Subsequent Test Dose Research Articles

Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome

We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems.

Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: A possible mechanism and the potential for clinical application

We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l-OHP. In addition, it was confirmed that repeated administration of liposomal l-OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy.

Improving the reliability of single-aliquot regenerative dose dating using a new method of data analysis

The study of quartz grains (diameter 90–125 μm) from a modern dune sand from Australia shows a lack of perfect proportionality between the regenerated OSL (L) signal and the subsequent test dose OSL (T) signal when using a single-aliquot regenerative dose (SAR) procedure with a fixed 15 Gy dose repeated five times. This lack of perfect proportionality results in both a broad De distribution and systematic offset for the doses measured both with and without a preheat step at the end of each cycle of the SAR procedure. The problems caused by the lack of proportionality are overcome by a new method of handling the data generated by use of the SAR protocol; the OSL intensity is sensitivity-corrected using the slope of a plot of L versus T obtained from a number of aliquots, rather than the ratio of L/T obtained for individual aliquots. This approach is validated using laboratory irradiated quartz with given doses ranging from 5 Gy to 60 Gy; for the larger doses, correct values can be recovered using the new data analysis procedure is applied, but not when using the ratio of L/T obtained using conventional SAR analysis.

Investigating quartz optically stimulated luminescence dose–response curves at high doses

Despite the general expectation that optically stimulated luminescence (OSL) growth should be described by a simple saturating exponential function, an additional high dose component is often reported in the dose response of quartz. Although often reported as linear, it appears that this response is the early expression of a second saturating exponential. While some studies using equivalent doses that fall in this high dose region have produced ages that correlate well with independent dating, others report that it results in unreliable age determinations. Two fine grain sedimentary quartz samples that display such a response were used to investigate the origin of this additional high dose component: three experiments were conducted to examine their dose–response up to >1000 Gy. The high dose rates provided by laboratory irradiation were found not to induce a sensitivity change in the response to a subsequent test dose, with the latter not being significantly different from those generated following naturally acquired doses. The relative percentage contributions of the fast and medium OSL components remained fixed throughout the dose–response curve, suggesting that the electron traps that give rise to the initial OSL do not change with dose. An attempt was made to investigate a change in luminescence centre recombination probability by monitoring the depletion of the ‘325 °C’ thermoluminescence (TL) during the optical stimulation that would result in depletion of the OSL signal. The emissions measured through both the conventional ultraviolet (UV), and a longer wavelength violet/blue (VB) window, displayed similar relative growth with dose, although it was not possible to resolve the origin of the VB emissions. No evidence was found to indicate whether the additional component at high doses occurs naturally or is a product of laboratory treatment. However, it appears that these samples display an increased sensitivity of quartz OSL to high doses that is not recorded by the sensitivity to a subsequent test dose, and which results in a change in the sensitivity-corrected dose–response curve.

Formula omitted] determination for young samples using the standardised OSL response of coarse-grain quartz

It has recently been shown that it is possible to construct standardised curves of the sensitivity corrected growth in optically stimulated luminescence (OSL) with exposure to ionising radiation, and that they may be used in the dating of quartz and polymineral samples. Standardised growth curves are particularly advantageous where measurement time is limited, as once they have been defined, only the natural signal and the response to a subsequent test dose are required in order to determine the equivalent dose of a sub-sample. The present study is concerned with the application of the standardised growth curve approach to OSL dating of Holocene age samples. Systematic changes in the shape of the standardised growth curve of coarse-grain quartz are identified as the size of the test dose is varied, because of non-proportionality between the test dose and the luminescence test response. The effect is characterised by fitting the change in gradient of the standardised growth curve as test dose is varied. An equation is defined to describe standardised growth as a function of regenerative dose and test dose. Regenerative dose responses of other samples in this study are treated as unknowns and recovered through different growth curves to compare precision and accuracy of various methods of D e determination. The standardised growth curve is found to yield similar precision to conventional fits of single aliquot regenerative data, but slightly poorer accuracy. The standardised growth curve approach was refined by incorporating the measurement of one regenerative response for each aliquot as well as its natural signal. Measurements of this additional data point for aliquots of 22 samples were used to adjust the standardised growth equation, improving its accuracy. The incorporation of this additional data point also indicated a systematic uncertainty of 2.4% in the estimates of D e .

Luminescence dating of quartz using an improved single-aliquot regenerative-dose protocol

Single aliquot protocols are now widely used as a means of measuring the equivalent dose ( D e) in quartz and feldspar optical stimulated luminescence (OSL) dating of both heated and sedimentary materials. The most recent of these is the single-aliquot regenerative-dose (SAR) protocol, first suggested by Murray and Roberts (Radiation Measurements 29, 503–515, 1998). In this approach, each natural or regenerated dose OSL measurement is corrected for changes in sensitivity using the OSL response to a subsequent test dose (10–20% of D e). If the sensitivity correction is adequate, then the corrected OSL response should be independent of prior dose and thermal/optical treatment, i.e. there should be no change in the sensitivity-corrected dose–response curve on remeasurement. Here we examine the interpretation of the sensitivity corrected growth curve as a function of dose, and the effect of changing measurement conditions (e.g. preheat temperature, size of test dose, stimulation temperature) on the estimation of D e. The dependence of the dose response on prior treatment is tested explicitly, and the significance of thermal transfer discussed. It is concluded that a robust SAR protocol is now available for quartz, and that it is applicable to a wide range of heated and unheated materials.

Nicotine induced locomotor activity in rats: The role of Pavlovian conditioning

Rats repeatedly exposed to small doses of nicotine will demonstrate a significant augmentation of locomotor activity in response to a subsequent test dose of nicotine. A sensitization of brain tissue is hypothesized to account for this effect but Pavlovian conditioning might also be a major factor. Therefore the present study assessed the possible role of Pavlovian conditioning in this nicotine effect. Two experiments were conducted. In the first, subjects were administered either saline or nicotine in either their home cages or in activity test cages for five days. All subjects were then tested in the activity test cages on day six. In the second experiment rats were administered either nicotine or saline in the presence of a complex stimulus and later tested for response to nicotine alone and the complex stimulus alone. Results from these experiments indicate that Pavlovian conditioning does not play a major role in nicotine's effect on locomotor activity.

Role of protein component of endotoxin in modification of host reactivity.

SummaryThe influence of endotoxins of varying nitrogen content on water intake and numbers of hemolysin-forming spleen cells in mice and on delayed skin reactivity in rabbits has been investigated. Pretreatment with an aqueous-ether endotoxin of S. enteritidis results in heightened reactivity to a subsequent test dose of the aqueous-ether or protein-free (Ribi) endotoxin, whereas pretreatment with the protein-free endotoxin fails to modify subsequent reactivity to either endotoxin. Similarly, pretreatment with the Boivin endotoxin of S. abortus equi increases reactivity on subsequent test with the Boivin or Westphal endotoxin, whereas pretreatment with the partially deproteinized Westphal endotoxin does not enhance reactivity to subsequent test with either endotoxin. The implications of these findings for the hypothesis that adult host reactivity to endotoxins is contributed to by an acquired delayed hypersensitivity are discussed.

AMELIORATION OF CORTISONE-INDUCED PITUITARY-ADRENAL SUPPRESSION BY ESTRADIOL.

Administration of cortisone acetate, 2.5 mg daily for 7 days, to male and female rats reduces both pituitary ACTH content and adrenal weight. Plasma corticosterone concentrations measured at rest and 30 min after ether stress or ACTH injection are decreased in cortisone-treated animals. A greater degree of depression is produced in male rats given steroid than in females. The concomitant administration of a depot ACTH preparation with cortisone leads to an increased plasma corticosterone response to a subsequent test dose of ACTH. However, no change is obtained in the impaired response to stress. Polyestradiol-17β phosphate (Estradurin), administered as a single depot injection of 2 mg/100 g body weight, significantly modifies all the effects of cortisone. Compared to cortisone-treated rats, pituitary ACTH content is higher in unstressed animals and the net falls in ACTH content are significantly greater after stress. Plasma corticosterone responses to both ACTH and stress are enhanced in rats given estra...

RÔLE OF INBORN RESISTANCE FACTORS IN MOUSE POPULATIONS INFECTED WITH BACILLUS ENTERITIDIS

1. Under conditions in which mouse typhoid is allowed to spread naturally among herds of mice comprised of different proportions of individuals of innately high or low susceptibility: (a) 85 to 95 per cent of the innately susceptible succumb to mouse typhoid in contrast to less than 5 per cent of the innately resistant, regardless of whether either constitutes 25, 50, or 75 per cent of the population respectively. (b) The surviving population is therefore comprised largely of individuals known at the outset to be innately resistant. These resistants are, nevertheless, apt to have become infected and to harbor mouse typhoid bacilli in their spleens and feces. 2. Under conditions in which recruits are added to surviving populations comprised chiefly of innately resistants among which mortalities have practically ceased: (a) Mouse typhoid infection spreads to both innately resistant and susceptible recruits. (b) Mortality from mouse typhoid is limited almost exclusively to the innately susceptible recruits and is "sporadic" or "epidemic" in character according to the numbers and proportion of susceptibles added. (c) Innately resistant recruits remain well unless subjected to some non-specific hazard, such as heat or overcrowding, in which case both they and the susceptibles succumb in proportions similar to their relative numbers in the population. 3. It was plain that survivors are almost exclusively the individuals known at the outset to have been innately resistant. 4. There was no tendency for known susceptibles to become immunized through herd exposure at epidemic times, at postepidemic times in which the dosage of mouse typhoid bacilli was relatively small, nor at repeated short intervals. Finally, susceptibles given repeated, known, sublethal doses of mouse typhoid bacilli or St. Louis encephalitis virus by a natural route failed to develop immunity against a subsequent test dose.