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PubMed1992

International cancer risk assessment: the impact of biologic mechanisms.

The use of risk assessment by different governments and agencies varies widely in theory and practice. One major difference is in the consideration given to the biologic mechanisms of cancer causation. U.S. government agencies consider all animal carcinogens to be presumptive human carcinogens and to act in a similar manner without regard to available knowledge on the mechanism of carcinogenicity. Accordingly, standardized models that give linear dose-response at low doses without a threshold are used for predicting human cancer risk from animal studies. Accumulated evidence on biologic mechanisms reveals that some animal carcinogens should not cause cancer in humans at low exposures; other should not at any exposure level. The Netherlands has included such considerations in their cancer classification and risk assessment process. Other governments evaluate each chemical on a case-by-case basis or do not use standardized risk assessment methods for regulatory decisions. To address these issues, the American Health Foundation has convened an International Expert Panel on Carcinogen Risk Assessment.

Animals↗

PubMed2005

Clinical applications for targeted therapy in bladder cancer.

The tremendous amount of data accumulated through genomics, proteomics, and metabolomic technologies has not led to a definitive understanding of the mechanisms underlying cancer. The challenge remains as to how to integrate all of the relevant knowledge and data in a systematic manner so that researchers can gain the knowledge needed to devise the best therapeutic and diagnostic strategies. Human transitional cell carcinoma of the bladder is genetically heterogeneous, and it is surrounded by a complex tissue microenvironment involving vasculature, stromal cells, and connective tissue. One of the most challenging problems facing cancer researchers is the lack of correlation between in vitro cell lines and animal tumor models and human in vivo tumors. A few promising approaches are being devised that will help address this issue in the coming years. One such approach is the measurements of molecular levels of receptors, ligands, pathways components, and so on, directly in human tumors through in vivo imaging, or through proteomic profiling, as it has been proposed as standard protocol for cancer diagnostics and therapeutics.

Antineoplastic Agents↗

PubMed1992

Idiopathic myelofibrosis in pregnancy: a case report and review of the literature.

Idiopathic myelofibrosis is a rare myeloproliferative disorder characterized by excessive accumulation of connective tissue in the bone marrow in association with anemia, splenomegaly, and extramedullary hematopoiesis. The cause of this disease is unknown, and the prognosis is generally poor. To our knowledge, this is the first case report of a patient with idiopathic myelofibrosis who carried a term pregnancy. In spite of the increased perinatal risks, a favorable outcome was possible with close antepartum surveillance.

Adult↗

PubMed2001

Identification of potent non-peptide somatostatin antagonists with sst(3) selectivity.

Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst(1-5)) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst(3) receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-beta-carboline derivatives 4. Among these, compounds 4k (BN81644) and 4n (BN81674) bind selectively and with high affinity to the sst(3) receptor subtype (K(i) = 0.64 and 0.92 nM, respectively). Furthermore, 4k and 4n reverse the inhibition of cyclic AMP accumulation induced by 1 nM somatostatin via sst(3) receptors, with IC(50) = 2.7 and 0.84 nM, respectively. The most potent compound 4n was shown to be a competitive antagonist of human sst(3) receptors by increasing the EC(50) of SRIF-14-mediated inhibition of cAMP accumulation with a K(B) of 2.8 nM (where K(B) is the concentration of antagonist that shifts the agonist dose-response 2-fold). These new derivatives are, to our knowledge, the first potent and highly selective non-peptide human sst(3) antagonists known and, as such, are useful tools for investigating the physiological role of sst(3) receptors.

Animals↗

PubMed1999

Bone loss in patients with inflammatory bowel disease is less than expected: a follow-up study.

BACKGROUND: In spite of the accumulating evidence of an increased prevalence of osteopenia and osteoporosis in patients with inflammatory bowel diseases (IBD), the time course of bone loss is not well described, and there is little knowledge about factors indicating an increased risk of rapid bone loss. METHODS: We conducted a follow-up study in 80 IBD patients (45 men and 25 premenopausal and 10 postmenopausal women), 19 with ulcerative colitis and 61 with Crohn disease, with a mean follow-up time of 568 +/- 60 days, to assess bone loss, risk factors of rapid bone loss, and value of bone markers to predict bone loss. Bone mineral density was measured by dual-energy X-ray absorptiometry, bone formation by bone alkaline phosphatase (BAP), and bone resorption by N-terminal telopeptide of type-I collagen (NTX) and free deoxypyridinoline (DPD). RESULTS: Bone density changes per year were 0.46% +/- 3% at the spine, 0.06% +/- 5.1% at the femoral neck, -1.1% +/- 7.7% at the triangle of Ward, and -0.52% +/- 1.86% at total body level. Type and duration of disease, sex, age, and level of NTX, DPD, and BAP at base line did not show significant differences between patients who lost and those who did not lose bone mass. Bone loss was significantly higher in patients with (n = 28) than in those without steroids (n = 52) at the femoral neck and Ward triangle but not at the spine and total body. CONCLUSIONS: Change in bone mass in IBD patients during short-term follow-up is low on average, but there is great heterogeneity within the population, which cannot be explained by the use of steroids alone. Bone loss cannot be predicted by analysis of bone markers.

Adult↗

PubMed2006

Differential biodistribution of adenoviral vector in vivo as monitored by bioluminescence imaging and quantitative polymerase chain reaction.

A better understanding of the in vivo biodistribution of adenoviral vectors would enable the researcher to anticipate potential side effects due to off-targeted site of transduction, and aid in the strategic design of gene therapy. We combined real-time polymerase chain reaction with in vivo optical imaging to examine viral transduction in liver, lung, spleen, kidney, prostate, and lymph nodes. A replication-deficient serotype 5 adenoviral vector expressing the firefly luciferase gene under the control of a constitutive cytomegalovirus promoter was administered in vivo via different routes. Intravenous and intraperitoneal injections resulted in greatest gene expression and viral DNA in the liver, whereas intraperitoneal injections led to a greater extent of gene delivery to the prostate. Although prostate-directed injection resulted in dominant gene expression in the targeted site, leakage of the vector to other organs was also observed. Vector injection into the lymphatic-rich paw tissue or the subcutaneous tissue of shoulder or chest followed the expected lymphatic drainage pattern, resulting in the accumulation of viral vector in ipsilateral brachial and axillary lymph nodes. Collectively, this study demonstrates that each tissue retains various amounts of adenoviral vector, depending on the route of administration. This knowledge is useful in the strategic design and implementation of adenovirus-mediated gene therapies.

Adenoviridae↗

PubMed2002

An analysis using the hobo genetic system reveals that combinatorial signaling by the Dpp and Wg pathways regulates dpp expression in leading edge cells of the dorsal ectoderm in Drosophila melanogaster.

Our laboratory has contributed to the development of a genetic system based upon the hobo transposable element in Drosophila melanogaster. We recently reported that hobo, like the better-known P element, is capable of local transposition. In that study, we mobilized a hobo enhancer trap vector and generated two unique alleles of decapentaplegic (dpp), a transforming growth factor-beta family member with numerous roles during development. Here we report a detailed study of one of those alleles (dpp(F11)). To our knowledge, this is the first application of the hobo genetic system to understanding developmental processes. First, we demonstrate that lacZ expression from the dpp(F11) enhancer trap accurately reflects dpp mRNA accumulation in leading edge cells of the dorsal ectoderm. Then we show that combinatorial signaling by the Wingless (Wg) pathway, the Dpp pathway, and the transcriptional coactivator Nejire (CBP/p300) regulates dpp(F11) expression in these cells. Our analysis of dpp(F11) suggests a model for the integration of Wg and Dpp signals that may be applicable to other developmental systems. Our analysis also illustrates several new features of the hobo genetic system and highlights the value of hobo, as an alternative to P, in addressing developmental questions.

Animals↗

PubMed1998

Periodontal disease and diet in domestic pets.

Periodontal disease is the most common oral condition seen in domestic pets. In addition to the discomfort caused in the affected animal, there is strong circumstantial evidence to show that a focus of infection in the mouth may cause disease of distant organs. Consequently, prevention of periodontal disease is of paramount importance for the general health and well-being of pets. The presence of plaque on the tooth surfaces is the primary cause of periodontal disease. However, the mechanisms by which disease develops are by no means fully understood. Dietary texture does have an effect on the accumulation of dental deposits and consequently on disease development and progression. Daily toothbrushing remains the single most effective means of removing plaque, thus preventing periodontal disease. On the basis of current knowledge, the best way to maintain healthy periodontal tissues in our pets is frequent toothbrushing. The use of a dental hygiene chew and/or a diet designed to reduce dental deposits can be useful adjunctive measures and should be recommended.

Animals↗

PubMed2002

Oncocytic metaplasia occurring in a spectrum of melanocytic nevi.

Oncocytosis is defined as a metaplastic change characterized by the presence of cells with finely granular eosinophilic cytoplasm caused by the accumulation of mitochondria. Although this histologic feature can be found in normal tissues, it can also be seen pathologically as a degenerative phenomenon, where an accumulation of mitochondria is thought to compensate for an uncoupling of oxidative metabolism secondary to cellular aging. Oncocytic metaplasia can be observed in a variety of cutaneous lesions but, to our knowledge, has not been described in melanocytic nevi. We retrospectively reviewed 87 melanocytic nevi from 83 patients that showed significant oncocytic change. We obtained patient clinical history through surveys completed by the patients' physicians. Ultrastructural studies were performed on 4 representative nevi to confirm the presence of increased mitochondria. We prospectively reviewed 100 randomly selected nevi looking for oncocytic changes. We subsequently did not find any correlation with patient demographics or medical histories. Histologic evaluation showed granular eosinophilic cytoplasm in 75% or greater of lesional cells in two thirds of cases. This phenomenon occurred in all types of melanocytic nevi. Ultrastructural studies revealed melanocytes with numerous mitochondria in close apposition to melanosomes. Focal oncocytic change was identified prospectively in 38 of 100 randomly selected melanocytic nevi. We conclude that oncocytosis in melanocytic nevi is a relatively common and underrecognized phenomenon.

Adolescent↗

PubMed2000

Lipids in the proximal tubules of the kidney in diabetic coma.

Vacuolization of the renal tubular epithelial cells (the Armanni-Ebstein lesion) associated with diabetic hyperglycemia is usually regarded as an accumulation of glycogen. In a case of death of diabetic coma, the vacuoles were stained strongly for lipids. This observation may have both clinical and therapeutic consequences, and may increase our knowledge of the metabolism in diabetes.

Diabetic Coma↗

PubMed2006

An unusual case of thymic carcinoma with endobronchial metastases manifesting as centrilobular opacities.

We report a case of a 75-year-old man having unusual manifestation of thymic carcinoma associated with endobronchial metastases. To our knowledge, endobronchial metastases secondary to thymic carcinoma has not been reported in the literature. On high-resolution computed tomograms, the tree-in-bud centrilobular opacities caused by metastatic cells accumulating within the small bronchioles is indistinguishable from that caused by inflammatory process. Thus, in patients with thymic carcinoma and persistent tree-in-bud centrilobular opacities, endobronchial metastatic disease should be considered.

Bronchial Neoplasms↗

PubMed2005

The alternative oxidase of plant mitochondria is involved in the acclimation of shoot growth at low temperature. A study of Arabidopsis AOX1a transgenic plants.

The alternative oxidase (AOX) pathway of plant mitochondria uncouples respiration from mitochondrial ATP production and may ameliorate plant performance under stressful environmental conditions, such as cold temperatures, by preventing excess accumulation of reactive oxygen species. We tested this model in whole tissues by growing AtAOX1a-transformed Arabidopsis (Arabidopsis thaliana) plants at 12 degrees C. For the first time, to our knowledge, in plants genetically engineered for AOX, we identified a vegetative shoot growth phenotype. Compared with wild type at day 21 after sowing, anti-sense and overexpressing lines showed, on average, 27% reduced leaf area and 25% smaller rosettes versus 30% increased leaf area and 33% larger rosette size, respectively. Lines overexpressing a mutated, constitutively active AOX1a showed smaller phenotypic effects. These phenotypic differences were not the result of a major alteration of the tissue redox state because the changes in levels of lipid peroxidation products, reflecting oxidative damage, and the expression of genes encoding antioxidant and electron transfer chain redox enzymes did not correspond with the shoot phenotypes. However, the observed phenotypes were correlated with the amount of total shoot anthocyanin at low temperature and with the transcription of the flavonoid pathway genes PAL1 and CHS. These results demonstrate that (1) AOX activity plays a role in shoot acclimation to low temperature in Arabidopsis, and that (2) AOX not only functions to prevent excess reactive oxygen species formation in whole tissues under stressful environmental conditions but also affects metabolism through more pervasive effects, including some that are extramitochondrial.

Acclimatization↗

PubMed1987

Changes in the levels of major sulfur metabolites and free amino acids in pea cotyledons recovering from sulfur deficiency.

Changes in levels of sulfur metabolites and free amino acids were followed in cotyledons of sulfur-deficient, developing pea seeds (Pisum sativum L.) for 24 hours after resupply of sulfate, during which time the legumin mRNA levels returned almost to normal. Two recovery situations were studied: cultured seeds, with sulfate added to the medium, and seeds attached to the intact plant, with sulfate added to the roots. In both situations the levels of cysteine, glutathione, and methionine rose rapidly, glutathione exhibiting an initial lag. In attached but not cultured seeds methionine markedly overshot the level normally found in sulfur-sufficient seeds. In the cultured seed S-adenosylmethionine (AdoMet), but not S-methylmethionine, showed a sustained rise; in the attached seed the changes were slight. The composition of the free amino acid pool did not change substantially in either recovery situation. In the cultured seed the large rise in AdoMet level occurred equally in nonrecovering seeds. It was accompanied by 6-fold and 10-fold increases in gamma-aminobutyrate and alanine, respectively. These effects are attributed to wounding resulting from excision of the seed. (35)S-labeling experiments showed that there was no significant accumulation of label in unidentified sulfur-containing amino compounds in either recovery situation. It was concluded from these results and those of other workers that, at the present level of knowledge, the most probable candidate for a ;signal' compound, eliciting recovery of legumin mRNA level in response to sulfur-feeding, is cysteine.

Journal Article↗

PubMed2004

[Cystinosis: diagnosis through the measurement of the leukocyte cystine content by HPLC].

BACKGROUND AND OBJECTIVE: Cystinosis is an autosomal recessive disorder characterized by an accumulation of intralysosomal cystine. Three disease forms exist, infantile, juvenile or late-onset, and ocular nonnephropathic cystinosis, delineated on the basis of severity of symptoms and age of onset. The knowledge of early clinic manifestations and the onset of the appropriate therapy delay the evolution of the disease and improve the general conditions. Therefore, it is necessary to develop a sensible diagnostic method for early detection and treatment of the disease. CLINICAL CASE AND METHODS: The leukocyte cystine content was determined by HPLC in a 42 years old female patient after renal transplantation, and with the clinical characteristic complications of the intermediate cystinosis. Equally, the molecular characterization of the structural defects of the cystinosin (CTNS) gene was made in the patient and in all family members. RESULTS: By measuring of the leukocyte cystine content in the patient and family members, we have determined 5 family members as heterozygous. This result was confirmed by molecular analysis that showed the approximately 65 kb deletion in the 5 family members. The patient was heterozygous for the approximately 65 kb deletion, and the second alteration was not determined. CONCLUSIONS: We presented a useful diagnostic method, based in the determination of cystine content of polymorphonuclear leukocytes, which permits to detect the heterozygous individuals.

Adult↗

PubMed2006

[Relationship between abnormalities of genes involved in DNA damage responses and malignant tumors/autoimmune diseases].

The maintenance of genomic stability is an essential cellular function for a variety of well-coordinated regulation of biological activities of organisms, and a failure in its function results in the accumulation of mutations and/or abnormality in the induction of apoptosis, eventually leading to onsets of various diseases, including malignant tumors. DNA damage responses, in particular cell-cycle checkpoint regulation, play important roles in maintaining genomic integrity. In response to DNA damages induced by gamma-irradiation, ultraviolet irradiation, various chemicals, or reactive oxygen species (ROS), intrinsic cell-cycle checkpoint machinery is rapidly activated to arrest cells at particular cell-cycle points, and during cell-cycle checkpoint arrest cells may try to repair damaged DNAs, and then re-start cell-cycle upon the completion of DNA repair. Alternatively, if the extents of DNA damage overwhelm the capacity of the cellular repair machinery, cells may undergo apoptosis to prevent the accumulation of mutations within the organisms. In this article, we will first explain about our current view of DNA damage responses, in particular cell-cycle checkpoint regulation, and summarize our knowledge of the relationships between abnormalities of genes involved in DNA damage responses and malignant tumors, including hematopoietic malignancies. We will also discuss a possible implication of DNA damage responses in autoimmune diseases, such as rheumatoid arthritis.

Apoptosis↗

PubMed2002

Acyl-CoA binding protein expression is fiber type- specific and elevated in muscles from the obese insulin-resistant Zucker rat.

Accumulation of acyl-CoA is hypothesized to be involved in development of insulin resistance. Acyl-CoA binds to acyl-CoA binding protein (ACBP) with high affinity, and therefore knowledge about ACBP concentration is important for interpreting acyl-CoA data. In the present study, we used a sandwich enzyme-linked immunosorbent assay to quantify ACBP concentration in different muscle fiber types. Furthermore, ACBP concentration was compared in muscles from lean and obese Zucker rats. Expression of ACBP was highest in the slow-twitch oxidative soleus muscle and lowest in the fast-twitch glycolytic white gastrocnemius (0.46 +/- 0.02 and 0.16 +/- 0.005 microg/mg protein, respectively). Expression of ACBP was soleus > red gastrocnemius > extensor digitorum longus > white gastrocnemius. Similar fiber type differences were found for carnitine palmitoyl transferase (CPT)-1, and a correlation was observed between ACBP and CPT-1. Muscles from obese Zucker rats had twice the triglyceride content, had approximately twice the long-chain acyl CoA content, and were severely insulin resistant. ACBP concentration was approximately 30% higher in all muscles from obese rats. Activities of CPT-1 and 3-hydroxy-acyl-CoA dehydrogenase were increased in muscles from obese rats, whereas citrate synthase activity was similar. In conclusion, ACBP expression is fiber type-specific with the highest concentration in oxidative muscles and the lowest in glycolytic muscles. The 90% increase in the concentration of acyl-CoA in obese Zucker muscle compared with only a 30% increase in the concentration of ACBP supports the hypothesis that an increased concentration of free acyl-CoA is involved in the development of insulin resistance.

Alcohol Oxidoreductases↗

PubMed1989

Implantation of dispersed cells into primate brain.

Although several experimental therapies such as dopaminergic cell implantation in parkinsonian models and intratumoral placement of lymphokine-activated killer cells require intracerebral deposition of dispersed cell suspensions, a successful technique of needle implantation of cells into primate brain has not been demonstrated. The authors have sought to establish a stereotaxic technique to predictably deposit dispersed cells in primate brain. Human lymphocytes were cultured in recombinant interleukin-2, labeled with sodium 51 chromate (51Cr), and stereotaxically injected into the frontal white matter of six anesthetized rhesus monkeys. A 10-microliters aliquot of cell suspension (2 X 10(7) cells/ml) was deposited 16 mm deep to the dura at 5 microliters/min via Hamilton No. 22s or 26s needles. Five control aliquots were counted for each injection. Reflux out of the needle track was absorbed on gauze, and the recovered cells were counted. The animals were sacrificed 1 hour after implantation and the brain was removed and sectioned such that the cortex and white matter along the needle track were separate. The tissue sections were then counted. Recovery was expressed as the percentage of total injected radioactivity (cpm) that was present in each brain section. Two additional injected hemispheres were processed for autoradiography and histological study. Cell recovery in the brain (mean +/- standard deviation) was 87.2% +/- 13.9% (3.3% +/- 4.9% in cortex and 83.9% +/- 15.9% in white matter). The autoradiograms and histological examination showed a dense accumulation of radioactivity (cells) at the target site and minimal radioactivity (cells) in the needle track. Accurate intracerebral deposition of dispersed cells in primates was achieved with the technique described. This knowledge permits reliable stereotaxic implantation of cells into the brains of nonhuman primates and humans for investigation and therapy.

Animals↗

PubMed2001

Accumulation of the lipophilic environmental contaminant lindane in metacercariae of Bucephaloides gracilescens (Trematoda, Bucephalidae) in the central nervous system of bullrout Myoxocephalus scorpius.

Bucephaloides gracilescens is a common parasite in the intestine of the angler fish Lophiuspiscatorius, and the metacercariae have been recorded from a number of gadoid intermediate hosts. In a toxicokinetic study of lindane (gamma-hexachlorocyclohexane) in bullrout Myoxocephalus scorpius, metacercariae of B. gracilescens were found in the central nervous system (CNS). Furthermore, the metacercariae accumulated concentrations of lindane that were higher than in the surrounding CNS tissue. This is the first report of metacercariae of B. gracilescens in bullrout. In addition the present results contribute knowledge of the disposition of an important environmental contaminant in the metacercarial stage of a trematode that has been pointed out as a promising sentinel species of pollution in the marine environment.

Animals↗