Hormone dependence of breast cancer cells and the effects of tamoxifen and estrogen:31P NMR studies

Many breast tumors appear to progress from estrogen-dependent growth to a more malignant phenotype characterized by estrogen-independent growth, antiestrogen resistance, and a high metastatic potential. Utilizing³¹P NMR spectroscopy on human breast cancer cells growingin vitro, we have investigated the effects of 17-estradiol and tamoxifen on the metabolic/bioenergetic spectra of a series of human breast cancer cells that vary in their estrogen and antiestrogen responsiveness. A comparison of baseline spectra associates higher levels of phosphodiesters and UDP-glucosides (e.g. UDP-glucose, UDP-N-acetylglucosamine), and lower phosphocholine/glycerylphosphocholine and phosphocholine/phosphoethanolamine ratios, with the acquisition of estrogen-independent growth in estrogen receptor expressing cells. No metabolic changes are clearly associated with the metastatic phenotype. Whilst estrogen treatment produces no consistently significant spectral changes in any of the cell lines, the estrogen-independent and estrogen-responsive MCF7/MIII cell line responds to tamoxifen treatment by significantly increasing all spectral resonances 30%-40% above baseline values. This may reflect a tamoxifen-induced change to a more differentiated or apoptotic phenotype, or an attempt by the cells to reverse the inhibitory effects of the drug. The ability to detect metabolic changes in response to tamoxifen by NMR spectroscopy may provide a novel means to identify those tumors that are responsive to antiestrogen therapy.Abbreviations CCS-IMEM steroid-deprived Improved Minimal Essential Medium - E2 17-estradiol - ER estrogen receptor - P_i inorganic phosphate - GPE glyceryl-phosphoethanolamine - GPC glyceryl-phosphocholine - PC phosphocholine - PE phosphoethanolamine - PDE phosphodiesters - PME phosphomonoesters - TAM tamoxifen (trans-1-(4--dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene) - UDPG uridine diphosphoglycoside     

Multileafkollimator: Erweiterte Qualit?tssicherung an einem GE-Linearbeschleuniger

Hintergrund: Ein Multileafkollimator stellt durch die Vielzahl der Lamellen sehr viel höhere Ansprüche an die Konstanzprüfverfahren als ein konventionelles Blendensystem. Zur täglichen Kontrolle der Lamellenpositionierung wird ein Qualitssicherungskonzept vorgestellt. Methode: Zwei Feldkonfigurationen, die bei maximaler Öffnung der Blockblenden sowohl maximale Öffnung als auch "Overtravel" einzelner Lamellen enthalten, werden in täglichem Wechsel online vom Verifikationssystem zum Linearbeschleuniger übertragen. Im Lichtfeld des Linearbeschleunigers erfolgt eine visuelle Kontrolle der Lamellenpositionen mit Hilfe eines speziellen Prüfkörpers. Abschließend wird die Lamellenpositionierung mittels eines Electronic-Portal-Imaging-Systems dokumentiert und nach Überlagerung eines Gitters mit einer Referenzaufnahme verglichen. Ergebnisse: Die Methode stellt eine schnelle und effektive Möglichkeit dar, die Funktionsfähigkeit des gesamten Systems durch Simulation des "Routinebetriebs" zu überprüfen. Schlußfolgerung: Der Arbeits- und Zeitaufwand für die Qualitätssicherung an einem Multileafkollimator unterscheidet sich nur unwesentlich von dem eines konventionellen Blendensystems. Background: In comparison to a conventional collimator, a multileaf collimator demands a great deal of quality assurance procedures due to its large number of leaves. A concept for daily quality assurance is presented, mainly concerning the positioning accuracy of the leaves. Material and Methods: Two leaf configurations including maximal opening as well as overtravel of single leaves, at a maximal opening of the jaws, are transmitted online in daily exchange from our record- and verify system to the linac. Aiming at a special test phantom a visual control of the positioning accuracy is performed. The leaf positioning is documented by an electronic portal imaging system and is compared with a reference shot by superposition of a grid. Results: This method of quality assurance offers a fast and effective possibility to guarantee the proper function of the whole system by simulating the routine treatment situation. Conclusions: Compared to a conventional collimator only a slightly greater workload is needed for quality assurance of a multileaf collimator.     

Physicochemical Characterization of Protein-Free Low Density Lipoprotein Models and Influence of Drug Loading

Purpose. Drug free and drug loaded protein-free low density lipoprotein (LDL) models consisting mainly of phospholipids, cholesterol, cholesterol esters, and triglycerides in ratios found for physiological LDL have been prepared. Their physicochemical characteristics were compared with those of physiological LDL. Methods. Different characterization methods were used: photon correlation spectroscopy, transmission electron microscopy, X-ray solution scattering, and ¹H nuclear magnetic resonance spectroscopy (NMR). Results. Particle sizes are highly dependent on the preparation method and in particular on the homogenization conditions. Electron microscopy indicates that the size distributions of model systems are much broader than those of physiological LDL. The X-ray solution scattering patterns of the model systems display a temperature dependent maximum near 3.8 nm similar to that found in the patterns of physiological LDL. NMR indicates a comparable mobility of the lipid molecules in model particles and in physiological LDL. The influence of drug loading is similar to that found earlier for physiological LDL. In particular, the incorporation of the anti-cancer drug WB 4291 seems to have a fluidizing effect on the lipids in the core region of the particles. Conclusions. The preparation method of LDL model systems is of crucial importance as only the solvent evaporation method yielded systems in the size range of physiological LDL with acceptable high lipid concentrations. The fluidizing influence of temperature and drug incorporation (WB 4291) may be a disadvantage in drug targeting.     

Organization development in mental health services

The term organization development encompasses a number of techniques developed largely in private industry to facilitate communication and collaborative problem solving in work groups. OD approaches now are being introduced into mental health organizations, so administrators need information related to making good decisions about whether an OD program might be beneficial in their settings. This discussion focuses on defining OD, describing its current use in mental health and other human service organizations, and assessing the potential payoffs and disadvantages of implementing an OD program in a mental health setting.Edward M. Glaser, Ph.D., is the president of the Human Interaction Research Institute, Los Angeles, and the managing associate of Edward Glaser & Associates, consulting psychologists to management, Los Angeles.Thomas E. Backer, Ph.D., is a senior staff associate of the Human Interaction Research Institute, Los Angeles, and consulting psychologist of Edward Glaser & Associates, Los Angeles.This article was prepared under the support of the National Institute of Mental Health, Mental Health Services Development Branch, Grant No. R12 MH27566-01.The authors are indebted to the following persons for their perceptive critiques of several draft versions of this article: Dr. John Bell, V. A. Hospital, Palo Alto; Dr. Leonard Goodstein, University of Arizona; Mr. Jim Kouzes, San Jose State University; and Mr. Marvin Weisbord, Organization Research & Development. Inputs from our editorial consultant, Ms. Molly Lewin, also were most helpful.     

Abrin Poisoning

Abrin is a toxic protein obtained from the seeds of Abrus precatorius (jequirity bean), which is similar in structure and properties to ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1–1 µg/kg, and has caused death after accidental and intentional poisoning. Abrin can be extracted from jequirity beans using a relatively simple and cheap procedure. This satisfies one criterion of a potential chemical warfare agent, although the lack of large scale production of jequirity seeds means that quantity is unavailable for ready mass production of abrin for weapons. This contrasts with the huge cultivation of Ricinus seeds for castor oil production. At the cellular level, abrin inhibits protein synthesis, thereby causing cell death. Many of the features observed in abrin poisoning can be explained by abrin-induced endothelial cell damage, which causes an increase in capillary permeability with consequent fluid and protein leakage and tissue oedema (the so-called vascular leak syndrome). Most reported cases of human poisoning involve the ingestion of jequirity beans, which predominantly cause gastrointestinal toxicity. Management is symptomatic and supportive. Experimental studies have shown that vaccination with abrin toxoid may offer some protection against a subsequent abrin challenge, although such an approach is unlikely to be of benefit in a civilian population that in all probability would be unprotected.     

Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II).

PURPOSE: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity. EXPERIMENTAL DESIGN: Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses. RESULTS: In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1') and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5-56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P < 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred. CONCLUSIONS: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.     

Cost-effectiveness of immediate postoperative radiographs after uncomplicated total knee arthroplasty: a retrospective and prospective study of 750 patients

We have questioned the value of postoperative radiographs after uncomplicated, primary total knee arthroplasty (TKA). A total of 750 patients were included in this 2-part study. In the first part, we retrospectively reviewed 200 consecutive, primary TKAs to determine if the immediate postoperative radiographs offered any information that altered the clinical course or if these radiographs could serve as baselines for future images. In the second part, 550 patients who underwent an uncomplicated TKA had their first postoperative radiographs taken at the initial visit. These patients were followed prospectively until the 6-week follow-up appointment to determine if any events occurred in which predischarge radiographs would have been useful as a comparison study. Of the 200 patients who underwent a primary TKA, 192 had postoperative radiographs performed before discharge. Among the 192 patients, the radiographs did not alter the postoperative management. In examining overall quality of the radiographs, only 36% were of sufficient quality to provide an accurate baseline for further studies. Total cost was approximately $36,000. In the 550 patients who had the first postoperative radiograph performed at 6 weeks, there were no instances in which radiographs taken before discharge were needed to aid in further management or legal defense. As with total hip arthroplasty, the past standard has been to obtain immediate postoperative radiographs after primary TKA. Although the information obtained in a total hip arthroplasty patient can be clinically important, the practice of obtaining routine, immediate postoperative knee radiographs in the absence of a specific clinical indication does not provide any additional clinical information and does not appear to benefit patient care.