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PubMed2000

Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network.

The release of amyloidogenic amyloid-beta peptide (Abeta) from amyloid-beta precursor protein (APP) requires cleavage by beta- and gamma-secretases. In contrast, alpha-secretase cleaves APP within the Abeta sequence and precludes amyloidogenesis. Regulated and unregulated alpha-secretase activities have been reported, and the fraction of cellular alpha-secretase activity regulated by protein kinase C (PKC) has been attributed to the ADAM (a disintegrin and metalloprotease) family members TACE and ADAM-10. Although unregulated alpha-secretase cleavage of APP has been shown to occur at the cell surface, we sought to identify the intracellular site of PKC-regulated alpha-secretase APP cleavage. To accomplish this, we measured levels of secreted ectodomains and C-terminal fragments of APP generated by alpha-secretase (sAPPalpha) (C83) versus beta-secretase (sAPPbeta) (C99) and secreted Abeta in cultured cells treated with PKC and inhibitors of TACE/ADAM-10. We found that PKC stimulation increased sAPPalpha but decreased sAPPbeta levels by altering the competition between alpha- versus beta-secretase for APP within the same organelle rather than by perturbing APP trafficking. Moreover, data implicating the trans-Golgi network (TGN) as a major site for beta-secretase activity prompted us to hypothesize that PKC-regulated alpha-secretase(s) also reside in this organelle. To test this hypothesis, we performed studies demonstrating proteolytically mature TACE intracellularly, and we also showed that regulated alpha-secretase APP cleavage occurs in the TGN using an APP mutant construct targeted specifically to the TGN. By detecting regulated alpha-secretase APP cleavage in the TGN by TACE/ADAM-10, we reveal ADAM activity in a novel location. Finally, the competition between TACE/ADAM-10 and beta-secretase for intracellular APP cleavage may represent a novel target for the discovery of new therapeutic agents to treat Alzheimer's disease.

Amyloid Precursor Protein Secretases↗
PubMed2005

Usability of gait analysis in the alignment of trans-tibial prostheses: a clinical study.

The purpose of the study was to investigate which systematic effects of prosthetic misalignment could be observed with the use of the SYBAR system. The alignment of the prosthesis of five well-trained unilateral trans-tibial amputees was changed 15 degrees in magnitude in varus, valgus, flexion, extension, endorotation, exorotation, dorsal flexion, and plantar flexion. Subjects walked over a distance of 8 m at a self-selected walking speed with the alignment of the prosthesis as it was at the start of the experiment (reference) and with each changed alignment. Two video cameras (frontal and sagittal) and a force plate of the SYBAR system (Noldus Information Technology, The Netherlands) were used to capture gait characteristics of the subjects. Temporal and spatial characteristics, the magnitude and timing of the ground reaction force (GRF), and the external joint moments were derived from these data. Despite the substantial perturbations to prosthetic alignment, only a few effects were observed in the temporal and spatial characteristics of gait, the magnitude and timing of the GRF, and the external joint moments. Only the pattern of the ground reaction force in the mediolateral direction and the joint moment around the ankle in the frontal plane during terminal stance showed a systematic effect when the alignment was set into varus and valgus or exorotation. It was concluded that using the SYBAR system in this study revealed little effect of perturbations in prosthetic alignment, for this group of patients, and for the selected parameters. It was questioned whether this is due to the relatively low resolution of the SYBAR system or the capacity of the well-trained subjects to compensate for the disturbance in alignment. It was suggested that the usability of the SYBAR system in clinical settings should be further explored.

Adult↗
PubMed1976

Cell kinetics and chemotherapy in neuroblastoma.

The proliferative behavior of neuroblastoma cells in bone marrow was evaluated before and after perturbation by chemotherapy. The data presented indicated that the proliferating fraction of the tumor cells before therapy was small. In most of the patients, initial therapy with a non-cell-cycle specific agent increased the mitotic and labeling indices. If initial therapy was followed by a cell cycle-specific agent, variable kinetic responses were observed. Although the number of patients was small and the follow-up was short, there was a correlation between the clinical response and the kinetic changes induced by the chemotherapy. Evaluation of cell kinetic changes during the initial course of chemotherapy might identify early those patients who are unlikely to have a good clinical response. Similar studies in the evaluation of new drugs to aid in identifying agents that favorably change cell kinetics and thus therapy for children with neuroblastoma was urged.

Antineoplastic Agents↗
PubMed2003

Expression of a bacterial xylose isomerase in potato tubers results in an altered hexose composition and a consequent induction of metabolism.

Here we investigate the role of hexoses in the metabolism of the developing potato (Solanum tuberosum) tuber by the expression of a bacterial xylose isomerase which catalyzes the interconversion of glucose and fructose. Previously, we found that glycolysis was induced in transgenic tubers expressing a yeast invertase in the cytosol and postulated that this was due either to the decreased levels of sucrose or to effects downstream of the sucrose cleavage. In the present study xylose isomerase was expressed under the control of the tuber-specific patatin promoter. Selected transformants exhibited minor changes in the levels of tuber glucose and fructose but not in sucrose. Analysis of the enzyme activities of the glycolytic pathway revealed minor yet significant increases in the maximal catalytic activities of aldolase and glyceraldehyde 3-phosphate dehydrogenase but no increase in the activities of other enzymes of glycolysis. These lines were also characterized by an elevated tuber number, glycolytic and sucrose synthetic fluxes and in some metabolite levels downstream of glycolysis. When considered together these data suggest that the perturbation of hexose levels can result in increased glycolytic and sucrose (re)synthetic fluxes in the potato tuber even in the absence of changes in the level of sucrose. The consequences of altering hexose levels in the tuber are, however, not as severe as those observed following perturbation of the level of tuber sucrose.

Aldose-Ketose Isomerases↗
PubMed2006

In vitro organ culture of the bovine intervertebral disc: effects of vertebral endplate and potential for mechanobiology studies.

STUDY DESIGN: Whole bovine coccygeal discs were cultured under static load, with or without vertebral endplates (VEPs), and assessed for cell viability, biochemical stability, biosynthetic activity, and biosynthetic responsiveness to changes in mechanical load. OBJECTIVES: To assess the effects of VEPs on biochemical and cellular stability of disc cells during in vitro culture of large disc explants. To determine whether cultured discs could respond to mechanical perturbation. SUMMARY OF BACKGROUND DATA: Previous methods for culturing the intervertebral disc have focused on rabbit and rat discs, but the small size of these discs limits the relevance of these culture systems to the human condition. Bovine coccygeal discs have similar dimensions to the human lumbar disc (i.e., similar size and nominal stresses), but long-term culture of these discs has not been reported. METHODS: Bovine coccygeal discs were harvested with or without VEPs, cultured under static load (5 kg, approximately 0.25 MPa, in situ swelling pressure) for up to 1 week, and evaluated for changes in hydration, glycosaminoglycan content, cell viability, and biosynthetic activity. Additionally, the biochemical and biosynthetic response of discs cultured without VEP to increasing the load to a 20-kg (approximately 1 MPa, the estimated stress in human lumbar disc during heavy lifting) static load for 6 hours was assessed. RESULTS: During the first 24 hours, culturing discs with endplates was moderately better with regards to maintaining in situ anulus hydration and nucleus glycosaminoglycan levels. The endplates, however, obstructed media flow to the disc, resulting in a marked decrease in cell viability after 1 week of culture. Nucleus pulposus cell viability was maintained in discs cultured without endplates, but there was a significant drop in biosynthetic activity within 2 days of culture. Despite this drop, the disc cells in the discs without VEP remained biosynthetically responsive to changes in mechanical loading. CONCLUSIONS: It is possible to maintain cell viability and the biosynthetic responsiveness of large discs for up to 1 week in vitro when the discs are cultured under static load and without VEP.

Animals↗
PubMed2001

Observation of two-magnon bound states in the two-leg ladders of (Ca,La)(14)Cu(24)O(41).

Phonon-assisted two-magnon absorption is studied in the spin- 1/2 two-leg ladders of (Ca,La)(14)Cu(24)O(41) for E parallel c (legs) and E parallel a (rungs). We verify the theoretically predicted existence of two-magnon singlet bound states, which give rise to peaks at approximately equal to 2140 and 2800 cm(-1). The two-magnon continuum is observed at approximately equal to 4000 cm(-1). Two different theoretical approaches (Jordan-Wigner fermions and perturbation theory) describe the data very well for J parallel approximately equal to 1020-1100 cm(-1), J parallel/J perpendicular approximately equal to 1-1.2. At high energies, the magnetic contribution to sigma(omega) is strikingly similar in the ladders and in the undoped high-T(c) cuprates, which emphasizes the importance of strong quantum fluctuations in the latter.

Journal Article↗
PubMed2003

Measurement of the proton spin structure function g1(x,Q2) for Q2 from 0.15 to 1.6 GeV2 with CLAS.

Double-polarization asymmetries for inclusive ep scattering were measured at Jefferson Lab using 2.6 and 4.3 GeV longitudinally polarized electrons incident on a longitudinally polarized NH3 target in the CLAS detector. The polarized structure function g(1)(x,Q2) was extracted throughout the nucleon resonance region and into the deep inelastic regime, for Q(2)=0.15-1.64 GeV2. The contributions to the first moment Gamma(1)(Q2)= integral g(1)(x,Q2) dx were determined up to Q(2)=1.2 GeV2. Using a parametrization for g(1) in the unmeasured low x regions, the complete first moment was estimated over this Q2 region. A rapid change in Gamma(1) is observed for Q2<1 GeV2, with a sign change near Q(2)=0.3 GeV2, indicating dominant contributions from the resonance region. At Q(2)=1.2 GeV2 our data are below the perturbative QCD evolved scaling value.

Journal Article↗
PubMed1999

The control of foot placement during compensatory stepping reactions: does speed of response take precedence over stability?

Rapid, reflex-like stepping movements are a prevalent and functional compensatory reaction to destabilization, however, little is known about the underlying control. In this paper, a model is developed to examine how speed and stability demands affect control of foot placement during forward and backward compensatory stepping reactions. The concept of the velocity stability margin (VSM) is introduced to characterize the degree to which the horizontal velocity of the falling body approaches biomechanical limits on the capacity to decelerate the center of mass; analogous limits on center-of-mass displacement are quantified in terms of the displacement stability margin (DSM). The model is used to predict, for any initial step characteristics, the variation in DSM and VSM that would occur as a function of changes in timing of foot placement. The VSM was found to prevail over the DSM in establishing limits of stability. Model simulations demonstrated that there typically exists a minimum swing duration that maximizes speed of response while meeting minimum requirements for stability (VSM > or = 0), as well as a slower speed of response (longer swing duration) at which stability (VSM) is maximized. Experimental data from platform-perturbation tests in 20 healthy young (22-28) and older (65-81) adults were used, in conjunction with the model, to investigate whether speed or stability takes precedence during natural behavior. Control of single-step reactions appeared to favor stability; although the model predicted that a minimally stable step (VSM = 0) could be attained by swing durations as short as 30 ms, the observed swing durations were, on average, 135 ms longer than this, and the average VSM was nearly as large (80%) as the optimally stable value predicted by the model. Control of the initial step of multiple-step reactions was distinctly different. The average swing duration was only 55 ms greater than the minimally stable value and the average VSM was 81% smaller than in the single-step reactions. This reduction in VSM is consistent with a need to execute additional steps and appears to support the validity of the model. This model may help to provide insight into the biomechanical factors that govern the neural control of compensatory stepping reactions.

Adult↗
PubMed2005

The effects of growth hormone status on circulating levels of vascular growth factors.

BACKGROUND: Vascular growth factors are important not only in angiogenesis but also for the maintenance of normal endothelial integrity and function. Elevated levels of vascular endothelial growth factor (VEGF), angiopoietin-2, hepatocyte growth factor (HGF), endostatin and angiogenin have been associated with endothelial dysfunction and atherosclerosis. Both acromegaly and growth hormone deficiency (GHD) are associated with endothelial dysfunction and changes in blood vessel morphology. AIM: To investigate the effect of GH status on the circulating levels of angiogenic factors. DESIGN: We measured the levels of six endothelial growth modulators, four angiogenic growth factors and two inhibitors of angiogenesis in 35 untreated acromegalics, 36 untreated GH-deficient subjects and 101 normal control subjects. Fifteen GH-deficient subjects were also studied before and 1 year after treatment with GH. RESULTS: Mean angiogenin concentrations were increased in acromegaly and decreased in GH-deficient subjects compared to control subjects. Endostatin levels showed a similar pattern although the elevated levels in acromegalic subjects did not achieve statistical significance. Angiogenin and endostatin levels both correlated significantly with IGF-I levels (R = 0.61, P < 0.001 and R = 0.22, P < 0.01, respectively). The relationship between angiogenin and IGF-I levels remained significant even after correction for gender, age, body mass index (BMI) and insulin resistance. There were no significant differences in the levels of HGF, VEGF, VEGF-C or angiopoietin-2 between the three groups. VEGF-D levels were elevated in both acromegalic and GH-deficient male subjects. A similar pattern was apparent in female subjects. After GH treatment, a significant reduction in VEGF-D levels and a significant rise in endostatin levels were observed in GH-deficient subjects. A nonsignificant increase in angiogenin levels was also observed. CONCLUSION: These data indicate that significant perturbations in the levels of vascular growth modulators are present in both acromegaly and GHD. While changes in endostatin and angiogenin levels appear to correlate with IGF-I levels, VEGF-D levels show similar perturbations in both acromegaly and GHD. Further studies are required to determine the relationship of the perturbations to endothelial dysfunction in these conditions.

Acromegaly↗
PubMed1975

An impaired response of adenylate cyclase to stimulation by epinephrine in adipocyte plasma membranes from genetically obese mice (ob/ob).

The present studies have established that there is an impaired response to epinephrine of the adenylate system in adipocyte preparations from obese hyperglycemic mice as compared to their thin littermates. In contrast, membrane preparations from both groups of animals were found to exhibit a similar response to fluoride ion. The response of adenylate cyclase to epinephrine was enhanced to a similar extent by increasing the ATP concentration in adipocyte plasma membranes from the two groups of animals. While GTP (0.1 muM) elicited an ATP-like response of similar magnitude in adenylate cyclase activity in both membrane preparations, it did not therefore abolish the impaired response to epinephrine of adenylate cyclase activity in membranes of obese mice. The response of adenylate cyclase activity to (--)-epinephrine in membrane preparations from obese mice progressively diminished with the age of these animals. In contrast, the concentration of (--)-epinephrine required for half-maximal stimulation of adenylate cyclase was similar and remained unchanged with the age for both membrane preparations. These data suggest that a perturbation may occur in the coupling step between the hormone receptor and the catalytic site of the adenylate cyclase system in obese mice. While a 15-day restrictive diet or a 72-h period of fasting was found to normalize the hyperinsulinemia of obese animals, neither affected the response of adenylate cyclase to epinephrine in preparations of adipocyte membranes from these mice. These results suggest that the observed defect in the response of plasma membrane adenylate cyclase activity to epinephrine in obese mice does not result from their hyperinsulinism.

Adenosine Triphosphate↗
PubMed1999

An EPR investigation of surfactant action on bacterial membranes.

The effects of the surfactants, alcohol ethoxylate, amine ethoxylate, amine oxide and SDS on cell membranes were investigated using the lipid soluble spin label 5-doxyl stearic acid (5-DS). Electron paramagnetic resonance (EPR) spectroscopy revealed that the action of the surfactants was to significantly increase membrane fluidity of Proteus mirabilis, Staphylococcus aureus and Saccharomyces cerevisiae. The action of these surfactants as biocides was investigated and found to be dependent on the type of organism tested. There was, however, no direct correlation between enhanced membrane fluidity observed due to the action of the surfactants and biocidal activity. Data presented suggest that perturbing the fluidity of the cytoplasmic membrane is not immediately responsible for cell death.

Cell Membrane↗
PubMed2002

Reconstruction of electron spectra using singular component decomposition.

Reconstruction of electron spectra of medical accelerators from measured depth dose distributions is an attractive tool for commissioning of a Monte Carlo treatment planning system. However, the reconstruction method is an inverse radiation transport problem which is poorly conditioned, in the sense it may become unstable due to small perturbations in the input data. Predicting the sharp (delta-like) peak in the electron spectrum provides an additional challenge for the numerical reconstruction technique. To improve efficiency and robustness of the reconstruction technique, we developed an algorithm based on a separation of the electron spectrum into singular and regular components. We approximate the singular peak of the spectrum by a narrow weighted Gaussian function. The parameters of this Gaussian function are sought using only the fall-off and toe regions of the depth-dose curve. Analytical representation of the spectral peak by a Gaussian has benefit since only one weight and the mean and variance must be derived from the depth-dose curve instead of multiple spectra weights. The regular part of the spectrum is reconstructed from the residual depth-dose distribution using a variational method combined with a regularization technique to avoid the nonphysical oscillations. The effectiveness of the method is demonstrated by comparing predictions to "benchmark" spectra and depth-dose distributions from Monte Carlo simulation of medical accelerators.

Algorithms↗
PubMed1994

Automatic three-dimensional correlation of CT-CT, CT-MRI, and CT-SPECT using chamfer matching.

Image correlation is often required to utilize the complementary information in CT, MRI, and SPECT. A practical method for automatic image correlation in three-dimensions (3D) based on chamfer matching is described. The method starts with automatic extraction of contour points in one modality and automatic segmentation of the corresponding feature in the other modality. A distance transform is applied to the segmented volume and a cost function is defined that operates between the contour points and the distance transform. Matching is performed by iteratively optimizing the cost function for 3D translation, rotation, and scaling of the contour points. The complete matching process including segmentation requires no user interaction and takes about 100 s on an HP715/50 workstation. Perturbation tests on clinical data with cost functions based on mean, rms, and maximum distances in combination with two general purpose optimization procedures have been performed. The performance of the methods has been quantified in terms of accuracy, capture range, and reliability. The best results on clinical data are obtained with the cost function based on the mean distance and the simplex optimization method. The accuracy is 0.3 mm for CT-CT, 1.0 mm for CT-MRI, and 0.7 mm for CT-SPECT correlation of the head. The accuracy is usually at subpixel level but is limited by global geometric distortions, e.g., for CT-MRI correlation. Both for CT-CT and CT-MRI correlation the capture range is about 6 cm, which is higher than normal differences in patient setup found on the scanners (less than 4 cm). This means that the correlation procedure seldom fails (better than 98% reliability) and user interaction is unnecessary. For CT-SPECT matching the capture range is about 3 cm (80% reliability), and must be further improved. The method has already been introduced in clinical practice.

Biophysical Phenomena↗
PubMed1988

Microvascular exchange and interstitial volume regulation in the rat: model validation.

A dynamic mathematical model is formulated and used to describe the distribution and transport of fluid and plasma proteins between the circulation, interstitial space of skin and muscle, and the lymphatics in the rat. Two descriptions of transcapillary exchange are investigated: a homoporous "Starling model" and a heteroporous "plasma leak model." Parameters used in the two hypothetical transport mechanisms are determined based on statistical fitting procedures between simulation predictions and selected experimental data. These data consist of interstitial fluid volume and colloid osmotic pressure measurements as a function of venous pressure for muscle and interstitial colloid osmotic pressure vs. venous pressure for skin. The values determined for the transport parameters compare well with data in the literature. The fully determined model is used to simulate steady-state conditions of hypoproteinemia, overhydration, and dehydration, as well as the dynamic response to changes in venous pressure and intravascularly administered protein tracers. Comparisons between the simulation predictions and experimental data for these various perturbations are made. The plasma leak model appears to provide a better description of microvascular exchange.

Algorithms↗
PubMed2004

New concepts of the pathogenesis of cystic fibrosis lung disease.

Although there has been impressive progress in the elucidation of the genetic and molecular basis of cystic fibrosis (CF), the pathogenesis of CF lung disease remains obscure. The elucidation of the pathogenesis of CF lung disease requires both a full description of normal innate airway defence and how absent function of the cystic fibrosis transmembrane regulator protein (CFTR) adversely perturbs this activity. Recent data have linked the abnormal ion transport properties of CF airway epithelia to depleted airway surface liquid (ASL) volume, reflecting the combined defects of accelerated Na+ transport and the failure to secrete Cl-. Depletion of a specific compartment of the ASL, i.e. the periciliary liquid (PCL), appears to abrogate both cilia-dependent and cough clearance. Subsequent to PCL depletion, mucus adheres to airway surfaces and persistent mucin secretion generates the formation of "thickened" mucus plaques and plugs, which become the nidus for bacterial infection. The paucity of liquid in these plaques/plugs, and the hypoxia in this environment, appear to promote biofilm bacterial infection. Therapeutic agents that restore airway surface liquid volume, i.e. blockers of Na+ transport, initiators of Cl- transport and osmolytes, are reviewed, as are strategies that may be required to use volume-restoring agents safely in patients with cystic fibrosis.

Cystic Fibrosis↗
PubMed2005

A role for the Tec family kinase ITK in regulating SEB-induced interleukin-2 production in vivo via c-jun phosphorylation.

BACKGROUND: Exposure to Staphylococcal Enterotoxin B (SEB), a bacterial superantigen secreted by the Gram-positive bacteria Staphyloccocus aureus, results in the expansion and eventual clonal deletion and anergy of Vbeta8+ T cells, as well as massive cytokine release, including Interleukin-2 (IL-2). This IL-2 is rapidly secreted following exposure to SEB and may contribute to the symptoms seen following exposure to this bacterial toxin. The Tec family kinase ITK has been shown to be important for the production of IL-2 by T cells stimulated in vitro and may represent a good target for blocking the production of this cytokine in vivo. In order to determine if ITK represents such a target, mice lacking ITK were analyzed for their response to SEB exposure. RESULTS: It was found that T cells from mice lacking ITK exhibited significantly reduced proliferative responses to SEB exposure in vitro, as well as in vivo. Examination of IL-2 production revealed that ITK null mice produced reduced levels of this cytokine in vitro, and more dramatically, in vivo. In vivo analysis of c-jun phosphorylation, previously shown to be critical for regulating IL-2 production, revealed that this pathway was specifically activated in SEB reactive Vbeta8+ (but not non-reactive Vbeta6+) T cells from WT mice, but not in Vbeta8+ T cells from ITK null mice. However, toxicity analysis indicated that both WT and ITK null animals were similarly affected by SEB exposure. CONCLUSION: These data show that ITK is required for IL-2 production induced by SEB in vivo, and may regulate signals leading IL-2 production, in part by regulating phosphorylation of c-jun. The data also suggest that perturbing T cell activation pathways leading to IL-2 does not necessarily lead to improved responses to SEB toxicity.

Animals↗
PubMed2006

Identification and properties of proteases from an Acanthamoeba isolate capable of producing granulomatous encephalitis.

BACKGROUND: Granulomatous amoebic encephalitis due to Acanthamoeba is often a fatal human disease. However, the pathogenesis and pathophysiology of Acanthamoeba encephalitis remain unclear. In this study, the role of extracellular Acanthamoeba proteases in central nervous system pathogenesis and pathophysiology was examined. RESULTS: Using an encephalitis isolate belonging to T1 genotype, we observed two major proteases with approximate molecular weights of 150 KD and 130 KD on SDS-PAGE gels using gelatin as substrate. The 130 KD protease was inhibited with phenylmethylsulfonyl fluoride (PMSF) suggesting that it is a serine protease, while the 150 KD protease was inhibited with 1, 10-phenanthroline suggesting that it is a metalloprotease. Both proteases exhibited maximal activity at neutral pH and over a range of temperatures, indicating their physiological relevance. These proteases degrade extracellular matrix (ECM), which provide structural and functional support to the brain tissue, as shown by the degradation of collagen I and III (major components of collagenous ECM), elastin (elastic fibrils of ECM), plasminogen (involved in proteolytic degradation of ECM), as well as casein and haemoglobin. The proteases were purified partially using ion-exchange chromatography and their effects were tested in an in vitro model of the blood-brain barrier using human brain microvascular endothelial cells (HBMEC). Neither the serine nor the metalloprotease exhibited HBMEC cytotoxicity. However, the serine protease exhibited HBMEC monolayer disruptions (trypsin-like) suggesting a role in blood-brain barrier perturbations. CONCLUSION: Overall, these data suggest that Acanthamoeba proteases digest ECM, which may play crucial role(s) in invasion of the brain tissue by amoebae.

Acanthamoeba↗
PubMed1999

Colon cancer is induced by a single low dose of azoxymethane in fasted-refed rats.

We reported previously that fasting-refeeding enhanced the growth of preneoplastic lesions in the colon of rats induced by 20 mg/kg of azoxymethane (AOM). Here we studied whether fasting-refeeding could also affect 1) the induction of colon cancer by the same dose of AOM and 2) the induction of foci by lower doses of AOM that do not induce foci in fully fed rats. Fully fed and fasted-refed rats were given AOM by single subcutaneous injection, and the development of foci or tumors was evaluated three months or one year later. The results of the long-term carcinogenesis experiments showed that the total incidence of tumors was increased in the fasted-refed rats. Moreover, although fully fed rats developed foci only when injected with 7.5, 10, or 20 mg/kg of the carcinogen, a significant number of foci were also induced by 5 mg/kg in fasted-refed rats. The crypt multiplicity of foci was also higher when rats were exposed to fasting-refeeding, even when the number of foci was unchanged. These data suggest that growth perturbations induced by fasting-refeeding lead to the development of preneoplastic lesions with doses of AOM too low to trigger foci in fully fed rats and produce enhanced sensitivity to the development of intestinal tumors.

Animals↗