ABSTRACT
Plant cells show many signs of a unique evolutionary history. This is seen in the system of intracellular organelles and vesicle transport pathways plants use to traffic molecular cargo. Bioinformatic and cell biological work in this area is beginning to tackle the question of how plant cells have evolved, and what this tells us about the evolution of other eukaryotes. Key protein families with membrane trafficking function, including Rabs, SNAREs, vesicle coat proteins, and ArfGAPs, show patterns of evolution that indicate both specialization and conservation in plants. These changes are accompanied by changes at the level of organelles and trafficking pathways between them. Major specializations include losses of several ancient Rabs, novel functions of many proteins, and apparent modification of trafficking in endocytosis and cytokinesis. Nevertheless, plants show extensive conservation of ancestral membrane trafficking genes, and conservation of their ancestral function in most duplicates. Moreover, plants have retained several ancient membrane trafficking genes lost in the evolution of animals and fungi. Considering this, plants such as Arabidopsis are highly valuable for investigating not only plant-specific aspects of membrane trafficking, but also general eukaryotic mechanisms.
Subject(s)
Cell Movement/physiology , Eukaryota/metabolism , Eukaryotic Cells/metabolism , Protein Transport/physiology , Animals , Embryonic Development/physiology , Endocytosis/physiologyABSTRACT
Chronic hepatitis C infection is associated with hypolipidaemia that resolves with viral clearance. Lipid levels in a subgroup of patients rebound to levels that may increase the risk of coronary heart disease. The impact of acute hepatitis C infection and its clearance on lipid levels is unknown. We undertook a retrospective evaluation of subjects with acute hepatitis C infection evaluating lipid levels before, during and following acute infection. Thirty-eight subjects with acute hepatitis C infection had lipid levels available. Twelve patients had pre-infection and intra-infection lipid levels available. Cholesterol (197.8-152.4 mg/dL, P = 0.025), low-density lipoprotein (LDL) (116.1-76.3 mg/dL, P = 0.001) and non-high-density lipoprotein (non-HDL) cholesterol (164.0-122.7 mg/dL, P = 0.007) decreased dramatically during acute hepatitis C virus infection. Nineteen patients who achieved viral clearance had lipid levels available during infection and following resolution of infection. In these patients, cholesterol (145.0-176.0 mg/dL, P = 0.01), LDL (87.0-110.1 P = 0.0046) and non-HDL cholesterol (108.6-133.6 mg/dL, P = 0.008) increased significantly. No change was seen in patients who developed chronic infection. Four patients had lipid levels before, during and following resolution of infections and had increased postinfection LDL, cholesterol and non-HDL cholesterol from pre-infection levels, indicating acute infection may be associated with an increase in postinfection lipid levels and may confer an increased risk of coronary heart disease. Acute hepatitis C infection results in hypolipidaemia with decreased LDL, cholesterol and non-HDL cholesterol levels that increase following infection resolution. Levels may increase above pre-infection baseline lipid levels and should be monitored.
Subject(s)
Hepatitis C/blood , Lipids/blood , Acute Disease , Adult , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Coronary Disease/blood , Female , Hepacivirus/genetics , Humans , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Male , Middle Aged , RNA, Viral/blood , Risk Factors , Triglycerides/bloodABSTRACT
An L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) was evaluated in 66 dogs with stages III-V lymphoma. Results were compared with a historical group of 71 dogs treated with an L-CHOP protocol. Complete remission (CR) rates (85 and 80%, respectively) did not differ significantly between protocols (P = 0.48). First CR duration for dogs treated with L-CHOP-CCNU-MOPP was significantly longer: median, 317 days; 2-year CR rate, 35% versus median, 298 days; 2-year CR rate, 13%, P = 0.05). For the L-CHOP-CCNU-MOPP protocol, dogs in substage-b had a 4.3 times greater hazard of having a relapse than dogs in substage-a (P = 0.002). Frequency of adverse chemotherapy-associated gastrointestinal effects did not differ between protocols (P = 0.77). Neutropenia (primarily after CCNU) occurred more frequently in dogs treated with L-CHOP-CCNU-MOPP (P < 0.001). In summary, the L-CHOP-CCNU-MOPP protocol showed an improved duration of first CR as compared with an L-CHOP protocol, but the relevance of this finding might be subject to clinical judgement.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asparagine/therapeutic use , Dog Diseases/drug therapy , Lomustine/therapeutic use , Lymphoma/veterinary , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Asparagine/administration & dosage , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Dogs , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Female , Lomustine/administration & dosage , Lymphoma/drug therapy , Male , Mechlorethamine/administration & dosage , Mechlorethamine/therapeutic use , Prednisone/administration & dosage , Prednisone/therapeutic use , Procarbazine/administration & dosage , Procarbazine/therapeutic use , Retrospective Studies , Risk Factors , Vincristine/administration & dosage , Vincristine/therapeutic useABSTRACT
While the taste periphery has been studied for over a century, we are only beginning to understand how this important sensory system is maintained throughout adult life. With the advent of molecular genetics in rodent models, and the upswing in translational approaches that impact human patients, we expect the field will make significant advances in the near future.
Subject(s)
Regeneration/physiology , Stem Cells/physiology , Taste Buds/cytology , Taste/physiology , Animals , HumansABSTRACT
BACKGROUND: A lowering of colorectal cancer risk for the birth cohorts born around World War II (WWII) has previously been observed in Norway, a country which suffered some 20% caloric restriction during the war. The purpose of the study was to conduct a similar kind of analysis in the other Nordic countries and Estonia, which were also subjected to various degrees of energy restriction during WWII. METHODS: All new cases of colorectal cancer in the Nordic countries and Estonia diagnosed between 40 and 84 years of age and born between 1874 and 1953, were collected from the national cancer registries. The incidence data were fitted to an age-period-cohort model. RESULTS: A transient drop in the estimated colorectal cancer incidence rate was observed for the birth cohorts born around WWII in Estonia, together with a tendency of decreased risk in Sweden and Denmark. CONCLUSION: The previously observed lowering of colorectal cancer risk for persons born during WWII in Norway also prevails in Estonia. Energy restriction is a possible explanation for these findings, since the countries suffered from varying nutritional conditions during the war. Exogenous factors acting during periods early in life may have an impact on later colorectal cancer risk.
Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/etiology , Malnutrition , Registries/statistics & numerical data , World War II , Adult , Aged , Aged, 80 and over , Cohort Studies , Estonia/epidemiology , Female , Humans , Incidence , Male , Middle Aged , Risk Factors , Scandinavian and Nordic Countries/epidemiologyABSTRACT
INTRODUCTION: Data on the survival of all incident cases collected by population-based cancer registries make it possible to evaluate the overall performance of diagnostic and therapeutic actions on cancer in those populations. EUROCARE-3 is the third round of the EUROCARE project, the largest cancer registry population based collaborative study on survival in European cancer patients. The EUROCARE-3 study analysed the survival of cancer patients diagnosed from 1990 to 1994 and followed-up to 1999. Sixty-seven cancer registries of 22 European countries characterised by differing health systems participated in the study. This paper includes essays providing brief overviews of the state and evolution of the health systems of the considered countries and comments on the relation between cancer survival in Europe and some European macro-economic and health system indicators, in the 1990s. OVERVIEW OF THE EUROPEAN HEALTH SYSTEMS: The European health systems underwent a great deal of reorganisation in the last decade; a general tendency being to facilitate expanding involvement of the private sector in health care, a process which occurred mainly in the eastern countries (i.e. the Czech Republic, Estonia, Poland, Slovakia and Slovenia). In contrast, organisational changes in the northern European countries (i.e. Denmark, Iceland, Finland and Sweden) tended to confirm the established public sector systems. Other countries, including the UK and some southern European countries (i.e. England, Scotland, Wales, Malta and Italy) have reduced the public role while the systems remain basically public, at least at present. Our findings clearly suggest that cancer survival (all cancer combined) is related to macro-economic variables such as the gross domestic product (GDP), the total national (public and private) expenditure on health (TNEH) and the total public expenditure on health (TPEH). We found, however, that survival is related to wealth (GDP), but only up to a certain level, after which survival continues to be related to the level of health investment (both TNEH and TPEH). According to the Organisation for Economic Co-operation and Development (OECD), the TNEH increased during the 1990s in all EUROCARE-3 countries, while the ratio of TPEH to TNEH reduced in all countries except Portugal. CONCLUSIONS: Cancer survival depends on the widespread application of effective diagnosis and treatment modalities, but our enquiry suggests that the availability of these depends on macro-economic determinants, including health and public health investment. Analysis of the relationship between health system organisation and cancer outcome is complicated and requires more information than is at present available. To describe cancer and cancer management in Europe, the European Cancer Health Indicator Project (EUROCHIP) has proposed a list of indicators that have to be adopted to evaluate the effects on outcome of proposed health system modifications.
Subject(s)
Community Health Planning/standards , Neoplasms/diagnosis , Neoplasms/therapy , Community Health Planning/statistics & numerical data , Europe/epidemiology , Humans , Neoplasms/epidemiology , Registries/statistics & numerical data , Survival AnalysisABSTRACT
Angiopoietin-1 is a promoter of physiological vasculogenesis and angiogenesis because it induces vascular branching and smooth muscle recruitment to newly formed blood vessels. However, angiopoietin-1 expression in tumours appears to be uncommon, and angiopoietin-1 overexpression in cancer cells has been reported to lead to inhibition of xenograft tumour growth. We report here that angiopoietin-1 overexpression resulted in stabilization of tumour edge-associated blood vessels, as it prevented vessel dilation and dissociation of smooth muscle cells from existing vessels. In addition, angiopoietin-1 stimulated an infiltration of mesenchymal cells into the tumours, such that the coverage of microvessels by pericytes increased markedly, and the cancer cells were separated into small masses by the host stroma. The rates of both cancer cell proliferation and apoptosis decreased significantly in the presence of angiopoietin-1. Tie2, the receptor for angiopoietin-1, was found to be present in vascular smooth muscle cells in culture in addition to endothelial cells. These findings suggest that a vascular stabilization effect of angiopoietin-1 accounts for the inhibition of tumour growth.
Subject(s)
Breast Neoplasms/blood supply , Endothelium, Vascular/metabolism , Membrane Glycoproteins/physiology , Muscle, Smooth, Vascular/metabolism , Neovascularization, Pathologic/metabolism , Angiopoietin-1 , Animals , Apoptosis/physiology , Blotting, Western , Cell Division/physiology , Female , Humans , Mice , Mice, Nude , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, TIE-2 , Transplantation, Heterologous , Tumor Cells, Cultured , VasodilationABSTRACT
Vascular endothelial growth inhibitor (VEGI), a new member of the tumor necrosis factor family, is an endothelial cell-specific gene and a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. We report here that VEGI mediates the following two activities in endothelial cells: early G(1) arrest in G(0)/G(1) cells responding to growth stimuli, and programmed death in proliferating cells. G(0)/G(1)-synchronized bovine aortic endothelial cells were treated with VEGI before and after the onset of the growth cycle. When the cells were stimulated with growth conditions but treated simultaneously with VEGI, a reversible, early-G(1) growth arrest occurred, evidenced by the lack of late G(1) markers such as hyperphosphorylation of the retinoblastoma gene product and upregulation of the c-myc gene. Additionally, VEGI treatment led to inhibition of the activities of cyclin-dependent kinases CDK2, CDK4, and CDK6. In contrast, VEGI treatment of cells that had entered the growth cycle resulted in apoptotic cell death, as evidenced by terminal deoxytransferase labeling of fragmented DNA, caspase 3 activation, and annexin V staining, all of which were lacking in nonproliferating cells treated with VEGI. Additionally, stress-signaling proteins p38 and JNK were not as fully activated by VEGI in quiescent as compared with proliferating populations. These findings suggest a dual role for VEGI, the maintenance of growth arrest and induction of apoptosis, in the modulation of the endothelial cell cycle.
Subject(s)
Apoptosis , CDC2-CDC28 Kinases , Endothelium, Vascular/metabolism , Proto-Oncogene Proteins , Tumor Necrosis Factor-alpha/metabolism , Animals , Apoptosis/drug effects , Biomarkers/analysis , Caspase 3 , Caspases/metabolism , Cattle , Cell Count , Cell Division/drug effects , Cell Division/physiology , Cells, Cultured , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , G1 Phase/drug effects , Humans , Mice , Mitogen-Activated Protein Kinases/metabolism , Molecular Sequence Data , Organ Specificity , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/metabolism , Resting Phase, Cell Cycle/drug effects , Species Specificity , Thymidine/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15 , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/pharmacologySubject(s)
Health Status , Public Health/statistics & numerical data , Adolescent , Adult , Age Distribution , Age Factors , Aged , Aged, 80 and over , Anxiety/epidemiology , Asthma/epidemiology , Cardiovascular Diseases/epidemiology , Communicable Diseases/epidemiology , Dental Health Surveys , Diabetes Mellitus/epidemiology , Female , Humans , Hypersensitivity/epidemiology , Incidence , Male , Mass Screening , Mental Disorders/epidemiology , Middle Aged , Musculoskeletal Diseases/epidemiology , Neoplasms/epidemiology , Prevalence , Risk Factors , Sex Distribution , Sex Factors , Stress, Psychological/epidemiology , Sweden/epidemiology , Urinary Incontinence/epidemiology , Wounds and Injuries/epidemiologyABSTRACT
The development of taste buds is an autonomous property of the pharyngeal endoderm, and this inherent capacity is acquired by the time gastrulation is complete. These results are surprising, given the general view that taste bud development is nerve dependent, and occurs at the end of embryogenesis. The pharyngeal endoderm sits at the dorsal lip of the blastopore at the onset of gastrulation, and because this taste bud-bearing endoderm is specified to make taste buds by the end of gastrulation, signals that this tissue encounters during gastrulation might be responsible for its specification. To test this idea, tissue contacts during gastrulation were manipulated systematically in axolotl embryos, and the subsequent ability of the pharyngeal endoderm to generate taste buds was assessed. Disruption of both putative planar and vertical signals from neurectoderm failed to prevent the differentiation of taste buds in endoderm. However, manipulations of contact between presumptive pharyngeal endoderm and axial mesoderm during gastrulation indicate that signals from axial mesoderm (the notochord and prechordal mesoderm) specify the pharyngeal endoderm, conferring upon the endoderm the ability to autonomously differentiate taste buds. These findings further emphasize that despite the late differentiation of taste buds, the tissue-intrinsic mechanisms that generate these chemoreceptive organs are set in motion very early in embryonic development.
Subject(s)
Ambystoma/embryology , Notochord/embryology , Pharynx/embryology , Taste Buds/embryology , Animals , Cell Communication , Cell Differentiation , Culture Techniques , Embryo, Nonmammalian/surgery , Endoderm , Gastrula , MesodermABSTRACT
BACKGROUND: In some rare inherited disorders such as Li-Fraumeni syndrome, relatives of children with cancer are at increased risk of cancer. We aimed to assess relations between childhood cancer and sibling risk, and evaluate the influence of recessive conditions in cancer causation. METHODS: We did a population-based cohort study in the Nordic countries of 42277 siblings of 25605 children with cancer. Children with cancer were identified from records in the five Nordic cancer registries, and their siblings from nationwide population registries. Cancers in siblings were documented through record linkage with cancer registries and compared with national incidence rates. We also assessed cancer incidence in parents to identify familial cancer syndromes. FINDINGS: 284.2 cancers were expected in siblings, whereas 353 were diagnosed (standardised incidence ratio 1.24 95% CI 1.12-1.38). Risk ratios for siblings were highest in the first decade of life (2.59, 1.89-3.46). We excluded 56 families with genetic syndromes linked to cancer, which reduced this ratio from 1.7 to 1.0 (0.7-1.3) for siblings younger than 20 years, and from 1.3 to 1.0 (0.8-1.3) for those aged 20-29 years. We found no new patterns of familial cancer that indicated inherited susceptibility, or evidence that recessive conditions might contribute to cancers not explained by syndromes. 40% of cancers in siblings that occurred before age 20 years could be attributed to known genetic factors, whereas 60% remained unexplained. INTERPRETATION: Apart from rare cancer syndromes, paediatric cancer is not an indicator of increased cancer risk in siblings.
Subject(s)
Neoplasms/epidemiology , Nuclear Family , Population Surveillance , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Incidence , Infant , Male , Neoplasms/genetics , Registries , Risk , Scandinavian and Nordic Countries/epidemiologyABSTRACT
PURPOSE: To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases. PATIENTS AND METHODS: This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk. RESULTS: The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment. CONCLUSION: Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.
Subject(s)
Neoplasms/mortality , Adolescent , Adult , Age of Onset , Cause of Death , Child , Child, Preschool , Cohort Studies , Female , Finland/epidemiology , Humans , Iceland/epidemiology , Infant , Infant, Newborn , Male , Neoplasms/complications , Neoplasms/therapy , Proportional Hazards Models , Risk , Scandinavian and Nordic Countries/epidemiology , Survival Analysis , Time FactorsABSTRACT
Malignant mesothelioma is associated with asbestos exposure and remains resistant to all therapeutic intervention. Previous studies have suggested an enhancing role for platelet-derived growth factor (PDGF) in mesothelial tumorigenicity, although the mechanism by which PDGF facilitates tumorigenicity is unknown. Here, we evaluate the contribution of PDGF-A expression to mesothelial tumorigenicity using ectopic modulation of PDGF-A expression. We find, in accordance with other reports, that the receptor for PDGF-A, although expressed at high levels in normal human mesothelial cells, is not easily detectable in mesothelioma. Further, we show that PDGF-A overexpression is responsible for autocrine downregulation of its receptor. Our data indicate, surprisingly, that for mesothelioma cells in vitro, high-level activation of a PDGF-A-PDGF receptor loop is antiproliferative whereas abrogation of PDGF-A expression stimulates growth. These data suggest that PDGF-A does not contribute to tumorigenicity by autocrine stimulation of proliferation. In contrast, increased PDGF-A expression in vivo increases tumor incidence and growth rate and decreases the latency period to tumor formation whereas abrogation of PDGF-A expression decreases tumor incidence and increases latency. Thus, the tumorigenic effect of PDGF-A must act through paracrine mechanisms relevant at early stages of tumor initiation.
Subject(s)
Cell Transformation, Neoplastic , Mesothelioma/etiology , Platelet-Derived Growth Factor/biosynthesis , Animals , Autocrine Communication , Down-Regulation , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Paracrine Communication , Receptor, Platelet-Derived Growth Factor alpha/biosynthesisABSTRACT
The estimation of object volume from rotationally randomised sections relies on an ancient geometrical principle due to the Alexandrian mathematician Pappus. In this paper we describe two studies that make estimates of eye volume using a stereological version of the Pappus principle. The first study uses a design-based version of the Pappus theorem to make estimates of eye volume in Sprague-Dawley rats and the second uses a model-based implementation for estimating eye volume in juvenile Dover sole. In the sole study we compare the estimates of volume with estimates made using the Cavalieri method and show that the Pappus method gives identical volume estimates with a markedly lower coefficient of variation (2.5%) than the Cavalieri method (13.5%).
Subject(s)
Eye/anatomy & histology , Microscopy/methods , Animals , Eye/embryology , Fishes , Larva , Mathematics , Models, Animal , Rats , Rats, Sprague-DawleyABSTRACT
Adult axolotls have approximately 1,400 taste buds in the epithelium of the pharyngeal roof and floor and the medial surfaces of the visceral bars. These receptors are most dense on the lingual surfaces of the upper and lower jaws, slightly less dense throughout lateral portions of the pharyngeal roof and floor, and more sparse within medial portions of the pharyngeal roof and floor, except for a median oval patch of receptors located rostrally between the vomerine tooth fields. Each taste bud is a pear-shaped organ, situated at the center of a raised hillock and averaging 80 and 87 microm in height and width, respectively. Each comprises 50 to 80 cells, which can be classified as basal, dark fusiform, or light fusiform, based on differences in their morphology. The distal ends of the apical processes of the fusiform cells reach the surface of each hillock, forming a single taste pore with an average diameter of 15 microm. Each apical process terminates in one of three ways: as short, evenly spaced microvilli; as long clustered microvilli; or as large, stereocilia-like microvilli. The pharyngeal epithelium and associated taste buds in axolotls are innervated solely by rami of the facial, glossopharyngeal and vagal nerves. Approximately, the rostral one half of the pharyngeal roof is innervated by the palatine rami of the facial nerve, whereas the caudal one half of the pharyngeal roof is innervated by the pharyngeal rami of the glossopharyngeal and vagal nerves. The lingual surface of the lower jaw is innervated by the pretrematic (mandibular) ramus of the facial nerve. The dorsal two-thirds of the visceral arches, and the ventral one-third of the visceral arches and the pharyngeal floor, are innervated by both the pretrematic and post-trematic rami of the glossopharyngeal and vagal nerves, respectively.
Subject(s)
Ambystoma/anatomy & histology , Cranial Nerves , Pharynx/innervation , Pharynx/ultrastructure , Taste Buds/ultrastructure , Taste/physiology , Ambystoma/physiology , AnimalsABSTRACT
Twenty-one otherwise healthy dogs that presented for surgical repair of a ruptured cranial cruciate ligament were blindly and randomly given either carprofen (2.2 mg/kg body weight, orally) or a placebo beginning 12 hours preoperatively and continuing every 12 hours for a total of three doses. The patients were assessed for postoperative pain using a subjective pain score and given oxymorphone (0.1 mg/kg body weight, intramuscularly) every four hours if the pain score was 2 or greater. Blood samples were also collected to determine serum cortisol levels. There was a significant increase in serum cortisol levels in the immediate postoperative period in both the placebo group and the carprofen group (p less than 0.05). There was no significant difference in the percentage of increase in serum cortisol levels between the two groups. No correlation was evident between the serum cortisol levels and the corresponding pain scores in either group. This subjective method of assessing postoperative pain was not accurate and should not be relied upon for determination of postoperative analgesic administration. Perioperative oral administration of carprofen did not appear to be effective in controlling postoperative pain in these patients.
Subject(s)
Anterior Cruciate Ligament Injuries , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Carbazoles/therapeutic use , Dogs/physiology , Pain, Postoperative/veterinary , Administration, Oral , Animals , Anterior Cruciate Ligament/surgery , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Carbazoles/administration & dosage , Dogs/injuries , Dogs/surgery , Female , Hydrocortisone/blood , Male , Pain, Postoperative/drug therapy , Rupture/veterinary , Treatment OutcomeABSTRACT
Accumulating data demonstrate overexpression of both inducible NO synthase (NOS2) and cyclooxygenase-2 (COX2) in many epithelial neoplasias. In addition, cyclooxygenase inhibitors have been shown to have antineoplastic and prophylactic efficacy against human colon cancer and in mouse models of this disease. Mesothelioma arises in a context of asbestos exposure and chronic inflammation, which would be expected to enhance the expression of these inducible enzymes. This study demonstrates that both inducible enzymes were expressed in 30 human mesothelioma tissues but were not detectable in nonreactive mesothelial tissues from the same individuals. In contrast, areas of reactive mesothelial cells stained positively for these enzymes. In vitro exposure of human mesothelioma cell lines to the COX2 inhibitor, NS398, revealed dose- and time-dependent antiproliferative activity, whereas the NOS2 inhibitor, 1400W, had no detectable inhibitory effect. Surprisingly, nonmalignant human mesothelial isolates expressed both NOS2 and COX2 in vitro at the same level as mesothelioma cell lines but were less sensitive to NS398 inhibition. This finding indicates that these nonmalignant isolates may retain properties of reactive mesothelial cells and suggests that targets in addition to COX2 may be involved in the antiproliferative response of mesothelioma cell lines. These results have clinical significance because of the selective activity of the drug coupled with the therapeutic resistance and poor prognosis of mesothelioma. The findings presented here suggest that further preclinical studies of these inhibitors in animal models of mesothelioma would be of great interest.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/biosynthesis , Isoenzymes/pharmacology , Lung Neoplasms/enzymology , Mesothelioma/enzymology , Nitric Oxide Synthase/biosynthesis , Prostaglandin-Endoperoxide Synthases/biosynthesis , Prostaglandin-Endoperoxide Synthases/pharmacology , Adult , Aged , Amidines/pharmacology , Asbestos/adverse effects , Benzylamines/pharmacology , Cell Division/drug effects , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Female , Humans , Immunohistochemistry , Lung/drug effects , Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/etiology , Lung Neoplasms/mortality , Male , Membrane Proteins , Mesothelioma/drug therapy , Mesothelioma/etiology , Mesothelioma/mortality , Middle Aged , Nitric Oxide Synthase Type II , Nitrobenzenes/pharmacology , Sulfonamides/pharmacology , Time Factors , Tumor Cells, CulturedABSTRACT
The objective of this study was to evaluate the effects of a chondroprotective agent on hematologic, hemostatic, and biochemical variables in clinically normal cats when administered at twice the recommended levels for 30 days. Fifteen clinically normal female domestic shorthaired cats were used. Twelve cats were given a chondroprotective agent orally, twice daily for 30 days. Three cats served as environmental controls and did not receive any treatment. The Wilcoxon's rank sum with a Bonferroni correction was used to evaluate the data statistically. Hematologic, hemostatic, and biochemical variables were assessed before treatment and on days 3, 14, and 30 of treatment. All cats remained healthy and showed no adverse reactions to treatment. No clinically and statistically significant shift outside a standard reference range was noted for any parameter. Hematocrit and red blood cell concentrations were decreased from pretreatment concentrations during days 3, 14, and 30 of treatment; however, these values were within a standard reference range at all time points. No significant changes were noted in platelet count, prothrombin time, or activated partial thromboplastin time. There were significant decreases in platelet aggregation response to high and low concentrations of collagen on day 3 and to the high concentration of collagen on days 14 and 30 compared with pretreatment values, but these values were not different from those of untreated cats. There was an increased time to response with the high concentration but not the low concentration of collagen on days 3, 14, and 30. Some parameters, such as potassium, anion gap, alkaline phosphatase, and bicarbonate, showed changes from pretreatment values at some but not all days of treatment. However, median concentrations remained within normal reference ranges, suggesting that these minor shifts were not indicative of clinical significance. Oral chondroprotective agents are widely prescribed in veterinary medicine for the treatment of degenerative joint disease. Safety studies have been performed in dogs; however, to date little is known about the safety of their use in cats. In this study, administration of this chondroprotective agent did not result in any clinically important change in hematologic, biochemical, and hemostatic variables when administered to healthy adult cats for 30 days at twice the recommended dosage.
Subject(s)
Blood Cell Count/veterinary , Cats/blood , Chondroitin Sulfates/adverse effects , Glycosaminoglycans/adverse effects , Administration, Oral , Animals , Chondroitin Sulfates/administration & dosage , Electrolytes/blood , Enzymes/blood , Female , Glycosaminoglycans/administration & dosage , Platelet Aggregation/drug effects , Prothrombin Time/veterinaryABSTRACT
While a great deal has been learned about the genetic control of B lymphocyte behavior through the observation of primary B cells from mice bearing targeted gene mutations, such studies can be restricted by the limited number and longevity of the cells ex vivo, by their heterogeneity, and by the inability to apply further genetic manipulations. Here we describe a protocol for the efficient derivation of mutant B lymphoma cell lines, by crossing mice bearing targeted mutations in genes affecting mature B cell function with transgenic mice bearing the lymphomagenic Emu-myc transgene. Pre-B and B lymphomas were obtained with high frequency, and the cells were readily adaptable to culture. The B lymphoma lines bore surface markers consistent with an immature phenotype and were amenable to cloning and to stable transfection. They are currently being used as a well-defined and unlimited cell source to study antigen receptor signalling and B cell-specific gene regulation, and the dependence of these processes on the products of the vav, CD45, lyn, oct-2, btk and OBF-1 genes.
Subject(s)
B-Lymphocytes/immunology , Genes, myc , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/immunology , Transformation, Genetic , Animals , Female , Immunologic Techniques , Immunophenotyping , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Transfection , Tumor Cells, CulturedABSTRACT
This report presents 20 years' of cancer incidence data by occupational group for the Nordic populations. The study covers the 10 million people aged 25-64 years at the time of the 1970 censuses in Denmark, Finland, Norway, and Sweden, and the 1 million incident cancer cases diagnosed among these people during the subsequent 20 years. The project was undertaken as a cohort study with linkage of individual records based on the personal identification numbers used in all the Nordic countries. In the 1970 censuses, information on occupation for each economically active member of the household was provided in free text in self-administered questionnaires. The data were centrally coded and computerized in the statistical offices. Norway, Sweden, and Finland used the Nordic Classification of Occupations, while Denmark used a national coding scheme. However, all the data could be reclassified into 53 occupational groups and 1 group of economically inactive persons. Person-years at risk were accumulated from 1 January 1971 until the date of emigration, date of death or 31 December 1987 in Denmark, 1989 in Sweden, 1990 in Finland, and 1991 in Norway. The 4 countries all had nationwide registration of incident cancer cases during the entire study period. All incident cancer cases during the individual risk periods were included in the analysis. Despite minor differences between the countries, the International Classification of Diseases, 7th revision, formed the core basis for the diagnostic coding in all 4 countries. For the present study the incident cancer cases have been classified into 35 broad diagnostic groups. The observed number of cancer cases in each group of persons defined by country, gender, and occupation was compared with the expected number calculated from the age-, gender-, and period-specific person-years and the incidence rates for the national population. The result has been presented as a standardized incidence ratio (SIR), defined as the observed number of cases divided by the expected number and multiplied by 100. In the tables of this report, all the SIR values for which the upper limit of the 95% confidence interval is below 100 are printed in green and all those for which the lower limit of the confidence interval is above 100 are printed in red. For all cancers combined, the study showed a wide variation among the men, from an SIR of 79 for farmers to 159 for waiters. The occupations with the highest SIR values also included seamen and workers producing beverages and tobacco. Among the women the SIR values varied from 83 for gardeners to 129 for tobacco workers. Low SIR values were found for farmers and teachers. Outdoor workers such as fishermen and gardeners had the highest risk of lip cancer, while the lowest risk was found among indoor workers such as physicians and artistic workers. Almost all pleural cancers are associated with asbestos exposure. Accordingly, plumbers, welders, mechanics, and seamen were the occupations with the highest risk. There was also an excess risk of pleural cancer in the occupational group of technical, chemical, physical, and biological workers, including, among others, engineers and chemists potentially exposed to asbestos. The wood workers included in the present study had the highest risk of nasal cancer. Most studies of nasal cancer have shown increased risks associated with exposure to wood dust, both for those in furniture making and for those exposed exclusively to soft wood. Nickel refinery workers are also known for their high risk of nasal cancer. In the present study they were included in the occupational group of smelting workers. Lung cancer was the most frequent cancer among men in the present study. Tobacco smoking is the major risk factor for this disease, but occupational exposures also play an important role. Waiters and tobacco workers had the highest risk of lung cancer. Miners and quarry workers also had a high risk of lung cancer, which may be related to