Squamous cell carcinoma and basal cell carcinoma of the lips: 25 years of experience in a northeast Brazilian population.

BACKGROUND: The lips are the transition zone between the facial skin and the oral mucosa and are the site of alterations related to a broad spectrum of etiologies. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most prevalent neoplasms affecting lips. This study evaluated the demographic and clinicopathological features of the SCC and BCC in the lip. MATERIAL AND METHODS: A retrospective cross-sectional descriptive study (1994-2019) was carried out. Demographic and clinicopathologic data were collected from a hospital's dermatological service and an oncologic hospital. The data were submitted to descriptive analysis and Pearson's chi-square and Fisher's exact tests (p ≤ 0.05). RESULTS: 417 medical records were analyzed, of which 323 corresponded to SCC (77.5%) and 94 to BCC (22.5%). SCC showed more frequency in males (58.8%) and BCC in females (54.3%). The lower lip was significantly affected in male patients (p < 0.0001) and by both neoplasms (70.6% and 56.4%, respectively; p = 0.014). SCC and BCC were mainly treated with surgery (88.3% and 93.2%, respectively). Surgical margin was frequently negative in SCC and BCC (87%; 72.3%, respectively), and no recurrence was observed in 79.9% of SCC and 69.1% of BCC cases. CONCLUSIONS: SCC was more frequent in male patients, while BCC showed more frequency in female patients. Both neoplasms mainly affect the lower lip. Understanding the epidemiological profile of these lesions in the lip, as well as their etiology and clinical features, is fundamental for appropriate clinical conduct and the creation and/or amplification of preventive measures.

New-onset lupus nephritis after male-to-female sex reassignment surgery.

We report an original case of a 27-year-old transgender woman who developed lupus nephritis after male-to-female sex reassignment surgery. The patient had been taking hormones to induce feminization since the age of 18. She was admitted with malar "butterfly" rash, anasarca and hypertension, associated with an increase in serum creatinine (1.7 mg/dl). Renal involvement was characterized by nephritic and nephrotic syndrome. Autoantibody tests were positive for antinuclear antibodies and anti-double-stranded DNA, and complement levels were markedly reduced. Renal biopsy demonstrated diffuse proliferative glomerulonephritis and granular immune complexes deposits with a "full-house" pattern at the immunofluorescence level. The induction treatment was realized with corticosteroid and cyclophosphamide and maintenance immunosuppression phase with mycophenolate, obtaining complete remission. We speculated that lupus nephritis was induced by estrogens and antiandrogen therapy and gonadectomy. In the present case, we discuss the role of sex hormones in systemic lupus erythematosus onset and review the cases linked to transgender patients.

Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer.

BACKGROUND: Currently used CA15-3 and CEA have found their clinical application particularly in the follow-up of patients with advanced disease. Novel biomarkers are urgent, especially for improving early diagnosis as well as for discriminating between benign and malignant disease. PATIENTS AND METHODS: In the present study, we used a proteomic approach based on surface-enhanced laser desorption/ionization-time of flight-mass spectrometry screening with the aim of identifying differentially expressed 2-30 kDa proteins in plasma of patients with malignant (65 cases) and benign (88 cases) breast lesions with respect to 121 healthy controls. RESULTS: We found that the most promising SELDI peaks were those corresponding to hepcidin-25 and ferritin light chain. We evaluated the capability of these peaks in predicting malignant and benign breast lesions using the area under the receiver operating characteristic curve (AUC). The results showed a good capacity to predict malignant breast lesions for hepcidin-25 [AUC: 0.82; 95% confidence interval (CI) 0.75-0.90] and ferritin light chain (AUC: 0.86; 95% CI 0.79-0.92). Conversely, a weak and satisfactory capability to predict benign breast lesion was observed for hepcidin-25 (AUC: 0.63; 95% CI 0.41-0.85) and ferritin light chain (AUC: 0.73; 95% CI 0.49-0.97). A significant association between HER2 status and hepcidin-25 was observed and the distribution of transferrin and ferritin were found significantly different in patients with breast cancer when compared with that of controls. CONCLUSIONS: This study provides evidence that hepcidin and ferritin light chain level in plasma may be of clinical usefulness to predict malignant and benign disease with respect to healthy controls.

GPT-based chatbot tools are still unreliable in the management of prosthetic joint infections.

BACKGROUND: Artificial intelligence chatbot tools responses might discern patterns and correlations that may elude human observation, leading to more accurate and timely interventions. However, their reliability to answer healthcare-related questions is still debated. This study aimed to assess the performance of the three versions of GPT-based chatbots about prosthetic joint infections (PJI). METHODS: Thirty questions concerning the diagnosis and treatment of hip and knee PJIs, stratified by a priori established difficulty, were generated by a team of experts, and administered to ChatGPT 3.5, BingChat, and ChatGPT 4.0. Responses were rated by three orthopedic surgeons and two infectious diseases physicians using a five-point Likert-like scale with numerical values to quantify the quality of responses. Inter-rater reliability was assessed by interclass correlation statistics. RESULTS: Responses averaged "good-to-very good" for all chatbots examined, both in diagnosis and treatment, with no significant differences according to the difficulty of the questions. However, BingChat ratings were significantly lower in the treatment setting (p = 0.025), particularly in terms of accuracy (p = 0.02) and completeness (p = 0.004). Agreement in ratings among examiners appeared to be very poor. CONCLUSIONS: On average, the quality of responses is rated positively by experts, but with ratings that frequently may vary widely. This currently suggests that AI chatbot tools are still unreliable in the management of PJI.

Sandwich ELISA assay for the quantitation of palytoxin and its analogs in natural samples.

Palytoxins are potent marine biotoxins that have recently become endemic to the Mediterranean Sea, and are becoming more frequently associated with seafood. Due to their high toxicity, suitable methods to quantify palytoxins are needed. Thus, we developed an indirect sandwich ELISA for palytoxin and 42-hydroxy-palytoxin. An intralaboratory study demonstrated sensitivity (limit of detection, LOD = 1.1 ng/mL; limit of quantitation, LOQ = 2.2 ng/mL), accuracy (bias of 2.1%), repeatability (RSDr = 6% and 9% for intra- and interassay variability, respectively) and specificity: other common marine toxins (okadaic acid, domoic acid, saxitoxin, brevetoxin-3, and yessotoxin) do not cross-react in this assay. It performed well in three different matrices: observed LOQs were 11.0, 9.6, and 2.4 ng/mL for mussel extracts, algal net samples and seawater, respectively, with good accuracy and precision. The LOQ in seafood is 11 µg palytoxin/kg mussel meat, lower than that of the most common detection technique, LC-MS/MS.

Swine manure treatment technologies as drivers for circular economy in agribusiness: A techno-economic and life cycle assessment approach.

Anaerobic digestion has been employed as a technology capable of adding value to waste coupled with environmental impact mitigation. However, many issues need to be elucidated to ensure the systems viability based on this technology. In this sense, the present study evaluated technically, environmentally, and economically, four configurations of swine waste treatment systems focused on the promotion of decarbonization and circularity of the swine chain. For this, a reference plant, based on a compact treatment process named SISTRATES® (Portuguese acronym for swine effluent treatment system) was adopted to serve as a model for comparison and validation. The results showed the importance of prioritization of the energy recuperation routes through anaerobic digestion, providing increased economic benefits and minimizing environmental damage. Thus, the SISTRATES® configuration was the one that presented the best designs in a circular context, maximizing the recovery of energy and nutrients, along with the reduction of greenhouse gas emissions, ensuring the sustainability of the pig production chain.

[Three tasks for the exploration of verbal fluency: evidence of test-retest reliability in Argentine adults]. / Tres tareas para la exploración de la fluidez verbal: evidencias de su fiabilidad test-retest en adultos argentinos.

INTRODUCTION: The phonological and semantic verbal fluency tasks are frequently used in neuropsychological assessment due to their easy application and good sensitivity to dementia. In Argentina, the psychometric evidence for these tasks is limited, with a special lack of knowledge of the temporal stability of its measurements. The psychometric production is even lower for the action fluency variant (emission of verbs in the infinitive in one minute). In effect, this research analyzes the test-retest reliability of three verbal fluency tasks in Argentine adults. SUBJECTS AND METHODS: The sample was made up of 85 Argentine (average age, 63.7 years), 75,3% women and with a medium-high educational level. A prospective longitudinal design was carried out, administering phonological, semantic and action fluency tasks at two different times with an interval of up to four months. The intraclass correlation coefficient (ICC), a statistical method suggested for test-retest reliability studies, was analyzed. For the interpretation of the ICC, the Fleiss criteria were adopted. RESULTS: The phonological and semantic fluency tasks showed good reliability, with ICCs of 0.77 and 0.79. The fluidity of action variant yielded ICC of 0.90, indicating excellent reliability. CONCLUSIONS: All fluency tasks have appropriate temporal stability, and their use is recommended when prospective neuropsychological research is planned (with language evaluation at different times) or as a method of monitoring the evolution of aphasic patients undergoing neurorehabilitation. Based on its excellent reliability, it is recommended to use the action variant more frequently.

TITLE: Tres tareas para la exploración de la fluidez verbal: evidencias de su fiabilidad test-retest en adultos argentinos.Introducción. Las tareas de fluidez fonológica y semántica son de uso frecuente en la evaluación neuropsicológica por su fácil aplicación y buena sensibilidad al deterioro cognitivo. En Argentina es limitado el cuerpo de evidencia psicométrica para dichas tareas, con especial desconocimiento de la estabilidad temporal de sus medidas. La producción psicométrica es aún menor para la variante fluidez de acción (emisión de verbos en infinitivo en un minuto). En efecto, este estudio analiza la fiabilidad test-retest de tres tareas de fluidez en adultos argentinos. Sujetos y métodos. La muestra se compuso de 85 argentinos (medida de edad, 63,7) de población general no clínica, un 75,3% mujeres, de nivel de instrucción medio-alto. Se efectuó un diseño longitudinal-prospectivo administrando tareas de fluidez fonológica, semántica y de acción en dos momentos distintos con un intervalo hasta de cuatro meses. Se analizó el coeficiente de correlación intraclase (CCI), método estadístico sugerido para estudios de fiabilidad test-retest. Para interpretar el CCI se adoptaron los criterios de Fleiss. Resultados. Las tareas de fluidez fonológica y semántica demostraron buena fiabilidad, con un CCI de 0,77 y 0,79. La fluidez de acción obtuvo excelente fiabilidad, con un CCI de 0,9. Conclusión. Las tareas de fluidez relevadas poseen apropiada estabilidad temporal, por lo que se sugiere su uso en investigaciones neuropsicológicas prospectivas (cuando se evalúe el lenguaje en distintos momentos) o cuando se requiera un seguimiento de la evolución de pacientes afásicos en neurorrehabilitación. Basándose en su excelente fiabilidad, se recomienda utilizar con más frecuencia la variante de acción.

[Cognitive Reserve Questionnaire: psychometric analysis from the item response theory]. / Cuestionario de reserva cognitiva: análisis psicométrico desde la teoría de respuesta al ítem.

INTRODUCTION: Cognitive reserve is the ability to better tolerate brain damage through pre-existing and compensatory cognitive resources. One assessment method is the Rami CRQ-Cognitive Reserve Questionnaire. The objective was to carry out an analysis of the informative quality of the CRQ from the item response theory (IRT), in order to provide more precise data on the reliability of internal consistency. Convergent validity was also tested with measures of attention, working memory, and fluency. SUBJECTS AND METHODS: 210 Argentines from the general population (mean age, 66.8 years) participated. The CRQ was administered together with the digits test and three fluency tasks. A graded response model was fitted from IRT with estimation of discrimination parameters (a) and difficulty (b), and a CRQ information curve was created. Bivariate and partial correlations were made. RESULTS: The IRT indicated high discrimination for the CRQ items 'Education' and 'Occupation level' (both for the 8-item version and the 6-item version). In the CRQ of 8 items, low discrimination was obtained for 'Musical training' and 'Intellectual games'. In both versions of the CRQ, the curve indicates greater informational value at a low level of the construct. There was a correlation with the digits test and with fluency tasks, even when controlling for age. CONCLUSIONS: This study is the first analysis of CRQ from IRT, concluding that the instrument is more reliable when applied to subjects with less reserve. The CRQ has acceptable convergent validity.

TITLE: Cuestionario de reserva cognitiva: análisis psicométrico desde la teoría de respuesta al ítem.Introducción. La reserva cognitiva es la capacidad para tolerar mejor el daño cerebral mediante recursos cognitivos preexistentes y compensatorios. Un método de evaluación es el cuestionario de reserva cognitiva (CRC) de Rami. El objetivo fue realizar un análisis de la calidad informativa del CRC desde la teoría de respuesta al ítem (TRI), con el fin de aportar datos más precisos sobre la fiabilidad de consistencia interna. Se probó, además, la validez convergente con medidas de atención, memoria de trabajo y fluidez. Sujetos y métodos. Participaron 210 argentinos de población general (media edad, 66,8 años). El CRC se administró junto con el test de dígitos y tres tareas de fluidez. Se ajustó un modelo de respuesta graduada desde la TRI con estimación de parámetros de discriminación (a) y dificultad (b), y se elaboró una curva de información del CRC. Se efectuaron correlaciones bivariadas y parciales. Resultados. La TRI indicó una alta discriminación para los ítems del CRC 'Escolaridad' y 'Nivel de ocupación' (tanto para la versión de ocho ítems como para la versión de seis ítems). En el CRC de ocho ítems se obtuvo una baja discriminación para 'Formación musical' y 'Juegos intelectuales'. En ambas versiones del CRC, la curva indica mayor valor informacional a bajo nivel del constructo. Hubo correlación con el test de dígitos y con las tareas de fluidez, incluso al controlar por edad. Conclusiones. El presente estudio es el primer análisis del CRC desde la TRI, que concluye que el instrumento resulta más confiable cuando se aplica a sujetos con menor reserva. El CRC posee aceptable validez convergente.

[Cerebral vasoreactivity: Concordance of breath holding test and acetazolamide injection in current practice: 20 cases of asymptomatic carotid artery stenosis]. / Étude de la vasoréactivité cérébrale en Doppler transcrânien : évaluation du test d'apnée comparé à l'injection d'acetazolamide en soins courants. Exploration de 20 sténoses carotidiennes asymptomatiques.

INTRODUCTION: Cerebral vasoreactivity (CVR) is the ability of the brain's vascular system to keep cerebral blood inflow stable. Impaired CVR is a risk marker of stroke in patients with asymptomatic carotid stenosis. The gold standard to assess CVR with transcranial ultrasound is acetazolamide (ACTZ) injection. The breath holding test (BHT) might be easier to perform. CVR proved to be efficient in laboratory conditions but not in routine practice. OBJECTIVES: To study the validity of BHT versus ACTZ in routine practice in a vascular exploration unit in patients with asymptomatic carotid stenosis. METHODS: Study of concordance of BHT and ACTZ, to assess CVR in patients consecutively explored on the same day. RESULTS: Eighteen patients with 20 carotid stenosis were included. The temporal window was missing in 20% of cases. Only 11 out of the 20 procedures were analyzed. Concordance was low between BHT and ACTZ to assess CVR (k=0.3714). CONCLUSION: BHT cannot replace ACTZ injection. It might be a first-step test so that ACTZ injection might be avoided if CVR is normal. Our present results must be confirmed by further study enrolling many more patients.

Cuestionario de reserva cognitiva: análisis psicométrico desde la teoría de respuesta al ítem / Cognitive Reserve Questionnaire: psychometric analysis from the item response theory

Introducción: La reserva cognitiva es la capacidad para tolerar mejor el daño cerebral mediante recursos cognitivos preexistentes y compensatorios. Un método de evaluación es el cuestionario de reserva cognitiva (CRC) de Rami. El objetivo fue realizar un análisis de la calidad informativa del CRC desde la teoría de respuesta al ítem (TRI), con el fin de aportar datos más precisos sobre la fiabilidad de consistencia interna. Se probó, además, la validez convergente con medidas de atención, memoria de trabajo y fluidez. Sujetos y métodos: Participaron 210 argentinos de población general (media edad, 66,8 años). El CRC se administró junto con el test de dígitos y tres tareas de fluidez. Se ajustó un modelo de respuesta graduada desde la TRI con estimación de parámetros de discriminación (a) y dificultad (b), y se elaboró una curva de información del CRC. Se efectuaron correlaciones bivariadas y parciales. Resultados: La TRI indicó una alta discriminación para los ítems del CRC ‘Escolaridad’ y ‘Nivel de ocupación’ (tanto para la versión de ocho ítems como para la versión de seis ítems). En el CRC de ocho ítems se obtuvo una baja discriminación para ‘Formación musical’ y ‘Juegos intelectuales’. En ambas versiones del CRC, la curva indica mayor valor informacional a bajo nivel del constructo. Hubo correlación con el test de dígitos y con las tareas de fluidez, incluso al controlar por edad. Conclusiones: El presente estudio es el primer análisis del CRC desde la TRI, que concluye que el instrumento resulta más confiable cuando se aplica a sujetos con menor reserva. El CRC posee aceptable validez convergente.(AU)

INTRODUCTION: Cognitive reserve is the ability to better tolerate brain damage through pre-existing and compensatory cognitive resources. One assessment method is the Rami CRQ-Cognitive Reserve Questionnaire. The objective was to carry out an analysis of the informative quality of the CRQ from the item response theory (IRT), in order to provide more precise data on the reliability of internal consistency. Convergent validity was also tested with measures of attention, working memory, and fluency. SUBJECTS AND METHODS: 210 Argentines from the general population (mean age, 66.8 years) participated. The CRQ was administered together with the digits test and three fluency tasks. A graded response model was fitted from IRT with estimation of discrimination parameters (a) and difficulty (b), and a CRQ information curve was created. Bivariate and partial correlations were made. RESULTS: The IRT indicated high discrimination for the CRQ items ‘Education’ and ‘Occupation level’ (both for the 8-item version and the 6-item version). In the CRQ of 8 items, low discrimination was obtained for ‘Musical training’ and ‘Intellectual games’. In both versions of the CRQ, the curve indicates greater informational value at a low level of the construct. There was a correlation with the digits test and with fluency tasks, even when controlling for age. CONCLUSIONS: This study is the first analysis of CRQ from IRT, concluding that the instrument is more reliable when applied to subjects with less reserve. The CRQ has acceptable convergent validity.(AU)

Tres tareas para la exploración de la fluidez verbal: evidencias de su fiabilidad test-retest en adultos argentinos / Three tasks for the exploration of verbal fluency: evidence of test-retest reliability in Argentine adults

Introducción: Las tareas de fluidez fonológica y semántica son de uso frecuente en la evaluación neuropsicológica por su fácil aplicación y buena sensibilidad al deterioro cognitivo. En Argentina es limitado el cuerpo de evidencia psicométrica para dichas tareas, con especial desconocimiento de la estabilidad temporal de sus medidas. La producción psicométrica es aún menor para la variante fluidez de acción (emisión de verbos en infinitivo en un minuto). En efecto, este estudio analiza la fiabilidad test-retest de tres tareas de fluidez en adultos argentinos. Sujetos y métodos: La muestra se compuso de 85 argentinos (medida de edad, 63,7) de población general no clínica, un 75,3% mujeres, de nivel de instrucción medio-alto. Se efectuó un diseño longitudinal-prospectivo administrando tareas de fluidez fonológica, semántica y de acción en dos momentos distintos con un intervalo hasta de cuatro meses. Se analizó el coeficiente de correlación intraclase (CCI), método estadístico sugerido para estudios de fiabilidad test-retest. Para interpretar el CCI se adoptaron los criterios de Fleiss. Resultados: Las tareas de fluidez fonológica y semántica demostraron buena fiabilidad, con un CCI de 0,77 y 0,79. La fluidez de acción obtuvo excelente fiabilidad, con un CCI de 0,9. Conclusión: Las tareas de fluidez relevadas poseen apropiada estabilidad temporal, por lo que se sugiere su uso en investigaciones neuropsicológicas prospectivas (cuando se evalúe el lenguaje en distintos momentos) o cuando se requiera un seguimiento de la evolución de pacientes afásicos en neurorrehabilitación. Basándose en su excelente fiabilidad, se recomienda utilizar con más frecuencia la variante de acción.(AU)

Introduction: The phonological and semantic verbal fluency tasks are frequently used in neuropsychological assessment due to their easy application and good sensitivity to dementia. In Argentina, the psychometric evidence for these tasks is limited, with a special lack of knowledge of the temporal stability of its measurements. The psychometric production is even lower for the action fluency variant (emission of verbs in the infinitive in one minute). In effect, this research analyzes the test-retest reliability of three verbal fluency tasks in Argentine adults. Subjects and methods: The sample was made up of 85 Argentine (average age, 63.7 years), 75,3% women and with a medium-high educational level. A prospective longitudinal design was carried out, administering phonological, semantic and action fluency tasks at two different times with an interval of up to four months. The intraclass correlation coefficient (ICC), a statistical method suggested for test-retest reliability studies, was analyzed. For the interpretation of the ICC, the Fleiss criteria were adopted. Results: The phonological and semantic fluency tasks showed good reliability, with ICCs of 0.77 and 0.79. The fluidity of action variant yielded ICC of 0.90, indicating excellent reliability. Conclusions: All fluency tasks have appropriate temporal stability, and their use is recommended when prospective neuropsychological research is planned (with language evaluation at di fferent times) or as a method of monitoring the evolution of aphasic patients undergoing neurorehabilitation. Based on its excellent reliability, it is recommended to use the action variant more frequently.(AU)

Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells.

The c-erbB-2 oncogene is thought to play a relevant role in the development and progression of mammary neoplasia. Using the human breast cancer cell lines T47D and MCF7, we found that the arrest of cell growth induced by a steroid-depleted medium was accompanied by a strong increase of c-erbB-2 mRNA and of the c-erbB-2-encoded p185 protein. The treatment of arrested cells with estrogens was found to resume cell proliferation and to inhibit dramatically c-erbB-2 expression at both mRNA and protein level. The regulation of c-erbB-2 expression was remarkably different from that observed for c-myc, which was strongly stimulated by estrogens, and ras, whose expression was unaffected all through the treatments. In addition, in the normal rat mammary gland undergoing development and differentiation during pregnancy and lactation, p185 expression was detected only in the functionally differentiated tissue. Altogether, our data indicate that the expression of c-erbB-2 is repressed during estrogen-induced proliferation and enhanced during growth arrest and/or differentiation of mammary cells.

AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen.

Transcription of the ERBB2 oncogene is repressed by oestrogen in human breast cancer cells. We show that a 218 bp fragment of the human ERBB2 gene promoter is responsive to oestrogen in transient transfection in ZR75.1 and SKBR.3 cells when the oestrogen receptor is expressed. Deletion analysis of this fragment shows that a sequence located at the 5' end, which is known to mediate ERBB2 overexpression in breast cancer, is also responsible for the oestrogen response. This sequence binds AP-2 transcription factors and appears functionally identical to an element of the oestrogen-dependent enhancer described in the first intron of human ERBB2. We observed that oestrogen treatment down-regulates expression of AP-2 proteins but does not affect the DNA binding activity of AP-2. Constitutive expression of AP-2beta or AP-2gamma, but not AP-2alpha, abrogates the estrogenic repression. Our results demonstrate that AP-2 transcription factors are implicated in the oestrogenic regulation of ERBB2 gene expression and suggest a complex interplay involving the different AP-2 isoforms and other unidentified factors.

Overexpression of the RON gene in human breast carcinoma.

Constitutive activation of the RON gene, known to code for the tyrosine-kinase receptor for Macrophage Stimulating Protein (also known as Scatter Factor 2), has been shown to induce invasive-metastatic phenotype in vitro. As yet, nothing is known about the expression of this novel member of the MET-oncogene family in spontaneously occurring human cancers. Here we report that Ron is expressed at abnormally high levels in about 50% primary breast carcinomas (35/74 patients). Among these, the expression is increased more than 20-fold in 12 cases and the overexpressed protein is constitutively phosphorylated on tyrosine residues. Notably, Ron is only barely detectable in epithelial cells of the mammary gland, and its expression remains unchanged in benign breast lesions (including adenomas and papillomas). Overexpression was observed in different histotypic variants of carcinomas; it is associated with the disease at any stage and correlates with the post-menopausal status. In breast carcinoma cells grown in vitro, activation of the Ron receptor resulted in proliferation, migration and invasion through reconstituted basement membranes. Altogether, these data suggest a role for the RON gene in progression of human breast carcinomas to the invasive-metastatic phenotype.

Tamoxifen up-regulates c-erbB-2 expression in oestrogen-responsive breast cancer cells in vitro.

Expression of the c-erbB-2 proto-oncogene is inhibited by oestrogens in oestrogen-responsive human breast cancer cells, at both mRNA and protein level. Here we report that, where the regulation of c-erbB-2 is concerned, tamoxifen displays a full anti-oestrogenic activity, enhancing the expression of c-erbB-2 in oestrogen receptor-positive cells cultured with untreated fetal calf serum or reversing the inhibitory effect of added oestrogens. Meanwhile, tamoxifen strongly inhibited cell growth. Tamoxifen was inactive on both c-erbB-2 expression and growth of oestrogen receptor-negative cells. These results may have important implications to explain occasional failure of tamoxifen therapy in oestrogen receptor-positive breast cancers.

Adrenergic intracerebroventricular stimulation affects progesterone concentration in the ovarian vein of the rat: participation of the superior ovarian nerve.

The present study investigates the acute consequences of central adrenergic stimulation on the release of steroids from the ovary. The influence of the superior ovarian nerve (SON) and the relationship between the neural effect and peripheral LH levels were also examined. The intracerebroventricular (i.c.v.) injection of 5 microg epinephrine in SON-intact rats on day 1 of dioestrus (D1) increased progesterone levels in ovarian vein blood from 7 to 21 min after injection but the same injection in SON-intact rats on day 2 of dioestrus (D2) decreased progesterone levels in ovarian vein blood from 1 to 25 min. A smaller dose (0.5 microg) of epinephrine injected i.c.v. in SON-intact rats produced a decrease in progesterone levels in ovarian vein blood of shorter duration. In SON-transected (SONt) animals, 0.5 microg epinephrine i.c.v. caused a smaller decrease in progesterone levels compared with SON-intact rats (P<0.05). On the other hand, in SON-intact rats on D2, the i.c. v. injection of 0.5 microg epinephrine did not modify the peripheral LH levels during 25 min, but 5 microg epinephrine injected i.c.v. raised the peripheral LH level from the third minute after injection (P<0.05). Oestradiol levels in the ovarian vein blood did not change after epinephrine i.c.v. injection in rats on D2. To avoid any humoral influence, SONt and SON-intact rats on D2 were injected i.c.v. with 5 microg epinephrine or with vehicle, and 5 min later the ovaries were incubated in vitro with or without LH. Under these conditions, it was demonstrated that the previous injection of epinephrine in SON-intact rats resulted in a diminished release of progesterone from ovaries incubated with or without LH. These results suggest that a central adrenergic stimulus increases progesterone release from the ovary on D1 and decreases it on D2. Also, this neural input would arrive at the ovary through the SON, and would condition the ovarian response to LH on D2. Ovarian progesterone changes could be attributed to signals coming from ganglionar neurons, which are affected by the central adrenergic stimulation.

Epinephrine intracerebroventricular stimulation modifies the LH effect on ovarian progesterone and androstenedione release.

This study investigates the interaction between the effect of epinephrine intracerebroventricular (icv) injection and LH on the progesterone concentration in ovarian vein blood (Po) in vivo, and also, on the release of ovarian progesterone and androstenedione in vitro, in rats on dioestrus day 2. When 2 mg ovine LH were injected in vein (i.v.), Po increased reaching 120+/-12.2 and 151+/-17.5 ng ml(-1) at 22 and 25 min, respectively. Another group of rats was injected intracerebroventricular with 5 microgram epinephrine at time zero, and with 2 mg ovine LH i.v. 3 min later. This time Po decreased during the first 3 min, then increased, reaching 64+/-7.1 ng ml(-1) at 25 min, lower than the Po obtained 22 min after LH i.v. injection only (P<0.01). Moreover, rats were injected i.v. with 2 mg ovine LH at time zero, and 7 min later with epinephrine intracerebroventricular. Po increased during the first 7 min, decreased until the 13th minute and reached 70+/-8.9 ng ml(-1) at 25 min, lower than the Po obtained 25 min after LH i.v. injection only (P<0.01). In other experience, rats with one (either right or left) superior ovarian nerve transected (SON-t), were injected intracerebroventricular with epinephrine. Five minutes later, the ovaries were removed and incubated in vitro with LH. Both ovaries (right or left) in which the SON was intact at time of epinephrine i. c.v. injection, showed a reduction of progesterone and androstenedione released in vitro (P<0.05). These results suggest that, on dioestrus day 2, the central adrenergic stimulus competes with LH in the release of ovarian progesterone. Also, the neural input that arrives at the ovary through the SON would antagonize the ovarian progesterone and androstenedione response to LH.

Hormonal regulation of c-erbB-2 oncogene expression in breast cancer cells.

Expression of the c-erbB-2 (neu, HER-2) oncogene is found to be subjected to hormonal and developmental regulation in normal as well as neoplastic mammary cells. We have previously reported that estrogens inhibit c-erbB-2 expression at both the mRNA and protein level in estrogen receptor (ER)-positive, but not in ER-negative, breast cancer cell lines. Reversion of c-erbB-2 inhibition is seen with tamoxifen. The effect on c-erbB-2 expression of several other hormones and factors, which influence mammary cell growth and differentiation, has been studied. Our observations indicate that, in normal and neoplastic mammary cells, c-erbB-2 expression is inversely related to cell proliferation. While estrogens, anti-estrogens and cAMP clearly regulate c-erbB-2 mRNA levels, epidermal growth factor dramatically decreases the c-erbB-2 protein without affecting the level of c-erbB-2 mRNA. Therefore, different signals converging in terms of cell proliferation regulate c-erbB-2 expression by different molecular mechanisms.

Hormonal control of growth factor receptor expression.

In this report, we have discussed a series of results obtained in our laboratory that, together with data by other authors, demonstrate that the expression of the erbB-2 tyrosine kinase receptor oncogene in breast cancer cells is regulated by multiple factors and hormones, which modulate their growth and differentiation. In particular, we have shown that estrogens specifically inhibit erbB-2 expression by transcriptional repression, which is exerted through a sequence within the erbB-2 gene promoter. Estrogens control mammary cell growth directly, by inducing early gene expression, and indirectly, by increasing autocrine growth factor production or decreasing growth inhibitors. The data presented here suggest that mammary cells respond to estrogen also by modifying the receptor array on their surface, thus setting their own sensitivity to the different autocrine and paracrine factors. As a first consequence, the modulation of erbB-2 expression level by antiestrogen may represent a point to consider when selecting breast cancer patients for hormonal therapy, in those (few) cases where estrogen receptor positivity accompanies erbB-2 amplification. On the other hand, antiestrogen-induced upregulation of erbB-2 may improve tumor targeting of drugs designed to interact or interfere with erbB-2, such as humanized antibodies, immunotoxins, or engineered ligands. These possibilities should be tested in appropriate model systems in the future.