospective trials of MBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-01.
A COMPREHENSIVE METHOD FOR THE DETERMINATION OF URINARY CHLORPROMAZINE AND ITS OXIDATIVE METABOLITES
Authors: IRENE S. FORREST, MAGDALENA BERGER WECHSLER, JOSEPH E. SPERCO
Journal: American Journal of Psychiatry (1963)

1. A method for the determination of urinary chlorpromazine and its metabolites employing adsorption on Dowex 50 W-X4 cation exchange resin is described. 2. Polar, intermediary oxidative and conjugated metabolites constitute by far the largest drug fraction, amounting to approximately 80% of total urinary drug. 3. One half of administered daily drug doses was found to be excreted in the urine. 4. Recoveries by this method range from 88% to 97%.
TCT-316 Impact of Coronary Artery Size on Physiologic Microcirculatory Indices: A Volumetric Intravascular Ultrasound Study with Coronary Flow Assessment
Authors: Yuhei Kobayashi, Yasuhiro Honda, William F. Fearon, Shigemitsu Tanaka, Peter Fitzgerald, Alan Yeung, Jennifer A. Tremmel
Journal: Journal of the American College of Cardiology (2014)
Pharmacodynamics of Levofloxacin
Authors: Sandra L. Preston
Journal: JAMA (1998)

Context.—One purpose of early clinical trials is to establish the appropriate dose of an antibiotic for phase 3 trials. Development of a relationship between the ratio of drug exposure to organism minimum inhibitory concentration (MIC) and therapeutic response early in the development process would allow an optimal choice of dose to maximize response.Objective.—To prospectively quantitate the relationship between plasma levels of levofloxacin and successful clinical and/or microbiological outcomes and occurrence of adverse events in infected patients.Design.—Multicenter open-label trial.Setting.—Twenty-two enrolling university-affiliated medical centers.Patients.—A total of 313 patients with clinical signs and symptoms of bacterial infections of the respiratory tract, skin, or urinary tract.Main Outcome Measures.—Clinical response and microbiological eradication of pathogenic organisms.Results.—Of 313 patients, 272 had plasma concentration-time data obtained. Of these, 134 patients had a pathogen recovered from the primary infection site and had an MIC of the pathogen to levofloxacin determined. These patients constituted the primary analysis group for clinical outcome. Groups of 116 and 272 patients, respectively, were analyzed for microbiological outcome and incidence of adverse events. In a logistic regression analysis, the clinical outcome was predicted by the ratio of peak plasma concentration to MIC (Peak/MIC) and site of infection (P<.001). Microbiological eradication was predicted by the Peak/MIC ratio (P<.001). Both clinical and microbiological outcomes were most likely to be favorable if the Peak/MIC ratio was at least 12.2.Conclusions.—Levofloxacin generated clinical and microbiological response rates of 95% and 96%, respectively. These response rates included fluoroquinolone "problem pathogens," such as Streptococcus pneumoniae and Staphylococcus aureus. Exposure to levofloxacin was significantly associated with successful clinical and microbiological outcomes. The principles used in these analyses can be applied to other classes of drugs to develop similar relationships between exposure and outcome. This pharmacokinetic modeling could be used to determine optimal treatment dose in clinical trials in a shorter time frame with fewer patients. This modeling also should be evaluated for its potential to improve outcomes (maximizing therapeutic response, preventing emergence of resistance, and minimizing adverse events) of patients treated with this drug.