RESUMEN
Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.
Asunto(s)
Enfermedad por Cuerpos de Lewy/diagnóstico , Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , alfa-Sinucleína/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeoRESUMEN
There is accumulating evidence of preserved arithmetic knowledge in semantic dementia (SD), contrasting with patients' striking impairment in other domains of semantic memory. This important finding exemplifies domain specificity in the breakdown of semantic memory and supports notions of the functional independence of semantic number knowledge. Nevertheless, evidence for preserved arithmetic knowledge in SD comes largely from single case studies. It is not known whether such preservation is a universal finding, or whether it persists irrespective of disease severity. The present study examined performance of 14 SD patients, varying in the severity of their semantic impairment, on tasks assessing knowledge of arithmetic signs, and on single-digit and multi-digit calculation problems, permitting evaluation of fact retrieval and use of procedures. SD patients performed generally well compared to 10 healthy controls on tests of addition and subtraction. However, abnormalities were elicited, which were not explained by education or hemispheric side of atrophy, but increased as a function of semantic severity. Patients had difficulty identifying arithmetic signs. They used increasingly basic, inflexible strategies to retrieve multiplication table 'facts', and in multi-digit calculations they made procedural errors that pointed to a failure to understand the differential weighting of left and right hand columns. The pattern of responses and error types mirrors in reverse that found in children as they acquire arithmetic competence, and suggests a progressive degradation in conceptual understanding of arithmetic. Longitudinal study of two SD patients demonstrated an association between semantic decline and impaired arithmetic performance. The findings challenge the notion of arithmetic knowledge as a totally separate semantic domain and suggest that the temporal lobes play an important role in arithmetic understanding.
Asunto(s)
Demencia/fisiopatología , Conocimiento , Matemática , Semántica , Anciano , Anciano de 80 o más Años , Atrofia/etiología , Comprensión/fisiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Índice de Severidad de la Enfermedad , Estadísticas no ParamétricasRESUMEN
A well-documented feature of Huntington's disease (HD) is disproportionate impairment in the ability to recognise the emotional expression of disgust. However, this finding has been challenged by studies that report no differential disgust impairment and attribute apparent differences across emotions to task difficulty. The present study sought to shed light on disparities in findings through a comparative study of emotion recognition in HD and frontotemporal dementia (FTD). Ten HD, 12 FTD patients and 12 healthy controls were administered 10 tasks assessing facial and vocal recognition of emotions and comprehension of emotion terms. The findings were not consistent with either the 'selective disgust impairment' or 'task difficulty' view. Both HD and FTD groups were impaired compared to controls, deficits in HD being less severe. Impairments in FTD were elicited for all emotions whereas in HD they were demonstrated predominantly for negative emotions of fear, disgust and anger. Consistency in performance, despite varying task demands, excluded an explanation in terms of item difficulty, and was in keeping with the notion of distinct neural substrates for processing of negative emotions. Contrary to the notion of disproportionate disgust impairment, the most severe deficits in HD were elicited for anger, a finding that may have relevance for the poor anger control that is the hallmark of HD. The data raise the possibility that linguistic influences and conceptual complexities of the emotion of disgust may contribute to the variable finding of selective disgust impairment in HD.
Asunto(s)
Demencia/fisiopatología , Emociones/fisiología , Enfermedad de Huntington/fisiopatología , Reconocimiento en Psicología/fisiología , Adulto , Anciano , Conducta de Elección/fisiología , Expresión Facial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento Visual de Modelos , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiología , Estadísticas no ParamétricasRESUMEN
The influence of hepatic transit on the ability of exogenous cholecystokinin-8-sulfate and -33-sulfate (CCK-8 and CCK-33, respectively) to stimulate gallbladder contraction and exocrine pancreatic secretion, as well as on the peripheral plasma concentration of each agent, was evaluated in five conscious dogs with pancreatic and gallbladder fistulas and complete portacaval transposition. The gallbladder pressure increments after portal administration of CCK-8 (0.125, 0.25, 0.50, and 1.0 microgram/kg per h for 5 min) were diminished by 36, 45, 39 and 25%, respectively, in comparison with those obtained with systemic administration of identical doses of CCK-8 (P less than 0.05). In a subsequent experiment, the integrated pancreatic juice volume, bicarbonate, and protein secretion were diminished by 22, 32, and 48%, respectively, during a 30-min infusion of CCK-8 (0.10 micrograms/kg per h) into the portal venous system, in comparison with the results obtained with systemic administration of CCK-8 (P less than 0.05). In contrast, the gallbladder pressure and pancreatic exocrine secretory responses to portal administration of CCK-33 did not differ significantly (P greater than 0.05) from the results obtained with systemic administration of CCK-33. Radioimmunoassay for CCK-8 in plasma showed that the integrated CCK-8 value during portal administration was significantly lower (P less than 0.05) than it was during systemic administration. The results for CCK-33, however, did not vary, whether it was given by a systemic or portal route (P greater than 0.05). Thus, the present study demonstrates that CCK-8 is partially inactivated by the liver whereas CCK-33 is not, which suggests that CCK-3 in the circulation may play a significant role in the physiologic regulation of the gallbladder and exocrine pancreas.
Asunto(s)
Colecistoquinina/análisis , Hígado/metabolismo , Animales , Bioensayo , Perros , Vesícula Biliar/fisiología , Hígado/fisiología , Circulación Hepática , Páncreas/metabolismo , Presión , RadioinmunoensayoRESUMEN
Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.
Asunto(s)
Ácidos y Sales Biliares/fisiología , Pancreatitis/tratamiento farmacológico , Enfermedad Aguda , Amilasas/sangre , Animales , Ceruletida/farmacología , Colecistoquinina/sangre , Resina de Colestiramina/administración & dosificación , Deficiencia de Colina/fisiopatología , Retroalimentación , Femenino , Ratones , Pancreatitis/patología , Ácido Taurocólico/administración & dosificaciónRESUMEN
The traditional assumption that classical motor neurone disease (MND) invariably spares cognitive function is now recognised to be incorrect. Deficits have most commonly been demonstrated on executive tasks suggesting impaired function of frontal systems. Yet, crucial aspects of frontal lobe function have not hitherto been explored. The study used tests of theory of mind (ToM) (interpretation of cartoons and stories) to examine the ability of 16 patients with MND to interpret social situations and ascribe mental states to others. Only minor differences were elicited in the MND group as a whole compared to controls, and performance was not differentially affected for cartoons and stories requiring inference of another's mental state (mental) compared to control (physical) cartoons and stories. However, abnormalities were elicited on both mental and physical tasks in a subgroup of patients with bulbar signs. Moreover, examination of individual patient scores revealed a spectrum of performance ranging from normal to severely impaired. Errors were qualitatively similar to those seen in frontotemporal dementia (FTD). Performance on the ToM tasks was significantly correlated with conventional, untimed measures of executive function, suggesting that ToM deficits in MND are likely to be linked to a more general executive failure. The findings contribute to the understanding of ToM performance in neurodegenerative disease and provide further evidence of the association between MND and FTD.
Asunto(s)
Enfermedad de la Neurona Motora/psicología , Anciano , Cognición/fisiología , Estudios de Cohortes , Demencia/psicología , Femenino , Humanos , Enfermedad de Huntington/psicología , Lenguaje , Masculino , Memoria/fisiología , Procesos Mentales/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Desempeño Psicomotor/fisiología , Percepción Social , Percepción Espacial/fisiología , Ingenio y Humor como Asunto/psicologíaRESUMEN
REASON FOR PERFORMING STUDY: Lymphoid leukaemia (LL) is rare in equids. In man, immunophenotypic classification identifies distinct leukaemic types with different treatment strategies. Improved understanding and classification of equine LL may allow similar advances. OBJECTIVES: To document the clinical, immunophenotypic and functional characteristics in 6 cases of equine LL of T-cell origin. METHODS: The clinical records and pathological findings from 6 cases of equine LL were analysed. Immunohistochemistry to identify T or B lymphocytes was performed on paraffin embedded tissues in 4 cases. Peripheral blood mononuclear cells (PBMC) were phenotyped for expression of CD4, CD8, MHC class I and II and B-cell antigens in 4 cases using monoclonal antibodies (mAbs) and flow cytometry. Neoplastic lymphocytes from 4 horses were stimulated with mitogens. RESULTS AND CONCLUSIONS: Six horses of various breeds were identified with LL of T-cell origin. The clinical course and presenting signs varied. Neoplastic lymphocytes were identified in peripheral blood samples from all horses and tissue invasion was confirmed at examination post mortem in 4 horses. Immunophenotyping identified a predominance of CD3+ T-cells in lymphoid tissues and CD4+ T-cells in circulating peripheral blood mononuclear cells (PBMC) in the affected horses. Neoplastic lymphocytes from the 4 cases that were tested failed to proliferate in response to mitogens. POTENTIAL RELEVANCE: Characterisation of the clinical, pathological and immunological findings in 6 horses with LL has added to reports of this rare condition, characterised it in greater detail and therefore provides a starting point for further investigations.
Asunto(s)
Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Enfermedades de los Caballos/patología , Leucemia de Células T/veterinaria , Leucocitos Mononucleares/patología , Animales , Anticuerpos Monoclonales , Células de la Médula Ósea/patología , Antígenos CD4/inmunología , Antígenos CD8/inmunología , Femenino , Citometría de Flujo/veterinaria , Enfermedades de los Caballos/inmunología , Caballos , Inmunohistoquímica/veterinaria , Leucemia de Células T/inmunología , Leucemia de Células T/patología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , FenotipoRESUMEN
The growth and survival of hamster H2T pancreatic ductal adenocarcinoma in vitro are known to be significantly reduced by inhibitors of polyamine biosynthesis. alpha-Difluoromethylornithine (alpha-DFMO) is a specific and irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. alpha-DFMO treatment inhibits the growth of H2T pancreatic cancer cells and decreases H2T cell survival in vitro and in vivo. In the present study, the effects of cyclosporin A (CsA) were examined on growth, survival, and polyamine levels in H2T pancreatic ductal adenocarcinoma in vitro. CsA had inhibitory effects on H2T pancreatic cancer growth similar to those of alpha-DFMO; these effects were blocked by the addition of the polyamine putrescine. Polyamine levels were found to be significantly altered in cells treated with CsA and/or alpha-DFMO. The combination of CsA (8.3 X 10(-4) mM) and alpha-DFMO (0.5 mM or 1.0 mM) inhibited H2T cell survival to a greater extent than either agent alone. These results suggest that CsA in combination with other agents that inhibit polyamine synthesis may be useful for the treatment of pancreatic cancer.
Asunto(s)
Carcinoma Intraductal no Infiltrante/patología , Ciclosporinas/administración & dosificación , Eflornitina/administración & dosificación , Neoplasias Pancreáticas/patología , Animales , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cricetinae , Sinergismo Farmacológico , Inhibidores de la Ornitina Descarboxilasa , Neoplasias Pancreáticas/tratamiento farmacológico , Poliaminas/metabolismo , Putrescina/farmacologíaRESUMEN
Polyamines are essential for cell division and growth. Inhibition of polyamine biosynthesis by alpha-difluoromethylornithine (DFMO) on the growth of hamster H2T pancreatic cancer was investigated both in vitro and in vivo. Cell-doubling time (TD) and survival fraction were determined after a single treatment with DFMO (5 mM). We examined the ability of putrescine to reverse the growth-inhibitory effect of DFMO. The TD for cells treated with DFMO in vitro was 49.6 +/- 5.7 versus 25.4 +/- 2.6 hours for control. The addition of putrescine to DFMO-treated H2T cells showed a reversal of the growth-inhibitory effect of DFMO. Cytotoxicity in vitro increased with prolonged treatment; the survival fraction after 24 hours of treatment was 32%; after 48 hours, 19%; after 72 hours, 13%; and after 92 hours, 8%. We performed two separate animal experiments. In experiment I, H2T cells were injected into the cheek pouch of male Syrian golden hamsters; controls did not receive DFMO. Continuous treatment with 3% DFMO in the drinking water was begun 7 days before, on the day of, or 7 days after tumor cell injection. In experiment II, 4 groups were treated identically to those in experiment I. An additional group of 10 hamsters received 3% DFMO and no tumor, and another additional group of 10 hamsters were housed individually with 3% DFMO begun 7 days after tumor cell injection. Tumor size, body weight, water, and food intake were measured. DFMO treatment in vivo significantly inhibited tumor size and inhibited growth of pancreatic cancer by as much as 50% of control. Our results demonstrate a significant antiproliferative effect of DFMO on the growth of pancreatic adenocarcinoma both in vitro and in vivo.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Eflornitina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Poliaminas/biosíntesis , Animales , Peso Corporal/efectos de los fármacos , Cricetinae , Depresión Química , Eflornitina/farmacología , Masculino , MesocricetusRESUMEN
We recently reported trophic response of transplantable mouse colon cancer cells (MC-26) to pentagastrin, in vivo, and demonstrated gastrin receptors on MC-26 cells, in vitro. In the present study, growth of MC-26 cells in mice, in response to pentagastrin, was studied in relation to binding kinetics and capacity of gastrin receptor. Gastrin receptor levels on mouse fundic and colonic membranes and on MC-26 cellular membranes were determined before MC-26 cell inoculation and designated as Day 0 levels. Four groups of mice were next inoculated with MC-26 cells and given injections of either pentagastrin (treated) or normal saline (control) for 10 or 15 days. At the end of the treatment periods, body, tumor, fundic, and colon weights were noted and gastrin receptor measured. tumor and fundic weights increased significantly within 15 days of pentagastrin treatment, compared to control values. In control (non-pentagastrin treated) mice, the binding affinity of gastrin receptor on tumor membranes was significantly decreased and associated with the complete loss of high-affinity gastrin receptor (Kd = less than 0.5 nM) by Day 15 of tumor growth. On the other hand, both the binding affinity and gastrin receptor levels of tumor membranes were maintained at Day 0 values by pentagastrin treatment. Endogenous gastrin was therefore ineffective in maintaining high-affinity gastrin receptor on control tumors. A significant number of low-affinity gastrin-binding sites (Kd = less than 2 nM) appeared in control tumors by Day 15, which could reflect rapid dedifferentiation or conformational changes of gastrin receptor in the absence of high levels of normal regulatory hormones. These studies demonstrate that the trophic effects of gastrin on MC-26 cells are probably mediated by its regulation and maintenance of the binding affinity and capacity of gastrin receptor on the cancer cells, in vivo.
Asunto(s)
Neoplasias del Colon/patología , Gastrinas/fisiología , Receptores de Superficie Celular/fisiología , Animales , Peso Corporal/efectos de los fármacos , Colon/análisis , Neoplasias del Colon/análisis , Fundus Gástrico/análisis , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Pentagastrina/farmacología , Receptores de Superficie Celular/análisis , Receptores de Colecistoquinina , Factores de TiempoRESUMEN
We have measured gastrin receptors (GR) in surgical specimens from 67 patients with primary colon cancers in order to determine the clinical significance of GR in colon cancer. GR analysis was performed on these specimens, and 22 cancers (32.8%) had no detectable GR. Thirty-eight cancers (56.7%) had high-affinity (Kd less than 1.0 nM) levels of GR. Seven cancers (10.4%) had only low-affinity GR (Kd greater than 1.0 nM). Twenty patients (29.9%) had cancers with GR greater than 10 fmol/mg protein. Mean GR content was significantly greater (11.8 +/- 2.9 fmol/mg protein) in Dukes' Stage A and B cancers when compared to Stage C and D cancers (6.2 +/- 1.6 fmol/mg protein). A significantly greater percentage (52.4%) of patients in the early stages (A and B) had tumors with greater than 10 fmol/mg protein compared to patients with more advanced (C and D) cancers (19.6%). GR content did not correlate with histological differentiation, patient age, or preoperative carcinoembryonic antigen levels. No difference in the GR content was noted between left and right colon cancers or in patients of different sex or race. GR content of normal colon mucosa correlated with the GR content of colon cancers from the same surgical specimen, suggesting that these tumors maintain their normal complement of GR. In the early period of follow-up, 12 of 43 (28%) Stage C and D patients with GR less than 10 fmol/mg protein have died, whereas all 8 Stage C and D patients with GR greater than 10 fmol/mg protein are alive. GR content of colon cancers may have prognostic significance and may identify a group of patients with colon cancer that may benefit from hormonal therapy with antigastrin drugs.
Asunto(s)
Neoplasias del Colon/análisis , Receptores de Colecistoquinina/análisis , Antígeno Carcinoembrionario/análisis , Neoplasias del Colon/patología , HumanosRESUMEN
Bombesin-like peptides are found in many different human tumors and are thought to function as an autocrine growth factor for small cell lung cancer in humans. In this study, a human small cell lung carcinoma (NCI-H69) was s.c. implanted bilaterally into the flanks of 12 nude mice. The mice were randomized and divided into two groups and given either bombesin (20 micrograms/kg) or saline i.p. 3 times a day. Tumor areas were measured twice weekly for 6 wk. At sacrifice, the tumors and normal pancreas were excised, weighed, and assayed for DNA, RNA, and protein content. Significant stimulation of tumor growth was observed at weeks 4, 5, and 6. Tumor weight at sacrifice was significantly elevated (77%) above the control, as was DNA content (78%). Bombesin significantly increased the weight (42%), DNA (48%), and protein (61%) contents of the normal mouse pancreas. We conclude that bombesin may act as an autocrine growth factor, or indirectly through the release of other growth factors, on human small cell lung carcinoma.
Asunto(s)
Bombesina/farmacología , Carcinoma de Células Pequeñas/patología , Neoplasias Pulmonares/patología , Animales , Bombesina/análisis , Bombesina/inmunología , Péptido Liberador de Gastrina , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Péptidos/análisis , Péptidos/inmunología , Receptores de Bombesina , Receptores de Neurotransmisores/efectos de los fármacos , Trasplante HeterólogoRESUMEN
We studied loss of heterozygosity (LOH) on human chromosome 7q to determine the location of a putative tumor suppressor gene (TSG) in human primary prostate carcinomas. Samples were obtained from 16 primary prostate carcinomas surgically removed from patients at The University of Texas M. D. Anderson Cancer Center. Paired normal and tumor DNAs were used as template for PCR amplification of a set of 14 CA microsatellite repeats on 7q21-qter. Twelve of 16 cases studied had LOH at one or more loci on 7q. Eighty-three percent LOH (five of six informative cases) was detected with D7S522 at 7q31.1-7q31.2. Percentage of LOH was normally distributed around D7S522. The high incidence of LOH in primary prostate carcinomas suggests that there is a TSG relevant to the development of prostate cancers at 7q31.1-31.2, confirming our previous functional evidence for a TSG at this location. Further research needs to be conducted to establish the identity and function of this putative TSG.
Asunto(s)
Carcinoma/genética , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Genes Supresores de Tumor , Neoplasias de la Próstata/genética , Mapeo Cromosómico , ADN Satélite/genética , Humanos , MasculinoRESUMEN
Gastrin is a trophic factor for some human colon cancer cells. However, the signal-transduction pathways by which gastrin regulates growth are still unknown. We examined the effect of synthetic human gastrin-17 (G-17) on signal-transduction pathways and cell growth using 4 different human colon cancer cell lines (LoVo, COLO 320, HT-29, and HCT116). G-17 stimulated the production of cyclic AMP in LoVo, COLO 320, and HCT116 cells, while G-17 stimulated phosphatidylinositol hydrolysis and mobilization of intracellular calcium in HT-29 cells. The growth-regulatory effect of G-17 on these colon cancer cells (stimulatory on LoVo, COLO 320, and HT-29 cells; inhibitory on HCT116 cells) was well correlated with the effect of G-17 on the signal-transduction pathway in each cell line. We further examined the effect of a selective cholecystokinin-B type receptor antagonist, JMV 320, on G-17-induced signal-transduction pathways and G-17-regulated growth. In each cell line, the effect of JMV 320 on G-17-induced signal-transduction pathways was well correlated with that on G-17-regulated growth. G-17 appears to regulate, at least to some extent, growth of human colon cancer cells through gastrin receptor-linked signal-transduction pathways that are cell-specific.
Asunto(s)
Calcio/metabolismo , División Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Gastrinas/farmacología , Fosfatidilinositoles/metabolismo , Línea Celular , Neoplasias del Colon , Relación Dosis-Respuesta a Droga , Hormonas/farmacología , Humanos , Hidrólisis , Cinética , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
We have recently demonstrated that gastrin stimulates growth of mouse colon cancer (MC-26) in vivo by regulation of gastrin receptors (GR). In the present study, we have tested the effect of proglumide (PGL), a GR antagonist, on the trophic and GR-regulatory effects of gastrin on MC-26 tumors. Four groups of 12 mice each were inoculated with 5 X 10(4) MC-26 cells and given injections of either normal saline (control), pentagastrin (PG), PGL, or both PG + PGL for 21 days. At the end of the treatment period, body, tumor, fundic, and colon weights were noted and GR measured. Two types of specific gastrin-binding sites were found on tumor cell membranes of control mice, one with high binding affinity (Kd = less than 1.0 nM) and low capacity (GR), and the other with a very high capacity and a low affinity (Kd = greater than 0.1 microM) (type 2 gastrin-binding sites). Only the type 1 GR were observed on the fundic mucosal and colon membranes. PG treatment resulted in a significant weight increase of the tumors with an up-regulation of only type 1 GR. On the other hand, PG had no significant effect on fundic mucosal and colonic GR levels, but caused a significant increase in fundic mucosal weights. PGL completely inhibited both the trophic and GR up-regulatory effects of PG on tumors, but incompletely reduced the PG-stimulated fundic mucosal weight gain, indicating differential sensitivity of tumor and normal tissues to PGL. PGL, in the absence of PG, was slightly trophic for normal fundic mucosa, but had no effect on MC-26 tumors and normal colon. The one striking effect of PGL, in the presence of PG, was the significant lowering of the binding affinity of type 1 GR for gastrin on both the tumor and normal gastrointestinal tissues. This effect may be another mechanism by which PGL interferes with the actions of PG on MC-26 tumors and fundic mucosa of mice.
Asunto(s)
Neoplasias del Colon/patología , Glutamina/análogos & derivados , Pentagastrina/farmacología , Proglumida/farmacología , Receptores de Colecistoquinina/efectos de los fármacos , Animales , Colon/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Gastrinas/metabolismo , Masculino , RatonesRESUMEN
Consistent deletions and loss of heterozygosity (LOH) in polymorphic markers in a determinate chromosomal fragment are known to be indicative of a closely mapping tumor suppressor gene. Deletion of the long arm of chromosome 7 is a frequent trait in many kinds of human primary tumors. We studied LOH of 14 markers on chromosome 7q in order to determine the location of a putative tumor suppressor gene in human primary squamous cell carcinoma of the head and neck and in human primary colon carcinomas. Samples were obtained from 18 primary squamous cell carcinomas of the head and neck and 18 primary colon carcinomas surgically removed from patients at the Fox Chase Cancer Center. Loss of heterozygosity was studied performing PCR amplifications of a set of 14 CA microsatellite repeats encompassing 7q21-qter. Of 18 squamous cell carcinomas of the head and neck cases studied, 12 had LOH at one or more loci on 7q. Fifty-three percent of 15 informative cases had LOH of the CA microsatellite dinucleotide repeat marker D7S522 at 7q31.1-7q31.2. Eleven of 18 colon carcinoma cases had LOH of one or more markers assayed, and the maximum LOH (80% of 10 informative cases) was at D7S522. Distributions of percentage of LOH in both tumor types were normally distributed around microsatellite D7S522. The high incidence of LOH in both tumor types studied suggests that a tumor suppressor gene relevant to the development of epithelial cancers is present on the 7q31.1-31.2, confirming our previous functional evidence for a tumor suppressor gene on chromosome 7.
Asunto(s)
Carcinoma de Células Escamosas/genética , Deleción Cromosómica , Cromosomas Humanos Par 7 , Neoplasias del Colon/genética , Genes Supresores de Tumor , Neoplasias de Cabeza y Cuello/genética , ADN Satélite/genética , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
We studied the effect of inhibition of polyamine biosynthesis by alpha-difluoromethylornithine on the growth of a human gastric adenocarcinoma (CLEES) xenotransplanted in nude mice. CLEES is a well-differentiated gastric adenocarcinoma of the intestinal type. The doubling time has ranged from 7 to 10 days through 11 passages. Electron microscopic and immunohistochemical studies comparing the original tumor and xenotransplants showed similar structure and similar amounts of carcinoembryonic antigen. Polyamine biosynthesis is required for cell division. alpha-Difluoromethylornithine inhibits ornithine decarboxylase, the rate-limiting enzyme in polyamine biosynthesis. In this study, 48 athymic mice were used in two experiments. In the first experiment, two groups of 12 mice each were inoculated with CLEES tumor cells and received either tap water or a 3% alpha-difluoromethylornithine solution as drinking water. Tumor size was measured twice weekly. Tumor size was significantly decreased from controls by the fourth week of treatment and at all points of analysis thereafter for 7 wk. In the second experiment, alpha-difluoromethylornithine significantly reduced tumor concentrations of the polyamines putrescine and spermidine. In addition, the tumor content of DNA was significantly reduced in treated mice (0.64 +/- 0.16 mg) compared to controls (4.76 +/- 0.92 mg). Our data suggest that inhibition of polyamine biosynthesis may be a useful component of multidrug chemotherapy for human gastric adenocarcinoma. Establishment of tumor lines such as this gastric adenocarcinoma will facilitate further studies on the biological behavior of human gastric cancer and its response to chemotherapeutic manipulation in vivo.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Eflornitina/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Membrana Celular/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Poliaminas/análisis , Receptores de Colecistoquinina/análisis , Neoplasias Gástricas/patología , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
CASE HISTORY AND CLINICAL FINDINGS: A dairy cow, from a herd in the Waikato region of New Zealand, was reported with regenerative anaemia on 12 September 2014. Testing of blood from the animal using PCR assays for Theileria orientalis produced a negative result for both Chitose and Ikeda types. LABORATORY FINDINGS: Using PCR and DNA sequencing, blood from the cow was positive for Candidatus Mycoplasma haemobos. Further testing of another 12 animals from the case herd, 27 days after the affected cow was first reported, showed 11 animals were positive for Candidatus M. haemobos or Mycoplasma wenyonii in the PCR. None of these cattle were clinically anaemic or positive for T. orientalis Ikeda type using PCR. A convenience sample of 47 blood samples from cattle throughout New Zealand, submitted to the Investigation and Diagnostic Centre (Ministry for Primary Industries) for surveillance testing for T. orientalis Ikeda, was selected for further testing for bovine haemoplasmas. Of these samples, 6/47 (13%) and 13/47(28%) were positive for M. wenyonii and Candidatus M. haemobos, respectively. There was no difference in the proportion of samples positive for the bovine haemaplasmas between cattle with anaemia that were negative for T. orientalis (6/20, 33%), or without anaemia or T. orientalis (10/18, 56%), or from cattle herds experiencing anaemia and infection with T. orientalis Ikeda type (3/9, 33%). DIAGNOSIS: Bovine haemoplasmosis. CLINICAL RELEVANCE: The presence of bovine haemoplasmas in blood does not establish causality for anaemia in cattle. Diagnosis of anaemia associated with haemoplasmosis would require exclusion of other causes of regenerative anaemia and an association of the agent with anaemia in affected cattle herds. The data collected in this study did not provide evidence that bovine haemoplasmas were associated with a large number of outbreaks of anaemia in cattle in New Zealand.
Asunto(s)
Anemia/veterinaria , Enfermedades de los Bovinos/parasitología , Infecciones por Mycoplasma/veterinaria , Mycoplasma/aislamiento & purificación , Anemia/epidemiología , Anemia/parasitología , Animales , Bovinos , Enfermedades de los Bovinos/epidemiología , Infecciones por Mycoplasma/complicaciones , Infecciones por Mycoplasma/epidemiología , Infecciones por Mycoplasma/parasitología , Nueva Zelanda/epidemiologíaRESUMEN
Calcitonin is known to inhibit secretion of gastrin and insulin in vivo. The objective of this study was to determine whether calcitonin can act directly on pancreatic islets in vitro to inhibit insulin release. Isolated islets were obtained from collagenase-treated rat pancreas, and three peptides (gastrin-releasing peptide, cholecystokinin-8, bombesin) and glucose were used to stimulate insulin release. All agents caused a significant increase in insulin secretion and calcitonin inhibited these responses, but had no consistent effect on basal release. This study provides evidence that calcitonin is an effective inhibitor of insulin secretion and acts directly on islet tissue.