Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer

Insulin-like growth factor 1 (IGF-1) is a potent mitogen for human breast-cancer cells in vitro. In circulation, most of IGF-1 is bound to IGF-binding protein 3 (IGFBP-3). This high-affinity binding is thought to have an important limiting effect on the availability of IGF-1 for biological activity. To assess the availability of IGF-1 for receptor binding, we determined serum levels of IGF-1 and IGFBP-3 and IGF-1/IGFBP-3 ratios. In a case-control study, 150 women aged 38 to 75 years presenting with stage-l or-II breast cancer were investigated just prior to surgery (n = 76), or to irradiation one month after surgery (n = 74). The population-based control group consisted of 441 women of the same age having no breast cancer. Women reporting diabetes mellitus or other hormonal abnormalities were excluded. Premenopausal cases showed elevated IGF-1 serum concentrations, decreased IGFBP-3 levels and increased IGF-1/IGFBP-3 ratios. The IGF-1/IGFBP-3 ratio was a significant breast-cancer risk factor, also after adjustment for age, family history, height, body-mass index, body-fat distribution, and serum levels of C-peptide. The relative risk was 7.34 for the highest compared with the lowest quintile of IGF-1/IGFBP-3. The presence or absence of tumor had no influence on these results. Increased levels of available IGF-1 in the circulation of pre-menopausal women may contribute to the development of breast cancer. © 1995 Wiley-Liss Inc.     

Epidermal growth factor receptors and adenylate cyclase activity in human thyroid tissues

Thyroid stimulating hormone (TSH) and epidermal growth factor (EGF) are growth factors for some thyroid cells in cultures. We have previously found more EGF receptors in neoplastic human thyroid tissues than in normal thyroid tissues. We have also found a higher TSH-stimulated adenylate cyclase (AC) activity in neoplastic human thyroid tissues than in normal thyroid tissues. To clarify the relationship between the effect of EGF and TSH on thyroid tissue, we measured the binding of EGF and TSH and the basal, TSH-stimulated and forskolin-stimulated adenylate cyclase activity in 49 normal, hyperplastic and neoplastic human thyroid tissues (5 normal, 2 Hashimoto thyroiditis, 5 Graves' disease, 14 multinodular goiters, 9 follicular adenomas, S follicular carcinomas, 8 papillary carcinomas, and 1 undifferentiated carcinoma). Specific binding of EGF and TSH were measured by radioreceptor assays using competitive inhibition of radio-labeled ligand by unlabeled ligand. Basal, maximally (300 mU/ml) TSH-stimulated, and maximally (100 mM) forskolin-stimulated adenylate cyclase activities were also measured in the same membrane particulate fractions from the thyroid tissues. We found: neoplastic thyroid tissues bind more labeled EGF than nonneoplastic thyroid tissues; follicular adenomas and carcinomas have higher EGF binding than other thyroid tissues; a weak but significant correlation between specific EGF binding and specific TSH binding, and between specific EGF binding and TSH-stimulated adenylate cyclase activity of the thyroid membrane preparations. These findings are consistent with the hypothesis that TSH stimulates an increase in thyroid EGF receptors by increasing intracellular cAMP. The higher binding of EGF and the higher TSH-stimulated AC activity may explain why thyroid neoplasms grow to a larger size than normal thyroid tissues.

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Resumen La hormona estimuladora de tiroides (TSH) y el factor de crecimiento epidermal (EGF) son factores de crecimiento para algunas células tiroideas en cultivo tisular. Previamente hemos informado el hallazgo de más receptores de EGF en tejidos tiroideos neoplásicos humanos que en tejidos tiroideos normales. Con el objeto de clarificar la relación entre el efecto del EGF y de la TSH sobre el tejido tiroideo, realizamos la determinacion de la ligación del EGF y de la TSH y de la actividad basai y de la actividad estimulada por TSH y forskolina de la adenilato-ciclasa (AC) en 49 especímenes de tejido tiroideo humano (5 normales, 2 tiroiditis de Hashimoto, 5 enfermedad de Graves, 14 bocios multinodulares, 9 adenomas foliculares, 5 carcinomas foliculares, 8 carcinomas papilares, y 1 carcinoma indiferenciado). La ligadura especifica del EGF y de la TSH fue medida mediante determinaciones de receptores utilizando inhibición competitiva radiomarcada. También se determinó la actividad basai y la actividad estimulada por forskolina de la adenilato-ciclasa en las mismas fracciones de tejidos tiroideos. Se registraron los siguientes hallazgos: los tejidos neoplásicos ligan más EGF marcado que los tejidos tiroideos no neoplásicos; los adenomas foliculares y los carcinomas poseen una capacidad de ligación del EGF mayor que los otros tejidos tiroideos; hay una débil pero significativa correlación entre la ligación especifíca del TGF y la de la TSH, y entre la ligación específica del EGF y la actividad estimulada por TSH de la adenilato-ciclasa en las preparaciones de membrana tiroidea. Estos hallazgos aparecen consistentes con la hipótesis de que la TSH estimula un aumento en los receptores de EGF mediante el incremento de la cAMP intracelular. La aumentada ligación de EGF y la incrementada actividad estimulada de TSH pueden explicar el por qué los neoplasmas tiroideos crecen hasta un tamaño mayor que los tejidos tiroideos normales.

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Résumé La thyroid stimulating hormone (TSH) et l'epidermal growth factor (EGF) sont des facteurs de croissance agissant sur certaines cellules thyroïdes en culture. Nous avons trouvé qu'il y avait plus de récepteurs EGF dans le tissu thyroïde humain néoplasique que dans le tissu thyroïdien normal. Nous avons également montré qu'il y avait plus d'activité d'adenylate cyclase stimulée par la TSH dans le tissu thyroïden néoplasique par rapport au tissu normal. Pour clarifier le rapport entre les effets de l'E.GF et la TSH sur le tissu thyroïden, nous avons mesuré l'activité de liaison d'EGF, de TSH et l'activité adénulate cyclase de base, stimulée par la TSH, et par la forskoline chez 49 patients ayant du tissu normal, hyperplasique ou néoplasique (5 normaux, 2 thyroïdites de Hashimoto, 5 maladies de Basedow, 14 goîtres multinodulaires, 9 adénomes folliculaires, 5 cancers folliculaires, 8 cancers papillaires, et 1 cancer indifférencié). Les liaisons spécifiques d'EGF et de TSH ont été mesurées par le dosage des récepteurs nucléaires par la méthode de déplacement des ligands marqués par des ligands froids (non marquées). Les activités adénylate cyclase de base, maximale (300 mU/mL), stimulée par la TSH (300 mU/mL) et la forskoline (100 mM) ont été également mesurées dans les mêmes fractions de particules membranaires provenant des tissus thyroïdens. Nous avons trouvé que: les tissus néoplasiques se liaient davantage avec l'EGF que les tissus non néoplasiques; les adénomes folliculaires et les cancers avaient un index de liaison plus élevé que les autres tissus thyroïdens; et il y avait une corrélation faible mais significative entre la liaison spécifique EGF et TSH, et entre la liaison spécifique EGF et l'activité adénylate cyclase des préparations de membrane thyroïdienne. Ces résultats sont en faveur de l'hypothèse selon laquelle la TSH provoque une augmentation des récepteurs EGH de la thyroïde en augmentant la concentration intracellulaire d'AMP cyclique. Le degré de liaison d'EGF élevé, et l'augmentation de l'activité stimulée par la TSH peuvent expliquer la croissance accélérée des tissus néoplasiques par rapport à celle des tissus normaux.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.

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Supported in part by the Medical Research Service of the Veterans Administration Medical Center, San Francisco, California and the Affirmative Action Faculty Development Grant of the University of California, San Francisco, California.     

Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity.

BACKGROUND: Volumetric studies have reported reductions in the size of the corpus callosum (CC) in autism, but the callosal regions contributing to this deficit have differed among studies. In this study, a computational method was used to detect and map the spatial pattern of CC abnormalities in male patients with autism. METHODS: Twenty-four boys with autism (aged 10.0 +/- 3.3 years) and 26 control boys (aged 11.0 +/- 2.5 years) underwent a magnetic resonance imaging (MRI) scan at 3 Tesla. Total and regional areas of the CC were determined using traditional morphometric methods. Three-dimensional (3D) surface models of the CC were also created from the MRI scans. Statistical maps were created to visualize morphologic variability of the CC and to localize regions of callosal thinning in autism. RESULTS: Traditional morphometric methods detected a significant reduction in the total callosal area and in the anterior third of the CC in patients with autism; however, 3D maps revealed significant reductions in both the splenium and genu of the CC in patients. CONCLUSIONS: Statistical maps of the CC revealed callosal deficits in autism with greater precision than traditional morphometric methods. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism.     

A multicenter evaluation of safety of early extubation in liver transplant recipients.

Small single-institutional studies performed prior to the introduction of organ allocation using the Model for End-Stage Liver Disease (MELD) suggest that early airway extubation of liver transplant recipients is a safe practice. We designed a multicenter study to examine adverse events associated with early extubation in patients selected for liver transplantation using MELD score. A total of 7 institutions extubated all patients meeting study criteria and reported adverse events that occurred within 72 hours following surgery. Adverse events were uncommon: occurring in only 7.7% of 391 patients studied. Most adverse events were pulmonary or surgically related. Pulmonary complications were usually minor, requiring only an increase in ambient oxygen concentration. The majority of surgical adverse events required additional surgery. Analysis of a limited set of perioperative variables suggest that blood transfusions and technical factors were associated with an increased risk of adverse events. In conclusion, while early extubation appears to be safe under specified circumstances, there are performance differences between institutions that remain to be explained.     

Natural history of morbid obesity without surgical intervention.

BACKGROUND: To study the mortality among morbidly obese patients qualifying for bariatric surgery. Mortality from bariatric surgery for morbid obesity has been widely reported; however, little is known about the mortality in morbidly obese patients who defer surgery. METHODS: Consecutive patients evaluated for bariatric surgery with an initial encounter between 1997 and 2004 were identified. The Social Security Death Index and office records were used to identify mortality through 2006. We conducted telephone interviews to determine whether the 305 patients who did not undergo bariatric surgery at our institution had undergone the surgery elsewhere. Using Cox proportional hazards models, we compared the mortality in patients undergoing surgery with that of those who did not. To evaluate bias resulting from missing data, we conducted analyses assuming that all patients with missing data had (1) undergone surgery and (2) not undergone surgery. RESULTS: A total of 908 patients underwent bariatric surgery (880 patients at our institution and 28 patients elsewhere). A total of 112 patients did not undergo surgery. Data regarding surgery on 165 patients could not be obtained. The mortality in those patients who did not undergo surgery was 14.3% compared with 2.9% for those who did undergo surgery. Adjusting for age, gender, and body mass index, patients who had undergone surgery had an 82% reduction in mortality (hazard ratio 0.18, 95% confidence interval 0.09-0.35, P <.0001). Sensitivity analysis, assuming that all patients with missing data received surgery resulted in an 85% mortality reduction (P <.001) and assuming that patients did not receive surgery resulted in a 50% mortality reduction (P = .04). CONCLUSIONS: Mortality among morbidly obese patients without surgery was 14.3% during the study period. Surgical intervention offered a 50%-85% mortality reduction benefit.     

Brief dialectical behavior therapy (DBT-B) for suicidal behavior and non-suicidal self injury.

The purpose of this study is to evaluate the effectiveness of a shorter course of Dialectical Behavior Therapy (DBT) in enhancing treatment retention and reducing: urges to engage in non-suicidal self injury (NSSI), NSSI, suicide ideation, and subjective distress in borderline personality disorder (BPD). Twenty patients with BPD received a six-month course of Dialectical Behavior Therapy (DBT-B). DBT-B was delivered in the standard manner except for the shortened duration from one-year minimum to six months. All variables were measured at baseline, and at six months. Data were analyzed using paired t-tests. Treatment retention rate was 95%. Significant reductions were found in NSSI urges, NSSI, suicide ideation, subjective distress, depression, and hopelessness between baseline and six months. These results support the use of DBT-B in a six-month format when NSSI and suicidal behavior and ideation are the targeted behaviors. Target behaviors were reduced significantly and retention was extremely high in comparison to other interventions for this population. A large scale randomized controlled trial investigating its efficacy is warranted to determine if the results can be replicated and if improvement can be sustained.