Evanston Hospital

BACKGROUND: Percutaneous coronary intervention (PCI) involving drug-eluting stents is increasingly used to treat complex coronary artery disease, although coronary-artery bypass grafting (CABG) has been the treatment of choice historically. Our trial compared PCI and CABG for treating patients with previously untreated three-vessel or left main coronary artery disease (or both). METHODS: We randomly assigned 1800 patients with three-vessel or left main coronary artery disease to undergo CABG or PCI (in a 1:1 ratio). For all these patients, the local cardiac surgeon and interventional cardiologist determined that equivalent anatomical revascularization could be achieved with either treatment. A noninferiority comparison of the two groups was performed for the primary end point--a major adverse cardiac or cerebrovascular event (i.e., death from any cause, stroke, myocardial infarction, or repeat revascularization) during the 12-month period after randomization. Patients for whom only one of the two treatment options would be beneficial, because of anatomical features or clinical conditions, were entered into a parallel, nested CABG or PCI registry. RESULTS: Most of the preoperative characteristics were similar in the two groups. Rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the PCI group (17.8%, vs. 12.4% for CABG; P=0.002), in large part because of an increased rate of repeat revascularization (13.5% vs. 5.9%, P<0.001); as a result, the criterion for noninferiority was not met. At 12 months, the rates of death and myocardial infarction were similar between the two groups; stroke was significantly more likely to occur with CABG (2.2%, vs. 0.6% with PCI; P=0.003). CONCLUSIONS: CABG remains the standard of care for patients with three-vessel or left main coronary artery disease, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year. (ClinicalTrials.gov number, NCT00114972.)

Abeta1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid beta protein (Abeta) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Abeta oligomers (referred to as ADDLs, for Abeta-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.

Кваліфікаційну роботу магістра присвячено вивченню впливу різних жанрів музикотерапії на фізіологічні параметри, спектральні компоненти артеріальних осцилограм з метою створення психорегулюючої автоматизованої системи зворотного зв’язку для музикотерапії.&#13;\nВ роботі обґрунтовано застосування спектральних компонентів артеріальної осцилограми як маркерів рівня тривожності, доведено тісну кореляцію між рівнем тривожності і спектральними показниками LF і HF. Досліджено релаксуючий вплив аудіосимуляції «Класичною музикою» та «Природніми звуками» на біооб’єкт і збуджуючий вплив «Рок музики». Запропоновано створення автоматизованої системи зворотного зв’язку на основі відбору спектральних компонентів артеріальної осцилограми з метою оцінки психологічного стану, та способу психокорекції із використанням різних жанрів музикотерапії. &#13;\nСтворено загальний алгоритм психореабілітаційної автоматизованої системи зворотного зв’язку для музикотерапії та загальний алгоритм автоматизованого робочого місця психотерапевта з урахуванням системи для музикотерапії.

INTRODUCTION: Next to existing terminology of the lower urinary tract, due to its increasing complexity, the terminology for pelvic floor dysfunction in women may be better updated by a female-specific approach and clinically based consensus report. METHODS: This report combines the input of members of the Standardization and Terminology Committees of two international organizations, the International Urogynecological Association (IUGA), and the International Continence Society (ICS), assisted at intervals by many external referees. Appropriate core clinical categories and a subclassification were developed to give an alphanumeric coding to each definition. An extensive process of 15 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A terminology report for female pelvic floor dysfunction, encompassing over 250 separate definitions, has been developed. It is clinically based with the six most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Female-specific imaging (ultrasound, radiology, and MRI) has been a major addition while appropriate figures have been included to supplement and help clarify the text. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Journal Article Myopia and Inconsistency in Dynamic Utility Maximization Get access R. H. Strotz R. H. Strotz Evanston, Illinois Search for other works by this author on: Oxford Academic Google Scholar The Review of Economic Studies, Volume 23, Issue 3, 1955, Pages 165–180, https://doi.org/10.2307/2295722 Published: 01 December 1955

This paper presents a problem which I believe has not heretofore been analysed2 and provides a theory to explain, under different circumstances, three related phenomena: (1) spendthriftiness; (2) the deliberate regimenting of one’s future economic behaviour— even at a cost; and (3) thrift. The senses in which we deal with these topics can probably not be very well understood, however, until after the paper has been read; but a few sentences at this point may shed some light on what we are up to.

For the first time, stable aqueous dispersions of polymer-coated graphitic nanoplatelets can be prepared via an exfoliation/in-situ reduction of graphite oxide in the presence of poly(sodium 4-styrenesulfonate).

BACKGROUND: Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet. METHODS: We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days. RESULTS: At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline. CONCLUSIONS: Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274.).

Abstract Peptide amphiphiles are a class of molecules that combine the structural features of amphiphilic surfactants with the functions of bioactive peptides and are known to assemble into a variety of nanostructures. A specific type of peptide amphiphiles are known to self‐assemble into one‐dimensional nanostructures under physiological conditions, predominantly nanofibers with a cylindrical geometry. The resultant nanostructures could be highly bioactive and are of great interest in many biomedical applications, including tissue engineering, regenerative medicine, and drug delivery. In this context, we highlight our strategies for using molecular self‐assembly as a toolbox to produce peptide amphiphile nanostructures and materials and efforts to translate this technology into applications as therapeutics. We also review our recent progress in using these materials for treating spinal cord injury, inducing angiogenesis, and for hard tissue regeneration and replacement. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94:1–18, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.

Abstract Background. —Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in breast cancer and stratified them into categories reflecting the strength of published evidence. Materials and Methods. —Factors were ranked according to previously established College of American Pathologists categorical rankings: category I, factors proven to be of prognostic import and useful in clinical patient management; category II, factors that had been extensively studied biologically and clinically, but whose import remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected about existing prognostic factors, and (3) improving patient care. Results and Conclusions. —Factors ranked in category I included TNM staging information, histologic grade, histologic type, mitotic figure counts, and hormone receptor status. Category II factors included c- erb B-2 (Her2- neu ), proliferation markers, lymphatic and vascular channel invasion, and p53. Factors in category III included DNA ploidy analysis, microvessel density, epidermal growth factor receptor, transforming growth factor-α, bcl-2, pS2, and cathepsin D. This report constitutes a detailed outline of the findings and recommendations of the consensus conference group, organized according to structural guidelines as defined.

OBJECTIVE: The primary objectives of this report were, first, to determine the number and incidence of complications of transsphenoidal surgery performed by a cross-section of neurosurgeons in the United States and, second, to ascertain the influence of the surgeon's experience with the procedure on the occurrence of these complications. The secondary objective was to review complications of transsphenoidal surgery from the standpoint of their causation, treatment, and prevention. METHODS: Questionnaires regarding 14 specific complications of transsphenoidal surgery were mailed to 3172 neurosurgeons. The data reported were analyzed from the 958 respondents (82%) who reported performing the operation. The neurosurgeons surveyed were asked to estimate the number of transsphenoidal operations performed, to identify any complications observed, and to estimate the percentage of operations that had resulted in any of the 14 specific complications. The 958 respondents were placed into three experience groups, based on the number of transsphenoidal operations performed. The data were analyzed by using chi 2 tests and Spearman correlation coefficients. The secondary objectives were met through a detailed review of the literature, in light of our experience. RESULTS: Of the respondents, 87.3% reported having performed < 200 operations and 9.7% reported 200 to 500 previous operations. The remaining 3% reported more than 500 previous operations. More extensive previous experience with transsphenoidal surgery was associated with a greater likelihood of having witnessed each specific complication. The mean operative mortality rate for all three groups was 0.9%. Anterior pituitary insufficiency (19.4%) and diabetes insipidus (17.8%) were complications with the highest incidence of occurrence. The overall incidence of cerebrospinal fluid fistulas was 3.9%. Other significant complications, such as carotid artery injuries, hypothalamic injuries, loss of vision, and meningitis, occurred with incidence rates between 1 and 2%. An inverse relationship was found between the experience group and the likelihood of complications, as indicated by significant negative Spearman correlation coefficients for all but 2 of the 14 complications listed in the survey (P < 0.05). Thus, increased experience with transsphenoidal surgery seems to be associated with a decreased percentage of operations resulting in complications. Some caution should be exercised in interpreting these data, because they are based on the respondents' estimates. CONCLUSION: Transsphenoidal surgery seems to be a reasonably safe procedure, with a mortality rate of less than 1%. However, a significant number of complications do occur. The incidence of these complications seems to be higher, with statistical significance, in the hands of less experienced surgeons. The learning curve seems to be relatively shallow, because a statistically significantly decreased incidence of morbidity and death could be documented after 200 and even 500 transsphenoidal operations. Better understanding of the indications for transsphenoidal surgery and improved familiarity with the regional anatomy should further lower the incidence of death and morbidity resulting from this procedure in the hands of all neurosurgeons.

Primary and metastatic carcinomas are epithelial in origin and comprise by far the largest group of malignant tumors in humans. In most of these tumors, T and Tn antigens, whose epitopes have been synthesized, are uncovered and immunoreactive. In all other tissues T and Tn antigens are masked and not accessible to the immune system; they are generally precursors in normal complex carbohydrate chains. Thus, carcinomas have antigens recognized as foreign by the patients' immune system. The expression of T and Tn antigens has pathogenic and clinical consequences, and the antigens themselves are powerful histological markers in carcinoma diagnosis and frequently in prognosis. Most patients distinguish their carcinoma from all other cells, as shown by strong autoimmune responses to T antigen. These responses are readily measured by assays, and they allow detection of carcinomas with greater sensitivity and specificity frequently earlier than previously possible. Moreover, the extent of T and Tn expression often correlates with carcinoma differentiation; on a molecular level, clustered T- and Tn-active structures on carcinoma cell surfaces may be involved in invasion.

Peanut agglutinin was purified by affinity chromatography on Sepharose-epsilon-aminocaproyl-beta-D-galactopyranosylamine. The purified lectin obtained in a yield of 150 mg/100 g of defatted peanut was homogeneous on polyacrylamide gel electrophoresis, ultracentrifugation, and gel filtration. This intrinsic sedimentation coefficient (So20,w) and the intrinsic diffusion coefficient (Do20,w) were estimated at pH 7.4 as 5.7 +/- 0.1 S and 5.0 X 10(-7) cm2s(-1), respectively. The molecular weight of the agglutinin, determined by sedimentation and diffusion and by gel filtration, was found to be 110,000. Disc gel electrophoresis and gel filtration, both in the presence of sodium dodecyl sulfate, gave a single component of Mr = 27,500 suggesting that the lectin is a tetramer composed of four subunits. Four alanine residues per 110,000 g were found by NH2-terminal analysis and the sequence of the five NH2-terminal amino acids was: ALa-Glu-Ser-Val-Thr. Each cycle in a sequenator gave a single amino acid, suggesting that the four subunits are identical. Peanut agglutinin does not contain covalently bound sugar; it is devoid of cysteine and cystine, low in methionine, histidine, and tryptophan, but rich in acidic and hydroxyamino acids. The lectin agglutinated erthrocytes of human ABO blood types equally well, but only after they have been treated with neuraminidase. Of the monosaccharides tested for inhibition of hemagglutination only D-galactose and alpha- and beta-D-galactosides were active. High inhibitory activity was found with the Discaccharide DGalbeta(1 in equilibrium 3)DGalNAc and with the disialylated glycoproteins: alpha1-acid glycoprotein, fetuin, glycophorin, and human blood group NN or MM antigen. These desialylated glycoproteins also reacted with the lectin to form precipitin bands in Ouchterlony double diffusion in agar.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

CONTEXT: Persons with lower-extremity peripheral arterial disease (PAD) are often asymptomatic or have leg symptoms other than intermittent claudication (IC). OBJECTIVE: To identify clinical characteristics and functional limitations associated with a broad range of leg symptoms identified among patients with PAD. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 460 men and women with PAD and 130 without PAD, who were identified consecutively, conducted between October 1998 and January 2000 at 3 Chicago-area medical centers. MAIN OUTCOME MEASURES: Ankle-brachial index score of less than 0.90; scores from 6-minute walk, accelerometer-measured physical activity over 7 days, repeated chair raises, standing balance (full tandem stand), 4-m walking velocity, San Diego claudication questionnaire, Geriatric Depression Score Short-Form, and the Walking Impairment Questionnaire. RESULTS: All groups with PAD had poorer functioning than participants without PAD. The following values are for patients without IC vs those with IC. Participants in the group with leg pain on exertion and rest (n = 88) had a higher (poorer) score for neuropathy (5.6 vs 3.5; P<.001), prevalence of diabetes mellitus (48.9% vs 26.7%; P<.001), and spinal stenosis (20.8% vs 7.2%; P =.002). The atypical exertional leg pain/carry on group (exertional leg pain other than IC associated with walking through leg pain [n = 41]) and the atypical exertional leg pain/stop group (exertional leg pain other than IC that causes one to stop walking [n = 90]) had better functioning than the IC group. The group without exertional leg pain/inactive (no exertional leg pain in individual who walks </=6 blocks per week [n = 28]) and the leg pain on exertion and rest group had poorer functioning than those with IC. Adjusting for age, sex, race, and comorbidities and compared with IC, participants with atypical exertional leg pain/carry on achieved a greater distance on the 6-minute walk (404.3 vs 328.5 m; P<.001) and were less likely to stop during the 6-minute walk (6.8% vs 36%; P =.002). The group with pain on exertion and rest had a slower time for completing 5 chair raises (13.5 vs 11.9 seconds; P =.009), completed the tandem stand less frequently (37.5% vs 60.0%; P =.004), and had a slower 4-m walking velocity (0.80 vs 0.90 m/s; P<.001). CONCLUSIONS: There is a wide range of leg symptoms in persons with PAD beyond that of classic IC. Comorbid disease may contribute to these symptoms in PAD. Functional impairments are found in every PAD symptom group, and the degree of functional limitation varies depending on the type of leg symptom.

Introduction of tumor markers into routine clinical practice has been poorly controlled, with few criteria or guidelines as to how such markers should be used. We propose a Tumor Marker Utility Grading System (TMUGS) to evaluate the clinical utility of tumor markers and to establish an investigational agenda for evaluation of new tumor markers. A Tumor Marker Utility Grading Worksheet has been designed. The initial portion of this worksheet is used to clarify the precise characteristics of the marker in question. These characteristics include the marker designation, the molecule and/or substance and the relevant alteration from normalcy, the assay format and reagents, the specimen type, and the neoplastic disease for which the marker is being evaluated. To determine the clinical utility of each marker, one of several potential uses must be designated, including risk assessment, screening, differential diagnosis, prognosis, and monitoring clinical course. For each of these uses, associations between marker assay results and expected biologic process and end points must be determined. However, knowledge of tumor marker data should contribute to a decision in practice that results in a more favorable clinical outcome for the patient, including increased overall survival, increased disease-free survival, improvement in quality of life, or reduction in cost of care. Semiquantitative utility scales have been developed for each end point. The only markers recommended for use in routine clinical practice are those that are assigned utility scores of "++" or " " on a 6-point scale (ranging from 0 to ) in the categories relative to more favorable clinical outcomes. Each utility score assignment should be supported by documentation of the level of evidence used to evaluate the marker. TMUGS will establish a standardized analytic technique to evaluate clinical utility of known and future tumor markers. It should result in improved patient outcomes and more cost-efficient investigation and application of tumor markers.

The apoptotic signal triggered by ligation of members of the death receptor family is promoted by sequential activation of caspase zymogens. We show here that in a purified system, the initiator caspases-8 and -10 directly process the executioner pro-caspase-3 with activation rates (k cat/K m) of 8.7 × 105 and 2.8 × 105m−1 s−1, respectively. These rates are of sufficient magnitude to indicate direct processingin vivo. Differentially processed forms of caspase-3 that accumulate during its activation have similar rates of activation, activities, and specificities. The pattern and rate of caspase-8 induced activation of pro-caspase-3 in cytosolic extracts was the same as in a purified system. Moreover, immunodepletion of a putative intermediary in the pathway to activation, pro-caspase-9, was without consequence. Taken together these data demonstrate that the initiator caspase-8 can directly activate pro-caspase-3 without the requirement for an accelerator. The in vitro data thus help to deconvolute previous in vivo transfection studies which have debated the role of a direct versus indirect transmission of the apoptotic signal generated by ligation of death receptors. The apoptotic signal triggered by ligation of members of the death receptor family is promoted by sequential activation of caspase zymogens. We show here that in a purified system, the initiator caspases-8 and -10 directly process the executioner pro-caspase-3 with activation rates (k cat/K m) of 8.7 × 105 and 2.8 × 105m−1 s−1, respectively. These rates are of sufficient magnitude to indicate direct processingin vivo. Differentially processed forms of caspase-3 that accumulate during its activation have similar rates of activation, activities, and specificities. The pattern and rate of caspase-8 induced activation of pro-caspase-3 in cytosolic extracts was the same as in a purified system. Moreover, immunodepletion of a putative intermediary in the pathway to activation, pro-caspase-9, was without consequence. Taken together these data demonstrate that the initiator caspase-8 can directly activate pro-caspase-3 without the requirement for an accelerator. The in vitro data thus help to deconvolute previous in vivo transfection studies which have debated the role of a direct versus indirect transmission of the apoptotic signal generated by ligation of death receptors. tumor necrosis factor receptor 1 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate 7-amino-4-trifluoromethyl coumarin p-nitroanilide polyacrylamide gel electrophoresis bovine poly(ADP-ribose)polymerase tumor necrosis factor carbobenzoxy-Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl coumarin carbobenzoxy-Ile-Glu-Thr-Asp-7-amino-4-trifluoromethyl coumarin acetyl 1,4-piperazinediethanesulfonic acid polymerase chain reaction. Regulation of apoptosis is vital to the development and long term survival of metazoan animals. Apoptosis is required to maintain the balance between cell proliferation and cell death and, therefore, disruptions in the apoptotic program are associated with pathologies such as cancer, where there is too little cell death, and degenerative diseases, where there is too much cell death. Apoptosis can be initiated by at least three types of signals: (i) specific ligation of members on the tumor necrosis factor receptor (TNFR-1)1family, which includes Fas/Apo-1/CD95; (ii) cellular stress, which includes genotoxic damage and anti-neoplastic drugs; and (iii) delivery of granule-associated serine proteases from cytotoxic lymphocytes into target cells. Key mediators that initiate and execute the apoptotic program are members of the caspase family of cysteine proteases whose activation is believed to be essential for virtually all forms of apoptosis (1Salvesen G.S. Dixit V.M. Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar, 2Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4105) Google Scholar, 3Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar). Caspases-3, -6, and -7 are involved in the execution of cells in response to many apoptotic stimuli including ligation of death receptors of the TNFR-1 receptor family, resulting in cleavage of a number of proteins whose limited proteolysis is definitive of apoptosis. However, these executioner caspases are not directly activated by receptor ligation, but rely on the proteolytic activity of upstream initiator caspases-8 and -10 (4Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar, 5Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 6Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar). In the case of caspase-8 the activation occurs by recruitment of the zymogen to the cytosolic face of the death receptor, such that the initial proteolytic signal originates by autoprocessing of the clustered zymogen (7Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar, 8Yang X. Chang H.Y. Baltimore D. Mol Cell. 1998; 1: 319-325Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar).At the execution phase, caspase-3 seems to be upstream of caspases-6 and -7 and, therefore, its activation represents a key point in transmission of the proteolytic signal (9Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). However, the exact mechanism of how the death signal is conveyed from caspase-8 to caspase-3 remains unresolved. Is the apoptotic signal transmitted by direct activation of the executioners by the initiators, thus constituting a minimal two-step cascade that serves to mediate the apoptotic signals, or is the signal by the of as by Scaffidi C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google these have a of the activation of pro-caspase-3 by caspases-8 and -10 and proteases in a system, and to the activation of the zymogen by caspases-8 and -10 in cytosolic to the of that in transmission of the proteolytic death signal from the initiator caspases to the and on the of in vitro the that and of the apoptotic are required in are into and executioner (1Salvesen G.S. Dixit V.M. Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar, A.M. Dixit V.M. Biol. 1996; Full Text Full Text PDF PubMed Google Scholar). at which caspases initiate apoptotic is at the cell where members of the TNFR-1 family of death receptors a signal the cell receptor The point of the of X. J. R. X. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google G. 1997; Full Text PDF PubMed Scopus Google and pathway is is how the the apoptotic anti-neoplastic genotoxic and of cellular signal all to on the Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). point of the is specific caspase activation, and point In the death receptor the caspase-8 a proteolytic signal at the cytosolic face of the receptor (4Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar, 5Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 6Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar, T. R. J. S.M. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, C. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The signal for activation to be of that activity in its zymogen to proteolytic (7Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar, 8Yang X. Chang H.Y. Baltimore D. Mol Cell. 1998; 1: 319-325Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar, J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In the specific or delivery of D. S.M. Ahmad M. Alnemri E.S. X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar, T. G. J. Exp. Med. 1996; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, H. X. A. X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google to the in recruitment and activation of D. S.M. Ahmad M. Alnemri E.S. X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). caspase-8 and have to on in vitro and the executioner caspases whose activation with apoptosis. there are to activate the executioner and in caspases-8 and can be of as whose at the execution of caspases-8 and -10 can activate pro-caspase-3 in to the caspases directly or previous studies have on in vitro or cytosolic extracts S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar, M. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, T. R. J. S.M. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, K. Chinnaiyan A.M. M. Dixit V.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). We here demonstrate that caspase-8 and -10 can activate on caspase-8 that activation with the same rate in a cytosolic a requirement for an intermediary of from the on caspase activation by and cells in caspase-3 to of of in death apoptosis the and activation of caspase-3 which a to a role in caspase that are required to the apoptotic signal generated by of cells by but in a of cell C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar). that the caspase of the a In of the of caspase activity initiated by of caspase-8 to cytosolic extracts of is in the of T. M. Dixit S. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of to is is not a and the of activation of a caspase-3 or the caspase activity in extracts is to such an have not The data in not requirement for an intermediary between caspase-8 and the is the occurs in and caspase-8 its signal to the executioners in vivo. the for a role of in apoptosis triggered by death receptor ligation from studies of or which is to by apoptosis in Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). that apoptosis triggered by genotoxic and but there are in the data the of apoptosis induced by death receptors C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar, A.M. Dixit V.M. Biol. 1996; Full Text Full Text PDF PubMed Google Scholar, A. A. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, A. Krammer P.H. S. J. PubMed Scopus Google Scholar). In a of cell Scaffidi C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google that are not by from apoptosis triggered by However, the of and cell not be the to a role for apoptosis in which is on ligation, is in A. Krammer P.H. S. J. PubMed Scopus Google Scholar). In death of in was in A. M. T. A. A. D. A. Med. 1996; PubMed Scopus Google Scholar). These studies can be cells direct transmission of caspase-8 to a C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google is not processed by the upstream of the and, therefore, upstream of the the signal is activated by the of caspase-8 on or a that for apoptosis. The of the in death is not that a of cell to the caspase-8 direct transmission of the signal from caspase-8 to the executioner caspase-3 occurs in cell is the of a of are to as by the of the is not cells by a of to the death but studies on that cells in the that are to apoptosis during of the have death and the caspase-8 to direct transmission of the death and that pro-caspase-3 is a of caspase-8 Regulation of apoptosis is vital to the development and long term survival of metazoan animals. Apoptosis is required to maintain the balance between cell proliferation and cell death and, therefore, disruptions in the apoptotic program are associated with pathologies such as cancer, where there is too little cell death, and degenerative diseases, where there is too much cell death. Apoptosis can be initiated by at least three types of signals: (i) specific ligation of members on the tumor necrosis factor receptor (TNFR-1)1family, which includes Fas/Apo-1/CD95; (ii) cellular stress, which includes genotoxic damage and anti-neoplastic drugs; and (iii) delivery of granule-associated serine proteases from cytotoxic lymphocytes into target cells. Key mediators that initiate and execute the apoptotic program are members of the caspase family of cysteine proteases whose activation is believed to be essential for virtually all forms of apoptosis (1Salvesen G.S. Dixit V.M. Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar, 2Cohen G.M. Biochem. J. 1997; 326: 1-16Crossref PubMed Scopus (4105) Google Scholar, 3Nicholson D.W. Thornberry N.A. Trends Biochem. Sci. 1997; 22: 299-306Abstract Full Text PDF PubMed Scopus (2176) Google Scholar). Caspases-3, -6, and -7 are involved in the execution of cells in response to many apoptotic stimuli including ligation of death receptors of the TNFR-1 receptor family, resulting in cleavage of a number of proteins whose limited proteolysis is definitive of apoptosis. However, these executioner caspases are not directly activated by receptor ligation, but rely on the proteolytic activity of upstream initiator caspases-8 and -10 (4Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar, 5Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 6Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar). In the case of caspase-8 the activation occurs by recruitment of the zymogen to the cytosolic face of the death receptor, such that the initial proteolytic signal originates by autoprocessing of the clustered zymogen (7Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar, 8Yang X. Chang H.Y. Baltimore D. Mol Cell. 1998; 1: 319-325Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar). the execution phase, caspase-3 seems to be upstream of caspases-6 and -7 and, therefore, its activation represents a key point in transmission of the proteolytic signal (9Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). However, the exact mechanism of how the death signal is conveyed from caspase-8 to caspase-3 remains unresolved. Is the apoptotic signal transmitted by direct activation of the executioners by the initiators, thus constituting a minimal two-step cascade that serves to mediate the apoptotic signals, or is the signal by the of as by Scaffidi C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar). these have a of the activation of pro-caspase-3 by caspases-8 and -10 and proteases in a system, and to the activation of the zymogen by caspases-8 and -10 in cytosolic to the of that in transmission of the proteolytic death signal from the initiator caspases to the and on the of in vitro the that and of the apoptotic are required in vivo. are into and executioner (1Salvesen G.S. Dixit V.M. Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar, A.M. Dixit V.M. Biol. 1996; Full Text Full Text PDF PubMed Google Scholar). at which caspases initiate apoptotic is at the cell where members of the TNFR-1 family of death receptors a signal the cell receptor The point of the of X. J. R. X. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google G. 1997; Full Text PDF PubMed Scopus Google and pathway is is how the the apoptotic anti-neoplastic genotoxic and of cellular signal all to on the Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). point of the is specific caspase activation, and point In the death receptor the caspase-8 a proteolytic signal at the cytosolic face of the receptor (4Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar, 5Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 6Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar, T. R. J. S.M. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, C. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The signal for activation to be of that activity in its zymogen to proteolytic (7Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar, 8Yang X. Chang H.Y. Baltimore D. Mol Cell. 1998; 1: 319-325Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar, J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In the specific or delivery of D. S.M. Ahmad M. Alnemri E.S. X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar, T. G. J. Exp. Med. 1996; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, H. X. A. X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google to the in recruitment and activation of D. S.M. Ahmad M. Alnemri E.S. X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). caspase-8 and have to on in vitro and the executioner caspases whose activation with apoptosis. there are to activate the executioner and in caspases-8 and can be of as whose at the execution of caspases-8 and -10 can activate pro-caspase-3 in to the caspases directly or previous studies have on in vitro or cytosolic extracts S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar, M. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, T. R. J. S.M. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, K. Chinnaiyan A.M. M. Dixit V.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). We here demonstrate that caspase-8 and -10 can activate on caspase-8 that activation with the same rate in a cytosolic a requirement for an intermediary of from the on caspase activation by and cells in caspase-3 to of of in death apoptosis the and activation of caspase-3 which a to a role in caspase that are required to the apoptotic signal generated by of cells by but in a of cell C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar). that the caspase of the a In of the of caspase activity initiated by of caspase-8 to cytosolic extracts of is in the of T. M. Dixit S. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of to is is not a and the of activation of a caspase-3 or the caspase activity in extracts is to such an have not The data in not requirement for an intermediary between caspase-8 and the is the occurs in and caspase-8 its signal to the executioners in vivo. the for a role of in apoptosis triggered by death receptor ligation from studies of or which is to by apoptosis in Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). that apoptosis triggered by genotoxic and but there are in the data the of apoptosis induced by death receptors C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar, A.M. Dixit V.M. Biol. 1996; Full Text Full Text PDF PubMed Google Scholar, A. A. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, A. Krammer P.H. S. J. PubMed Scopus Google Scholar). In a of cell Scaffidi C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google that are not by from apoptosis triggered by However, the of and cell not be the to a role for apoptosis in which is on ligation, is in A. Krammer P.H. S. J. PubMed Scopus Google Scholar). In death of in was in A. M. T. A. A. D. A. Med. 1996; PubMed Scopus Google Scholar). These studies can be cells direct transmission of caspase-8 to a C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google is not processed by the upstream of the and, therefore, upstream of the the signal is activated by the of caspase-8 on or a that for apoptosis. The of the in death is not that a of cell to the caspase-8 direct transmission of the signal from caspase-8 to the executioner caspase-3 occurs in cell is the of a of are to as by the of the is not cells by a of to the death but studies on that cells in the that are to apoptosis during of the have death and the caspase-8 to direct transmission of the death and that pro-caspase-3 is a of caspase-8 are into and executioner (1Salvesen G.S. Dixit V.M. Cell. 1997; 91: 443-446Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar, A.M. Dixit V.M. Biol. 1996; Full Text Full Text PDF PubMed Google Scholar). at which caspases initiate apoptotic is at the cell where members of the TNFR-1 family of death receptors a signal the cell receptor The point of the of X. J. R. X. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google G. 1997; Full Text PDF PubMed Scopus Google and pathway is is how the the apoptotic anti-neoplastic genotoxic and of cellular signal all to on the Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). point of the is specific caspase activation, and point In the death receptor the caspase-8 a proteolytic signal at the cytosolic face of the receptor (4Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar, 5Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 6Srinivasula S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar, T. R. J. S.M. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, C. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The signal for activation to be of that activity in its zymogen to proteolytic (7Muzio M. Stockwell B.R. Stennicke H.R. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1998; 273: 2926-2930Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar, 8Yang X. Chang H.Y. Baltimore D. Mol Cell. 1998; 1: 319-325Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar, J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In the specific or delivery of D. S.M. Ahmad M. Alnemri E.S. X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar, T. G. J. Exp. Med. 1996; PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, H. X. A. X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google to the in recruitment and activation of D. S.M. Ahmad M. Alnemri E.S. X. Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). caspase-8 and have to on in vitro and the executioner caspases whose activation with apoptosis. there are to activate the executioner and in caspases-8 and can be of as whose at the execution of apoptosis. caspases-8 and -10 can activate pro-caspase-3 in to the caspases directly or previous studies have on in vitro or cytosolic extracts S.M. Ahmad M. Fernandes-Alnemri T. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14486-14491Crossref PubMed Scopus (480) Google Scholar, M. Salvesen G.S. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, T. R. J. S.M. Litwack G. Alnemri E.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar, K. Chinnaiyan A.M. M. Dixit V.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). We here demonstrate that caspase-8 and -10 can activate on caspase-8 that activation with the same rate in a cytosolic a requirement for an intermediary of from the on caspase activation by and cells in caspase-3 to of of in death apoptosis the and activation of caspase-3 which a to a role in caspase that are required to the apoptotic signal generated by of cells by but in a of cell C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar). that the caspase of the a In of the of caspase activity initiated by of caspase-8 to cytosolic extracts of is in the of T. M. Dixit S. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of to is is not a and the of activation of a caspase-3 or the caspase activity in extracts is to such an have not The data in not requirement for an intermediary between caspase-8 and the is the occurs in and caspase-8 its signal to the executioners in vivo. the for a role of in apoptosis triggered by death receptor ligation from studies of or which is to by apoptosis in Cell. 1997; 91: Full Text Full Text PDF PubMed Scopus Google Scholar). that apoptosis triggered by genotoxic and but there are in the data the of apoptosis induced by death receptors C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar, A.M. Dixit V.M. Biol. 1996; Full Text Full Text PDF PubMed Google Scholar, A. A. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, A. Krammer P.H. S. J. PubMed Scopus Google Scholar). In a of cell Scaffidi C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google that are not by from apoptosis triggered by However, the of and cell not be the to a role for apoptosis in which is on ligation, is in A. Krammer P.H. S. J. PubMed Scopus Google Scholar). In death of in was in A. M. T. A. A. D. A. Med. 1996; PubMed Scopus Google Scholar). These studies can be cells direct transmission of caspase-8 to a C. S. A. C. Krammer P.H. Peter M.E. J. 1998; PubMed Scopus Google Scholar). is not processed by the upstream of the and, therefore, upstream of the the signal is activated by the of caspase-8 on or a that for apoptosis. The of the in death is not that a of cell to the caspase-8 direct transmission of the signal from caspase-8 to the executioner caspase-3 occurs in cell is the of a of are to as by the of the is not cells by a of to the death but studies on that cells in the that are to apoptosis during of the have death and the caspase-8 to direct transmission of the death and that pro-caspase-3 is a of caspase-8 We Dixit for and and for

Background— The prospective, multinational, randomized Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial was designed to assess the optimal revascularization strategy between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), for patients with left main (LM) and/or 3-vessel coronary disease. Methods and Results— This observational hypothesis-generating analysis reports the results of a prespecified powered subgroup of 705 randomized patients who had LM disease among the 1800 patients with de novo 3-vessel disease and/or LM disease randomized to PCI with paclitaxel-eluting stents or CABG in the SYNTAX trial. Major adverse cardiac and cerebrovascular event rates at 1 year in LM patients were similar for CABG and PCI (13.7% versus 15.8%; Δ2.1% [95% confidence interval −3.2% to 7.4%]; P =0.44). At 1 year, stroke was significantly higher in the CABG arm (2.7% versus 0.3%; Δ−2.4% [95% confidence interval −4.2% to −0.1%]; P =0.009]), whereas repeat revascularization was significantly higher in the PCI arm (6.5% versus 11.8%; Δ5.3% [95% confidence interval 1.0% to 9.6%]; P =0.02); there was no observed difference between groups for other end points. When patients were scored for anatomic complexity, those with higher baseline SYNTAX scores had significantly worse outcomes with PCI than did patients with low or intermediate SYNTAX scores; outcomes for patients with CABG did not correlate with baseline SYNTAX score, but baseline EuroSCORE significantly predicted outcomes for both treatments. Conclusions— Patients with LM disease who had revascularization with PCI had safety and efficacy outcomes comparable to CABG at 1 year; longer follow-up is required to determine whether these 2 revascularization strategies offer comparable medium-term outcomes in this group of complex patients. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00114972.

BACKGROUND: We have previously reported that high expression of the erbB-2 gene (also known as HER-2/neu and ERBB2) in breast cancer is associated with patient response to dose-intensive treatment with cyclophosphamide, doxorubicin (Adriamycin), and 5-flurouracil (CAF) on the basis of short-term follow-up of 397 patients (set A) with axillary lymph node-positive tumors who were enrolled in Cancer and Leukemia Group B (CALGB) protocol 8541. METHODS: To validate those findings, we conducted immunohistochemical analyses of erbB-2 and p53 protein expression in an additional cohort of 595 patients (set B) from CALGB 8541, as well as a molecular analysis of erbB-2 gene amplification in tumors from all patients (sets A and B). Marker data were compared with clinical, histologic, treatment, and outcome data. RESULTS: Updated analyses of data from set A (median follow-up, 10.4 years) showed an even stronger interaction between erbB-2 expression and CAF dose, by use of either immunohistochemical or molecular data. A similar interaction between erbB-2 expression and CAF dose was observed in all 992 patients, analyzed as a single group. However, for set B alone (median follow-up, 8.2 years), results varied with the method of statistical analysis. By use of a proportional hazards model, the erbB-2 expression-CAF dose interaction was not significant for all patients. However, in the subgroups of patients randomly assigned to the high- or the moderate-dose arms, significance was achieved. When patient data were adjusted for differences by use of a prognostic index (to balance an apparent failure of randomization in the low-dose arm), the erbB-2 expression-CAF dose interaction was significant in all patients from the validation set B as well. An interaction was also observed between p53 immunopositivity and CAF dose. CONCLUSIONS: The hypothesis that patients whose breast tumors exhibit high erbB-2 expression benefit from dose-intensive CAF should be further validated before clinical implementation. Interactions between erbB-2 expression, p53 expression, and CAF dose underscore the complexities of predictive markers where multiple interactions may confound the outcome.