Long-term survival, prevalence, and cure of cancer: a population-based estimation for 818 902 Italian patients and 26 cancer types.

BACKGROUND: Persons living after a cancer diagnosis represent 4% of the whole population in high-income countries. The aim of the study was to provide estimates of indicators of long-term survival and cure for 26 cancer types, presently lacking. PATIENTS AND METHODS: Data on 818 902 Italian cancer patients diagnosed at age 15-74 years in 1985-2005 were included. Proportions of patients with the same death rates of the general population (cure fractions) and those of prevalent patients who were not at risk of dying as a result of cancer (cure prevalence) were calculated, using validated mixture cure models, by cancer type, sex, and age group. We also estimated complete prevalence, conditional relative survival (CRS), time to reach 5- and 10-year CRS >95%, and proportion of patients living longer than those thresholds. RESULTS: The cure fractions ranged from >90% for patients aged <45 years with thyroid and testis cancers to <10% for liver and pancreatic cancers of all ages. Five- or 10-year CRS >95% were both reached in <10 years by patients with cancers of the stomach, colon-rectum, pancreas, corpus and cervix uteri, brain, and Hodgkin lymphoma. For breast cancer patients, 5- and 10-year CRSs reached >95% after 19 and 25 years, respectively, and in 15 and 18 years for prostate cancer patients. Five-year CRS remained <95% for >25 years after cancer diagnosis in patients with liver and larynx cancers, non-Hodgkin lymphoma, myeloma, and leukaemia. Overall, the cure prevalence was 67% for men and 77% for women. Therefore, 21% of male and 31% of female patients had already reached 5-year CRS >95%, whereas 18% and 25% had reached 10-year CRS >95%. CONCLUSIONS: A quarter of Italian cancer patients can be considered cured. This observation has a high potential impact on health planning, clinical practice, and patients' perspective.

Prognostic value of EGFR expression in de novo and progressed atypical and anaplastic meningiomas: an immunohistochemical and fluorescence in situ hybridization pilot study.

AIM: The aim of this study was to assess both the epidermal growth factor receptor (EGFR) protein expression by immunohistochemistry and the EGFR gene amplification by fluorescence in situ hybridization in meningiomas of different grade, in order to evaluate their possible role in the development of the disease. EGFR protein belongs to the family of tyrosine kinase growth factor receptors, which also includes HER2, HER3 and HER4. Elevated expression or activity of EGFR has been reported in several cancers, including brain tumours. EGFR activation can enhance the malignant potential of epithelial tissues. METHODS: We investigated whether there was a difference in the EGFR protein expression and the EGFR gene amplification between the so called de novo malignant meningiomas and recurrent meningiomas with or without malignant progression from a previously lower grade tumor. Our goal was to evaluate if EGFR expression was a useful marker to select patients affected by meningioma with a major risk of recurrences. We also assessed the prognostic value of the EGFR expression on overall survival. RESULTS: Progression from benign meningiomas to atypical or anaplastic meningiomas correlated with an increase in the expression of EGFR protein. Our study shows that EGFR immunostaining in meningiomas directly correlates to the tumor's grade. The EGFR expression did not correlate with the overall survival and the recurrence-free survival of the patients affected by meningioma (de novo, recurrent and progressed). CONCLUSION: We submit that the EGFR expression is not a useful prognostic element to identify patients with a major risk of meningioma recurrence.

[Complete (R0) resection is the only valid prognostic factor in abdominoperineal resection for recurrent cancer of the anal canal (a consecutive series of 95 patients)]. / Résection R0, seul facteur pronostique dans les amputations abdominopérinéales de rattrapage des cancers du canal anal (série consécutive de 95 patients).

INTRODUCTION: When radiation therapy fails to control cancer of the anal canal, the only therapeutic alternative is salvage abdomino-perineal resection (APR). Its role remains debatable since very few long-term survivals have been reported. No prognostic factors have yet been identified in the limited series of reported cases. PATIENTS: 95 APR's performed over a 20 year period are reviewed and analyzed. RESULTS: Median follow-up was 5.5 years. Only one prognostic factor was identified: an R0 resection (n=76) versus either R1 (n=9) or R2 (n=9) resection. Median survival for R0 APR was more than 10 years versus 1 year for R1 and R2 resections (p=0.001). There was no prognostic difference between salvage APR for disease progression (n=55) or for late recurrence (n=40). The sub-group of women<45 years of age (n=5) had a particularly poor prognosis with no survivors beyond 2 years. CONCLUSION: When anal cancer recurs after radiation therapy, a salvage APR is indicated. If an R0 resection can be achieved, median survival is greater than 10 years. However, the justification for APR when only an R1 or R2 resection can be achieved is much less clear; in such cases there was no survival beyond 3 years.

Phased-array grating compression for high-energy chirped pulse amplification lasers.

The development of phased-array grating compressor is a crucial issue for high-energy, ultra-short pulse petawatt-class lasers. We present a theoretical and experimental analysis of two-grating phasing in a broadband pulse mosaic compressor. The phase defaults induced by misaligned gratings are studied. Monochromatic grating phasing is experimentally achieved with an interferometric technique and pulse compression is demonstrated with a two-phased-array grating system.

Efficient restricted gene expression in beta cells by lentivirus-mediated gene transfer into pancreatic stem/progenitor cells.

AIMS/HYPOTHESIS: Gene transfer into pancreatic beta cells, which produce and secrete insulin, is a promising strategy to protect such cells against autoimmune destruction and also to generate beta cells in mass, thereby providing a novel therapeutic approach to treat diabetic patients. Until recently, exogenous DNA has been directly transferred into mature beta cells with various levels of success. We investigated whether exogenous DNA could be stably transferred into pancreatic stem/progenitor cells, which would subsequently differentiate into mature beta cells expressing the transgene. METHODS: We designed transplantation and tissue culture procedures to obtain ex vivo models of pancreatic development. We next constructed recombinant lentiviruses expressing enhanced green fluorescent protein (eGFP) under the control of either the rat insulin promoter or a ubiquitous promoter, and performed viral infection of rat embryonic pancreatic tissue. RESULTS: Embryonic pancreas infected with recombinant lentiviruses resulted in endocrine cell differentiation and restricted cell type expression of the transgene according to the specificity of the promoter used in the viral construct. We next demonstrated that the efficiency of infection could be further improved upon infection of embryonic pancreatic epithelia, followed by their in vitro culture, using conditions that favour endocrine cell differentiation. Under these conditions, endocrine stem/progenitor cells expressing neurogenin 3 are efficiently transduced by recombinant lentiviral vectors. Moreover, when eGFP was placed under the control of the insulin promoter, 70.4% of the developed beta cells were eGFP-expressing cells. All of the eGFP-positive cells were insulin-producing cells. CONCLUSIONS/INTERPRETATION: We have demonstrated that mature rat pancreatic beta cells can be stably modified by infecting pancreatic stem/progenitor cells that undergo endocrine differentiation.

Interactions between verapamil and neutral and acidic liposomes: effects of the ionic strength.

Patients with cancer often develop major electrolyte disorders, which are aggravated by radiation therapy and chemotherapy and by the concomitant impairment of the renal function and the development of drug resistance. In addition, tumour cells have membranes with more negative charges than normal eukaryotic cells. This study was designed to test the hypothesis that the ability of the Ca(2+) blocker verapamil to mediate the reversal of multidrug resistance (MDR) by interacting with the membrane phospholipids may be correlated with the ionic strength and membrane surface potential in resistant tumours. The permeation properties of verapamil, which is the best-known MDR-modulator, were therefore studied by quantifying its ability to induce the leakage of carboxyfluorescein through unilamellar liposomes containing various mole fractions of phosphatidic acid (x(EPA)=0, 0.1 and 0.3), at four different ionic strengths (I=0.052, 0.124, 0.204 and 0.318 M). The dye leakage induced by verapamil varied greatly with I, depending on x(EPA). The permeation process was a co-operative one (1.3

Blood glucose normalization upon transplantation of human embryonic pancreas into beta-cell-deficient SCID mice.

AIMS/HYPOTHESIS: Transplanting human pancreatic islet beta cells could represent a radical new treatment of Type I (insulin-dependent) diabetes mellitus. However, beta cells available for grafting are scarce and finding new sources of such cells would be crucial for any cell therapy for diabetes. Undifferentiated precursor cells present in the human embryonic pancreas could represent such a source. METHODS: We grafted human embryonic pancreases (6-9 weeks of development) that contain very few beta cells onto NOD/scid mice. RESULTS: The human pancreatic tissue grew, increasing in weight 200 times within six months and endocrine cells differentiated, the number of human beta cells being increased by a factor 5000. Finally, the developed human endocrine tissue was mature enough to control the glycaemia of mice deficient in endogenous beta cells. CONCLUSION/INTERPRETATION: Human embryonic pancreas represent a source of immature cells that can proliferate and differentiate into mass beta cells after transplantation. Transplantation of human embryonic pancreas into NOD/scid mice is a useful model for understanding the development of the human pancreas during prenatal life.

Designing multidrug-resistance modulators circumventing the reverse pH gradient in tumours.

Multidrug-resistant tumours often exhibit a reverse pH gradient (acid outside), as they have an acid extracellular pH (pHe) and a neutral alkaline intracellular pH (pHi). This study was designed to test the hypothesis that the ability of lipophilic drugs to mediate multidrug resistance (MDR) reversal by interacting with the membrane phospholipids may be correlated with pH in resistant tumours. The permeation properties of five MDR modulators were therefore studied at 37 degrees C by quantifying their ability to induce the leakage of Sulfan blue through unilamellar anionic liposomes, over the range pH 6.5-7.7, and in the absence of any membrane potential (pHe = pHi). The dye leakage induced by two calcium blockers (diltiazem and verapamil) and two antiparasitic agents (thioacridine derivative and mepacrine) was found to significantly increase with the pH of the medium (P < 0.001), whereas that induced by a non-ionic detergent (Triton X-100) showed almost no pH-dependent variations. This process was a cooperative one (0.8 < Hill coefficient < 8.5) and the permeation doses inducing 50% dye leakage (PD50) ranged from 1.6 to 36.0 mM. The permeation ability of the MDR modulators (log(1/PD50)) significantly increased with their octanol-buffer distributions (logD) (slope = 0.35+/-0.06; y intercept = 1.65 +/- 0.14; P < 0.0001) and significantly decreased with their net electric charge (z) (slope = -0.48+/-0.07; y intercept = 2.85+/-0.08; P < 0.0001). A highly significant multiple correlation was found to exist between the variations of log(1/PD50) with those of logD and z (dlog(1/PD50)/dlogD = 0.21 +/- 0.05; dlog(1/PD50)/dz = -0.34+/-0.07; y intercept = 2.27+/-0.17; P < 0.000001). The results provide evidence that in resistant tumours (acid pHe and neutral alkaline pHi), the MDR reversal might be enhanced by favourable drug-membrane interactions if the modulators are designed in the form of highly lipophilic (logP approximately equals 4) mono-basic drugs with a near neutral pKa (pKa approximately equals 7-8).

Carbanion-induced decompositions of beta,gamma-unsaturated peroxides containing electron-deficient double bonds.

The treatment of a beta,gamma-unsaturated peroxide, containing an electron-deficient double bond, by a carbanion Z(-) led to the transformation of the compound by a process involving the addition of the carbanion to the double bond, followed by an S(N)i reaction on the peroxidic bond, with the liberation of an alkoxylate anion. When the carbanion was regenerated by proton abstraction from a ZH substrate by this oxyanion, the anionically induced decomposition occurred using catalytic amounts of sodium ethoxylate to initiate it. When this abstraction was not efficient, stoichiometric amounts of carbanion were necessary to decompose the unsaturated peroxide. These induced decompositions are a good source of epoxides, which were the end reaction products. However, in some cases, this heterocycle could give secondary reactions as a result of the attack of the liberated 1,1-dimethylethoxylate on it. The importance of these reactions depended upon the nature of the precursor of carbanion ZH.

Thermal dependence of multidrug-resistant-modulator efficiency: a study in anionic liposomes.

This study was designed to test the hypothesis that there exists a correlation between the ability of lipophilic drugs to mediate the reversal of multidrug-resistance (MDR) by interacting with the membrane phospholipids and the metabolic level in tissues. The permeation properties of five MDR-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through unilamellar liposomes, over the temperature range 27-42 degrees C. The dye leakage induced by a non-ionic detergent (Triton X-100), two calcium blockers (diltiazem and verapamil) and two antiparasitic agents (thioacridine derivative and mepacrine) was temperature-dependent. The permeation process was a co-operative one (1.1 < Hill coefficient < 7.5) and the permeation doses inducing 50% dye leakage (PD50) were 1.5 - 14.9 mM. The permeation ability of the MDR-modulators (log(1/PD50)) decreased significantly as the net electric charge (z) increased. The passive dye leakage (deltaG < 0) was found to be an endothermic process (deltaH > 0), favoured by an increase in the membrane disorder (deltaS > 0). The apparent enthalpy factor (deltaH50) associated with 50% dye leakage increased with the net electric charge of the compound, and this energetically non-favoured event was entirely offset by the concomitant increase in the entropy factor (deltaS50). The apparent permeation enthalpy (deltaH50) and entropy (deltaS50) showed the lowest values for Triton X-100 (deltaH50 = 7.1 +/- 0.53 kJ mol(-1), deltaS50 = 76.9 +/- 1.86 Jmol(-1) K(-1)), and the highest values for mepacrine (deltaH50 = 79.5 +/- 3.80 kJmol(-1), deltaS50 = 306.7 +/- 5-97 J mol(-1) K(-1)). When the temperature was increased from 27 to 42 degrees C, the apparent Gibbs free energy (deltaG50) of the dye leakage induced by Triton X-100 decreased by less than 10% of the initial value, and that induced by mepacrine decreased by nearly 40%. The results provide evidence that in tissues with high metabolic levels and therefore high temperatures, MDR-reversal is likely to be enhanced via favourable drug-membrane interactions controlled by the electric charge of the modulators.

Intramolecular homolytic displacements. 30. Functional decarbonylative transformations of aldehydes via homolytically induced decomposition of unsaturated peroxyacetals

Homolytically induced decompositions of unsaturated peroxyacetals, synthesized from aldehydes, gave alkoxyalkoxyl radicals that yielded alkyl radicals by rapid beta-scission. The latter radicals could react with several types of "transfer agents" to smoothly bring about homolytic decarbonylative functional group transformations of aldehydes into halides, hydrocarbons, xanthates, alkanenitriles, 2-alkyl-3-chloromaleic anhydrides, 1-phenylalk-1-ynes, and ethyl 2-alkylpropenoates.

Membrane permeation by multidrug-resistance-modulators and non-modulators: effects of hydrophobicity and electric charge.

This study was designed to test the hypothesis that lipophilic cationic drugs with only roughly similar structures mediate the reversal of multidrug-resistance (MDR) by interacting with membrane phospholipids. The permeation properties of MDR-modulators and non-modulators were studied by quantifying their ability to induce the leakage of Sulphan blue through the membrane of negatively charged unilamellar liposomes. Of the 22 compounds under investigation, only those bearing a net positive electric charge per molecule (z) > or = 0.2 induced dye leakage. All these efficient drugs are well-known MDR-modulators: calcium-channel blockers (propranolol, verapamil, diltiazem and dipyridamole), calmodulin antagonists (clomipramine and thioridazine) and antiparasitic agents (mepacrine, thioacridine derivatives and quinine). The non-modulators tested, including antineoplastic agents and steroids, did not induce any membrane permeation. The permeation process was a co-operative one (1.1 < Hill coefficient < 4.1) and the permeation doses inducing 50% dye leakage (PD50) were 1.9-11.2 mM. The permeation ability of the MDR-modulators (log(1/PD50)) increased significantly with octanol-buffer distributions per unit net electric charge ((logD)/z). The results provide evidence that a complex interplay occurs between the electric charge and the lipophilicity of the MDR-modulators when a dye leakage is induced through model membranes, and probably also when the MDR is reversed in leukaemic cells.

Potassium transport in opossum kidney cells: effects of Na-selective and K-selective ionizable cryptands, and of valinomycin, FCCP and nystatin.

The effects of two ionizable cryptands, the Na-selective (221)C10 and the K-selective (222)C10, and of valinomycin, FCCP and nystatin on K+ fluxes in opossum kidney (OK) cells have been quantified. The Na,K-ATPase (ouabain-sensitive 86Rb influx) was stimulated by nystatin (> or = 20%), and inhibited by the other ionophores (50-80%), by barium (K-channel blocker) (61%) and by amiloride (Na entry blocker) (34%). The Vmax of the Na,K-ATPase phosphatase activity was unmodified by the ionophores, indicating the absence of direct interaction with the enzyme. The ATPi content was unmodified by the inhibitors and nystatin, but was lowered by (221)C10 (47%), (222)C10 (75%), valinomycin (72%) and FCCP (88%). Amiloride was found to partially remove the inhibition caused by (222)C10 (51%) and valinomycin (49%). Rb efflux was stimulated by nystatin (32%), unmodified by valinomycin, and was inhibited by (221)C10 (19%), (222)C10 (19%) and FCCP (10%). Barium (39%) and amiloride (32%) inhibited this efflux and, in their presence, the nystatin effect persisted, whereas that of the other ionophores vanished. At pH 6.4, the Rb efflux decreased by 14% of its value at pH 7.4, with no additional inhibition by cryptands. Cryptands are shown to inhibit the pH-sensitive K+-conductance, probably by inducing a K+-H+ exchange at the plasma membrane, and by uncoupling oxidative phosphorylation by inducing the entry of K+ and H+ (and possibly Ca2+) ions into the mitochondria.

[Pain in lumbar puncture. Results of a 2-year discussion at the French Society of Pediatric Oncology]. / La douleur de la ponction lombaire. Résultats de 2 années de réflexion au sein de la Société Française d'Oncologie Pédiatrique.

BACKGROUND: Lumbar puncture is a common procedure in pediatric onco-hematology. Repeated invasive painful procedures may contribute to increase distress displayed during medical treatment, and cause regression, depression and other psychological disorders. MATERIAL AND METHODS: A two-year workshop of the Société française d'oncologie pédiatrique was reviewed through a questionnaire assessing changes in technical management of lumbar puncture, local anesthesia, sedation and cognitive-behavioral interventions. RESULTS: Significant changes were found for pain assessment, local anesthesia procedures, and nitrous oxide administration. The extensive use of the Emla cream largely contributed to reduce pain. Anxiety however remained an unsolved problem, particularly among young children. CONCLUSION: Pain in pediatrics remains a major challenge. This workshop is a model of reflexion to achieve a better management of pain during invasive medical procedures.

Transport of competing Na and K ions by (222) C10-cryptand, an ionizable mobile carrier: effects of pH and temperature.

The kinetics of the electroneutral exchange of competing sodium and potassium with protons across the membrane of large unilamellar vesicles (LUV) were determined at two pH values when transport was induced by the simultaneous presence of (222)C10-cryptand and FCCP (proton carrier) at various temperatures. The aim of the present work was to quantify the pH-dependent enthalpies of an ionizable mobile carrier affinities for competing alkali cations, and to focus on the effects of pH and temperature on the competitive transport selectivity of the carrier for K+ over Na+ ions. At any given temperature and pH, the apparent pH-dependent affinity of (222)C10 was higher for K+ than for Na+. The enthalpy of this affinity for K+ was significantly lower than that for Na+, whereas it varied similarly with the pH (delta H(KpHmK) = 32.8 and 37.0 kJ/mol, and delta H(KpHmNa) = 47.9 and 52.9 kJ/mol at pH 7.8 and 8.8, respectively). When using a kinetic model, the pH effect on these parameters was discriminated (delta H(KmK) = 37.9 kJ/mol and delta H(KmNa) = 53.9 kJ/mol). The pH-dependence of the delta H(KpHm) of the cations could therefore theoretically be shown to arise from the temperature-induced changes in the ionization of the buffer dissolved in the aqueous phases and of the amine groups of the binding cavity of the carrier. The K/Na competitive transport selectivity (Sc(K/Na)) of (222)C10 increased linearly with the K+ concentration. It decreased hyperbolically with increasing concentration of Na+ while being independent of pH at any given temperature. In equimolecular ionic mixtures, Sc(K/Na) varied from 2.2 to 3.0 when temperature rose from 20 degrees C to 35 degrees C (delta H(Sc(K/Na)) = 15.6 +/- 0.5 kJ/mol). The results are discussed in terms of the structural, physico-chemical and electrical characteristics of carriers and complexes.

Na/K competitive transport selectivity of (221)C10-cryptand: effects of pH and carrier concentration.

The kinetics of the competitive transport of Na+ and K+ ions across the membrane of large unilamellar vesicles (LUV) were determined when transport was induced by (221)C10-cryptand, an ionizable mobile carrier. The experiments were performed at various pH values (7.7 and 8.7) and carrier concentrations (0.1, 0.5 and 1.0 microM) in order to quantify the effects of these parameters on the Na/K competitive transport selectivity of this mobile carrier. At any given pH and carrier concentration, the apparent affinity of (221)C10 for Na+ was higher and less dependent on the concentration of the other competing ion than that for K+. The Na/K competitive transport selectivity (SC(Na/K)) of (221)C10 increased linearly with the Na+ concentrations, decreased hyperbolically with increasing those of K+ and was independent of the pH and of the carrier concentration. In equimolecular ionic mixtures, this competitive selectivity amounted to about 1.5 and when the pH rose, the carrier selectivity for Na+ over K+ ions was enhanced by cation competition compared to transport of cations as unique substrates. Equations were established to describe the variations of the competitive transport selectivity (SC) of cryptands, and for comparison of their noncompetitive selectivity (SNC), with the ionic concentrations, the Michaelis parameters of the cations and the pH. The reaction order in Na+ (n(Na)) increased significantly with decreasing the pH and the K+ concentration. The results are discussed in terms of the structural, physico-chemical and electrical characteristics of carriers and complexes.

Na/K competitive transport selectivity of (221) C10-cryptand: effect of temperature.

The kinetics of the competitive transport of Na+ and K+ ions across the membrane of large unilamellar vesicles (LUV) were determined when transport was induced by (221)C10-cryptand at various temperatures in order to quantify the temperature-dependence of the Na/K competitive transport selectivity of this ionizable mobile carrier. At any given temperature, the apparent affinity of (221)C10 for Na+ was higher and less dependent on the concentration of the other competing ion than that for K+. Its enthalpy for Na+ (delta H(KmNa) = 50.6 kJ/mol) was not significantly different from that for K+ (delta H(KmK) = 52.7 kJ/mol). The Na/K competitive transport selectivity (SC(Na/K)) of (221)C10 increased linearly with the Na+ concentrations and decreased hyperbolically with increasing those of K+. When the cation concentrations were equal, this competitive selectivity amounted to about 2 at any given temperature. Equations were established to describe the variations of the competitive transport selectivity (SC) of cryptands, and for comparison of their noncompetitive selectivity (SNC), with the ionic concentrations and the Michaelis parameters of the cations. It is theoretically demonstrated that the ratio between the competitive and noncompetitive transport selectivities, i.e., SC/SNC, of mobile carriers does not depend on the Jmax of the competing ions and that its value amounts to 1 when the specific concentrations (C'S/Km) of the ions are equal. Under these conditions, the transport selectivity of any given mobile carrier has the same value whether determined from competition or separated experiments. The reaction order in Na+ (n(Na)) increased significantly as the temperature rose and decreased significantly as the K+ concentration increased. The results are discussed in terms of the structural, physicochemical and electrical characteristics of carriers and complexes.

Structural requirements for unsaturated fatty acids and fatty alcohols to induce optimal biological responses: an approach using model membranes.

The permeation induced by unsaturated fatty acids and fatty alcohols through the membrane of dihexadecyl phosphate vesicles was quantified, using [Ru(bpy)3(2+)] ions as a permeant probe. In both the free fatty acid and the free fatty alcohol series, the permeation induced by the unsaturated isomers is higher than that of the corresponding saturated analogues. Moreover the permeant effect associated with free fatty acids or free fatty alcohols is under the control of structural and conformational parameters: carbon chain length, number and position of the double bonds, and the geometry Z or E of the double bond. Optimal membrane perturbing effects are observed for compounds having a carbon chain length ranging from 18 to 20 carbon atoms, incorporating two or four Z double bonds in the center of the carbon chain. Good correlation has been found between the membrane perturbing effect quantified as PD50 values and some of the biological properties associated with these fatty lipids. The PD50 values obtained for free fatty alcohols are in fair agreement with anesthetic properties reported by different authors, (Pringle et al., 1981) while PD50 values obtained for free fatty acids show a good correlation with their activity on the superoxide respiratory burst induced by chemotactic peptides. These preliminary results led to the conclusion that as far as a biological activity directly associated with unsaturated fatty acids or alcohols, involved a membrane barrier passage, the measure of their permeant properties using a DHP vesicle model appears to be an excellent criterion for the quantification of optimal biological effects.