Favorable Advantage Research Articles

Cardiac profiles of liposomal anthracyclines: greater cardiac safety versus conventional doxorubicin?

Although conventional doxorubicin is associated with favorable clinical outcomes in patients with a variety of tumor types, it long has been associated with the risk of development of cardiotoxicity. Therefore, researchers have focused their efforts on the development of new formulations to improve efficacy while minimizing associated toxicities. The most successful strategy reported to date has been liposomal encapsulation, which alters the pharmacokinetics of the drug, with the goal of maintaining efficacy and improving the therapeutic index. The cardiac profiles of three liposomal anthracyclines, liposomal daunorubicin, nonpegylated liposomal doxorubicin, and pegylated liposomal doxorubicin, were reviewed. More studies will be needed to determine the cardiac safety of liposomal daunorubicin. Although nonpegylated liposomal doxorubicin demonstrated more favorable cardiac safety compared with conventional doxorubicin, its cardiac safety appeared to be mitigated when high bolus doses were administered. Of the liposomal formulations, the strongest evidence of cardiac safety was observed with pegylated liposomal doxorubicin. Compared with conventional doxorubicin, pegylated liposomal doxorubicin was associated with a significantly lower risk of development of cardiac events (P < 0.001). Moreover, the risk of cardiotoxicity was not increased in patients who were treated with pegylated liposomal doxorubicin at cumulative doses > 450 mg/m(2) or in patients at increased risk for cardiotoxicity, such as those with prior adjuvant doxorubicin use. Liposomal doxorubicin formulations provided a favorable advantage over conventional doxorubicin in terms of cardiac safety. Recent evidence also suggests that the improved cardiac safety of liposomal doxorubicin formulations is reflected by their successful use in combination with trastuzumab and other chemotherapy agents.

In vivo selection of human hematopoietic cells in a xenograft model using combined pharmacologic and genetic manipulations.

Strategies that increase the ability of human hematopoietic stem and progenitor cells to repair alkylator-induced DNA damage may prevent the severe hematopoietic toxicity in patients with cancer undergoing high-dose alkylator therapy. In the context of genetic diseases, this approach may allow for selection of small numbers of cells that would not otherwise have a favorable growth advantage. No studies have tested this approach in vivo using human hematopoietic stem and progenitor cells. Human CD34(+) cells were transduced with a bicistronic oncoretrovirus vector that coexpresses a mutant form of O(6)-methylguanine DNA methyltransferase (MGMT(P140K)) and the enhanced green fluorescent protein (EGFP) and transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Mice were either not treated or treated with O(6)-benzylguanine (6BG) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). At 8-weeks postinjection, a 2- to 8-fold increase in the percentage of human CD45(+)EGFP(+) cells in 6BG/BCNU-treated versus nontreated mice was observed in the bone marrow and was associated with increased MGMT(P140K)-repair activity. Functionally, 6BG/BCNU-treated mice demonstrated multilineage differentiation in vivo, although some skewing in the maturation of myeloid and B cells was observed in mice transplanted with granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood compared to umbilical cord blood. Expansion of human cells in 6BG/BCNU-treated mice was observed in the majority of mice previously transplanted with transduced umbilical cord blood cells. In addition, a significant increase in the number of EGFP(+) progenitor colonies in treated versus nontreated mice were observed in highly engrafted mice indicating that selection and maintenance of human progenitor cells can be accomplished by expression of MGMT(P140K) and treatment with 6BG/BCNU.

Safety goals for a fusion reactor

The author proposes a new concept of fusion safety goals (SGs), which extends a framework of the International Nuclear Event Scales (INES), and incorporates medium risk characteristics of fusion power plants. Quantitative health objectives (QHOs) after a release of radioactive tritium and activated tokamak dust are incorporated with master risk curves. It is shown that one of the most favorable safety advantage of a fusion reactor is in its benign hazard characteristics, in which land contamination, equivalent to that experienced in the Chernobyl accident, can be physically excluded. No evacuation of the public is envisaged, although it is prudent to be prepared for potential agriculture restriction.

Modeling heavy-tailed correlated clutter via wavelet packet bases with application to seismic event estimation

A model for correlated and heavy-tailed background noise in time series data is introduced. The approach is based on a multi-resolution time adaptive wavelet packet expansion that assigns to each resolution and band a measure of spikiness associated with independent t distributed variates. The model is adaptive similarly in time, scale, and correlation structure within the dyadic structure of the wavelet packet framework. Parameter estimation is accomplished by recursions in time at each frequency band/scale. The model is applied to both ground motion data and shallow water ocean acoustic background noise. A comparison with the Gaussian model suggest its favorable advantage. Estimators for transient signals based on the new model are derived and show usefulness in extracting transients with unknown or weakly specified characteristics. The usefulness of the model and the estimator is demonstrated via a comparison with the fixed transform DWT on quarry blast seisms. The results show that the method outperforms DWT based estimation in MSE by a factor of 2 at a moderate SNR for these classes of transients. [Work supported by ONR.]

Prognostication in Chronic Obstructive Pulmonary Disease: Implications for Lung Transplantation

Chronic obstructive pulmonary disease (COPD) is the most common disease for which single lung transplantation (SLT) is performed and is a frequent reason for bilateral lung transplantation (BLT). Recent data suggest a favorable survival advantage for patients with COPD undergoing lung transplantation compared with other diagnoses. This has led some investigators to question whether transplantation leads to improved survival in COPD patients compared with alternative treatment and whether this surgical therapy is appropriate in these individuals. These viewpoints may reflect the difficulties inherent in accurately predicting short- and long-term survival in patients with advanced COPD. Our review of the available data suggests that clinical, physiological, and radiographic features allow the identification of COPD patients with increased mortality despite maximal medical therapy. In these high risk individuals transplantation remains a viable therapeutic option.

The role of estrogen receptor mutations in tamoxifen-stimulated breast cancer.

During the past 20 years, the hormonal therapy of choice for the treatment of breast cancer has been the antiestrogen, tamoxifen. The use of tamoxifen has been proved to produce a favorable response and survival advantage in patients whose tumors are classified as estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+). Additionally, tamoxifen is the only drug known to reduce the incidence of contralateral disease. This drug produces relatively few harmful side effects, while exhibiting several beneficial effects such as maintaining bone density and reducing the incidence of myocardial infarction in the postmenopausal woman. However, tumors eventually acquire a tamoxifen-resistant or tamoxifen-stimulated phenotype, resulting in disease recurrence. Several mechanisms have been proposed to account for tamoxifen-resistant breast cancer, in the hope of developing a more effective first-line or perhaps second-line treatment strategy. One popular theory is the occurrence of a mutation in the estrogen receptor, the drug target. A plethora of studies have reported the detection of estrogen receptor mRNA splice variants, and it has been suggested that the accumulation of these variant mRNAs are responsible for the development of tamoxifen-resistant breast cancer. In this review, several questions will be posed to address the suitability of both laboratory and clinical evidence to support this hypothesis. Although there is adequate data generated in the laboratory, there is, as yet, no compelling evidence to suggest that mutation of the estrogen receptor is the molecular mechanism producing tamoxifen-stimulated growth in human breast and endometrial cancer.

Mapping knowledge to rules for scheduling expert systems

Although the theoretical framework of expert systems has been well established, the process of developing a non-trivial expert system is still considered a difficult task. The main reason for this is that the nature of expert systems is knowledge-intensive. Also, it is usually difficult for domain experts to explain or communicate their expertise to the system professionals. Many methodologies have been proposed to overcome this domain knowledge representation problem. Most of them require the assistance of an expert system shell (tool). However, with a purpose of helping the system development in mind, most of them were not satisfactory. This research takes the experience of implementing a course scheduling expert system, and suggests two analysis methods to describe the characteristics of course scheduling knowledge. It is shown that these methods provide assistance on clarifying the complicated scheduling problem. Another favorable advantage of this method is its capability helping the transferring of domain knowledge to rules in the knowledge base.

Phase I study of intraperitoneal carboplatin as adjuvant therapy in early ovarian cancer

Early stage poor-risk ovarian cancer patients are at considerable risk for recurrent disease. Adjuvant radio- or chemotherapy has been found to improve disease-free and overall survival. Carboplatin, a second generation platinum, is documented comparable in efficacy to cisplatin in patients with advanced ovarian cancer. The toxicity profile is different from that of cisplatin. Dose-limiting toxicity is myelosuppression. The incidence and grade of renal and neurological toxicity is much lower compared with cisplatin, as is nausea and vomiting. Carboplatin given intraperitoneally (ip) is shown to have a favorable theoretical therapeutic advantage compared with iv administration since the peak peritoneal cavity/peak plasma concentration ratio is 18. Patients with early stage ovarian cancer seem suitable for carboplatin ip treatment. The study was designed to find the maximal tolerated dose (MTD). Three new patients were given two courses at each dose level. The MTD found was confirmed with further patients. Carboplatin was given in 2 liters of glucose via a subcutaneous implantable port without removal of fluid from the cavity. The starting dose was 300 mg/m2. Dose-limiting toxicity was thrombocytopenia and leukopenia. Leukocyte and platelet counts were reconstituted within 28 days in all cases. One case of severe but transient nephrotoxicity was observed. MTD was determined to 500 mg/m2.

Phase I study of intraperitoneal carboplatin as adjuvant therapy in early ovarian cancer

Early stage poor-risk ovarian cancer patients are at considerable risk for recurrent disease. Adjuvant radio- or chemotherapy has been found to improve disease-free and overall survival. Carboplatin, a second generation platinum, is documented comparable in efficacy to cisplatin in patients with advanced ovarian cancer. The toxicity profile is different from that of cisplatin. Dose-limiting toxicity is myelosuppression. The incidence and grade of renal and neurological toxicity is much lower compared with cisplatin, as is nausea and vomiting. Carboplatin given intraperitoneally (ip) is shown to have a favorable theoretical therapeutic advantage compared with iv administration since the peak peritoneal cavity/peak plasma concentration ratio is 18. Patients with early stage ovarian cancer seem suitable for carboplatin ip treatment. The study was designed to find the maximal tolerated dose (MTD). Three new patients were given two courses at each dose level. The MTD found was confirmed with further patients. Carboplatin was given in 2 liters of glucose via a subcutaneous implantable port without removal of fluid from the cavity. The starting dose was 300 mg/m 2. Dose-limiting toxicity was thrombocytopenia and leukopenia. Leukocyte and platelet counts were reconstituted within 28 days in all cases. One case of severe but transient nephrotoxicity was observed. MTD was determined to 500 mg/m 2.

Phase I/pharmacokinetic study of thioguanine administered as a 48-hour continuous intraperitoneal infusion.

Thioguanine (TG) is an antimetabolite with established antileukemic activity. The most pharmacologically rational manner of TG administration is continuous infusion. Intraperitoneal (IP) delivery of TG provides the opportunity to definitively test the concept of high-dose, long-term antimetabolite administration. The high systemic clearance and in vitro activity of TG against ovarian carcinoma suggested that it would be an excellent candidate for IP administration as a prolonged infusion. TG was administered as a 48-hour continuous IP infusion in this phase I/pharmacokinetic study. TG infusions were administered using a portable, programmable pump (Pancretec Provider Model 2000; Pancretec, Inc, San Diego). Twenty-five patients were treated. At a dose of 900 mg/m2/48 h, TG produced unacceptably severe myelosuppression. The dose-limiting toxicity was granulo-cytopenia. Other toxicities were mild: emesis, alopecia, skin rashes, and photosensitivity reactions. IP TG did not produce chemical peritonitis, hepatotoxicity, or mucositis. The pharmacokinetics of IP TG were determined in 16 patients. TG levels were measured by reverse-phase high-performance liquid chromatography (HPLC). At steady state, the mean peritoneal to plasma TG ratio was 1,800 at the maximum tolerated dose (MTD). Steady-state TG levels in the peritoneal cavity and plasma were 2 mmol/L and 1.1 mumol/L, respectively, at a dose of 744 mg/m2. The elimination half-life of TG from the peritoneal cavity was one hour. TG exhibited linear pharmacokinetics over the dosage range investigated. Encouraging clinical activity was seen with IP TG. There was one partial response (PR) and four minor responses (MR). TG can be safely administered by the IP route. The recommended dose for phase II testing is 744 mg/m2/48 h. IP TG has a favorable pharmacokinetic advantage and has demonstrated encouraging clinical activity. Further studies of IP TG infusions are warranted.

Performance of Layers Confronted with Monthly Changes in Diet Composition

Twelve replicate groups of 4 individually caged commercial strain White Leghorns were offered one of three diets formulated to common specifications. These formulations were: 1) corn-soybean as the sole major ingredient, 2) least cost using conventional ingredient level constraints, and 3) absolute least cost with no ingredient level constraints. Formulation of diets 2 and 3 fluctuated commensurate with ingredient prices during the trial through July 1976 to August 1977. Changes of diets fed were made abruptly each 28 days of production. Conventional production characteristics were measured each 28 days. Egg production was not significantly influenced by diet treatment, and feed intake was comparable in all but one treatment period. Birds consuming absolute least cost diets produced smaller eggs during two periods of production (P<.05) compared to birds offered the standard corn-soy diets; this former group of birds also produced eggs of inferior shell quality (P<.01) compared to all other birds during the first 28 days of production. Although not significantly different (P>.05), a 16.8% mortality of birds fed absolute least cost diets was more than double the rate observed for other treatment groups. Diet had no effect (P>.05) on economic analysis as measured by egg return minus feed cost. It is concluded that, although absolute least cost formulation of layer diets results in dramatic formulation changes, layer performance is not generally affected. Failure to elicit a favorable economic advantage, however, questions the risk involved in removing ingredient level constraints.

Turbomolecular pumps for high gas flow applications

Turbomolecular pumps used for maintaining a sputtering chamber in the 0.5–10 Pa region must be able to pump a large flow of gas as well as be able to exhaust the system to a suitable base pressure. This paper discusses the effects of turbomolecular-to-forepump speed ratio, or staging ratio, and the rotational velocity on the pumping performance in both the high-vacuum and high-gas-flow regions. It concludes that pumps having a low compression ratio for hydrogen require a low staging ratio, as low as 20:1, to maintain high hydrogen pumping speed in the high-vacuum region, and that the light gas compression ratio is increased in the presence of flowing argon. The favorable economic advantage of the turbomolecular pump relative to the diffusion pump and the cryogenic pump is discussed.

Equity, equality, and the protestant ethic: Allocating rewards following fair and unfair competition

Female undergraduates scoring high and low on the Mirels-Garrett Protestant Ethic (PE) Scale divided a fixed reward between themselves and a co-worker following competition on a clerical task. Half the subjects were told that they had either won or lost in fair competition. The remaining subjects were told they had either won or lost because of an error that gave a favorable advantage to one of the performers. When the competition was fair, high PEs distributed the rewards available according to an equity norm, keeping more than half when they won and less than half when they lost. When the competition was unfair, high PEs attempted to reestablish fairness by compensating the performer with the unfair disadvantage. However, low PEs kept approximately half the reward regardless of fairness and regardless of whether they won or lost.

The Effect of Ballot Position on Electoral Success

Although the relationship between ballot position and electoral success has been well established in other studies, a controlled experimental study was conducted to assess the impact of name identification, the length of the ballot, and the number of candidates. These intervening variables were found to be of some significance. Although the study demonstrates that candidates listed first enjoy a favorable advantage, it also demonstrates that the advantage is even greater for contests at the end of the ballot. Although the number of candidates in any particular contest seems to have no effect on the relationship, a high differential score in name identification offsets any advantage a candidate might enjoy as a consequence of ballot position. Finally, the study demonstrates that citizens are less likely to vote when the contenders are less well known.

О ПИТАЊИМА ЛАТИНСКИХ КРАТИЦА НА ДИПЛОМАТИЧКИМ ПОВЕЉАМА

Кратице, интерпункције, сигле, те друге врсте кратица и бројевним знацима биле суставни део и старовековних а посебно средњовековних повеља. Како је израда материјала за писање била веома скупоцена, посебно коже (пергамене), прибегавало се скраћивању речи у тексту како би се на мањем простору могло написати што више текста. Сложеност проблематике јест да је свака канцеларија и регија те врста латинског писма (од каролине, беневентане, куријале до готице и хуманистике) имала свој систем скраћивања слова. Начин дешифровања појединих скраћеница у повељама јест на граници науке и уметности, а у којем су неки ауторитети имали своје својствене ставове и решења. Дешифровање и ишчитавање латинских рукописа је дипломатици и палеографији дала врло важно место у помоћним историјским наукама, а на чему се заснива једно од темељних делова развоја историјске науке уопште.

Biologists and Political Issues

The letter by Anderson (Ecology and Politics, BioScience 18: 7, July 1968) provides a meritorious suggestion in urging concerned individuals to organize toward more effectively presenting ecological problems as political issues. Personal communication with Dr. Anderson reveals a discouraging response from readers of BioScience, of whom only four individuals replied. As an environmental physiologist, my concern is primarily with air, water, and soil contamination and the decrements in human adaptive capacity to physical-chemical pollutants induced by the psycho-social stress of crowding, nutritive state, or genetic endowment. Although the consequences of these deleterious effects are not readily sensed because of the gradual but inevitable accumulation of noxiousness, it becomes increasingly clear that planet Earth is a self-contained spaceship with a closed cycle environmental control system. Current technology assumes a favorable economic advantage from increasing production and consumption of goods without due regard to the disposal of concomitant waste. The traditional notion that the Earth represents a waste receptacle of infinite capacity might hold true if all that waste were biodegradable at a rate that is commensurate with its production. This notion must yield to the potential correlation of cumulative noxiousness in the environment with human chronic disability and altered metabolism or lethality in certain animal and plant species of the total ecosystem. If the biological community does not believe this, I would desire an expression of rational thinking for the disbelief. If the biological community agrees with the thesis, then their inactivity toward problem resolution is inexcusable. Must the biologists, too, in concert with the rest of humanity, wait for the calamitous onset of irreversible damage; or might we assume a communicative leadership to our legislatures toward providing a base for adequate legislation and effective urban planning for a continuing expanding population. Is the biologist also a citizen? The issues are political ones, and the candidates for office at the presidential level and below should be urged to express their viewpoints in a forthright manner. I would further suggest that regional organizations of concerned biologists be implemented throughout this Nation and patterned after the Committee for Environmental Information, the publisher of Scientist and Citizen. I'm certain that this Committee would provide advisory inputs for such an expanded effort. ROBERT S. POGRUND Associate Professor of Public Health University of California, Los Angeles

Biochemical disturbances and clinical symptoms during prolonged exchange resin therapy in congestive heart failure

1. 1. Twelve patients with congestive heart failure have been treated with 30 to 60 gm. per day of a carboxylic cation exchanger, 80 per cent in the hydrogen and 20 per cent in the potassium forms, for intervals up to fifteen months in length. These resins provided a relatively safe supplement to the basic therapy for approximately six months. Thereafter hyponatremia, hypopotassemia and hypocalcemia were frequently observed. The problem of hypocalcemia may prove to be a significant obstacle to longer, safe therapy with these materials. 2. 2. The exchangers did not permit significant liberalization of dietary sodium. The aforementioned findings indicate that an increase in the efficiency and specificity of the presently available exchange resins is necessary if they are to serve their uniquely favorable advantage of harmlessly liberalizing the intake of sodium in patients with edema.