The pharmacological pathways of GnRH mediating the inhibition of mammary tumours: implications in humans and domestic animals

The Gonadotropin-Releasing Hormone (GnRH) exists in two isoforms, GnRH-I and GnRH-II, in most vertebrates, including humans. Both of these isoforms and their respective receptors have been found in many healthy and pathologic extra nervous system tissues, such as cells found in cancers of the reproductive systems and, in particular, in breast cancer. GnRH analogues are used as therapeutic agents in the case of sex-hormone-dependent tumours. Besides acting as suppressors of steroidogenesis, GnRH analogues seem to interfere with mitogenic signal transduction pathways, thus behaving as negative regulators of tumour growth and progression. GnRH analogues counteract the proliferating effects of both epidermal growth factor (EGF) and insulin like growth factor (IGF-I); additionally, it affects the mitogen-activated protein kinase (MAPK) cascade and modulates the activity of the urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitory (PAI) system, which is involved in the process of metastasis. In addition, GnRH analogues decrease the expression of many growth factors involved in the development of human uterine myomas (as well as endometriotic tissue), such as the vascular endothelial growth factor (VEGF), which is deeply implied in the angiogenesis of many benign and malignant tumours, including breast cancer. Angiogenesis is one of the primary processes leading to the progression and metastasis of breast cancer cells, and a key therapeutic goal in the fight against tumours is the blocking of new vessel sprouts. Given these premises, this review provides an update on the background of anti-neoplastic properties of GnRH analogues..     

Changes in canine mammary gland histology during the estrous cycle

The histologic findings in sections through the mammary glands from 40 female beagle dogs were described for the stages of the estrous cycle. The histologic features progressed from rudimentary ductal structures in immature dogs to stromal and ductal proliferation in proestrus and estrus; alveolar proliferation, secretion and involution in metestrus; and further involution and decreased mammary components in anestrus.     

Hexadecylphosphocholine causes rapid cell death in canine mammary tumour cells

Hexadecylphosphocholine (HePC, Miltefosine) is an antitumour phospholipid and known inducer of apoptosis in human breast cancer cells. The mechanism underlying the induction of cell death by HePC, however, is not clear yet. In this study, we have investigated the cytotoxic effects of HePC on canine mammary tumour cells (CMTs) in vitro. Upon addition of HePC, CMTs rapidly exhibited several features that resembled apoptotic cell death. Cells showed externalization of phosphatidylserine, a hallmark of apoptosis, within 5 min after addition of HePC at concentrations as low as 10 microM. Furthermore, rapid swelling of mitochondria was observed. Rounding and detachment of cells followed within 30 min. However, fragmentation of nuclear DNA could not be observed. Overall, HePC was shown to induce a type of cell death in CMTs that in some aspects resembles apoptosis, though the process proceeds much more rapidly than reported for other tumour cell lines.     

Drug metabolism by tumours: its nature, relevance and therapeutic implications

Drug-metabolising enzymes (DMEs) are present in tumours and are capable of biotransforming a variety of antineoplastics. Tumoural drug metabolism is both a potential mechanism of resistance and a means of achieving optimal therapy. This review addresses the classes of DMEs, their cytotoxic substrates and distribution in specific malignancies. The limitations of preclinical and clinical studies are highlighted. Their role in predicting therapeutic response, the activation of prodrugs and the potential for their modulation for gain is also addressed. The contribution of tumoural DMEs to cancer therapy can only be ascertained through large prospective studies and supported by new technologies. Only then can efforts be concentrated in the design of better prodrugs or combination therapy to optimise individual therapy.     

IL-1 cytokines in cardiovascular disease: diagnostic, prognostic and therapeutic implications

Interleukins (ILs) are key mediators in the chronic vascular inflammatory response underlying several aspects of cardiovascular disease. Due to their powerful pro-inflammatory potential, and the fact that they are highly expressed by almost all cell types actively implicated in atherosclerosis, members of the IL-1 cytokine family were the first to be investigated in the field of vessel wall inflammation. The IL-1 family is comprised of five proteins that share considerable sequence homology: IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-18 (also known as IFNgamma-inducing factor), and the newly discovered ligand of the ST2L receptor, IL-33. Expression of IL-1s and their receptors has been demonstrated in atheromatous tissue, and serum levels of IL-1-cytokines have been correlated with various aspects of cardiovascular disease and their outcome. In vitro studies have confirmed pro-atherogenic properties of IL-1alpha, IL-1beta and IL-18 such as, up-regulation of endothelial adhesion molecules, the activation of macrophages and smooth muscle cell proliferation. In contrast with this, IL-1Ra, a natural antagonist of IL-1, possesses anti-inflammatory properties, mainly through the endogenous inhibition of IL-1 signaling. IL-33 was identified as a functional ligand of the, till recently, orphan receptor, ST2L. IL-33/ST2L signaling has been reported as a mechanically activated, cardioprotective paracrine system triggered by myocardial overload. As the roles of individual members of the IL-1 family are being revealed, novel therapies aimed at the modulation of interleukin function in several aspects of cardiovascular disease, are being proposed. Several approaches have produced promising results. However, none of these approaches has yet been applied in clinical practice.     

Canine mammary tumours as a model to study human breast cancer: most recent findings

Clinical and molecular similarities between canine mammary tumours and human breast cancer have been described in recent decades. Clinically, the similarities are very strong: spontaneous tumours, hormonal aetiology, age of onset and an identical course of the disease. The clinical characteristics that have an impact on the clinical outcome are also identical: tumour size, lymph node invasiveness and clinical stage. Nowadays, as far as human medicine is concerned, the goal is to identify prognostic factors, mainly at the molecular level, such as those involved in metastasis, which could be used as therapeutic targets to support a better outcome. Moreover, in this area, canine mammary tumours seem to mimic human breast cancer, as a range of similarities are found at the molecular level concerning the overexpression of steroid receptors, proliferation markers, epidermal growth factor, p53 supressor gene mutations, metalloproteinases, cyclooxygenases, among many others. Clinical and molecular data that support canine mammary tumours as a model to study human breast cancer are analysed in this review. Additionally, it is shown that some recent molecular targets in canine mammary tumours may be seen as indicators for similar research to be performed in the corresponding human disease.     

1H-NMR spectroscopy of serum in SHN mice with and without spontaneous mammary tumours.

Proton nuclear magnetic resonance (1H-NMR) spectra of serum were studied before and after the appearance of spontaneous mammary tumours in intact and anterior pituitary grafted SHN mice. In the sera of non-tumourous animals, the lipid CH2 and CH3 resonances at 1.31 and 0.88 ppm, possibly the peaks of very low density lipoprotein (VLDL), were unclear; however, such resonances were apparently observed in the sera of mammary tumour bearing mice. On the contrary, alanine, beta-hydroxybutyrate, valine and leucine, which peaked clearly in non-tumourous mice, declined greatly in tumourous mice. Livers of tumourous mice were heavier than those of non-tumourous animals. Quite similar trends in serum spectra and liver weight were observed in mice grafted with two anterior pituitaries. These findings indicate that tumour absorption of VLDL increases and other metabolic pathways are largely altered in association with mammary tumour progression. Prolactin, which is essential for mammary tumour development, had little effect on serum spectra of mice either with or without mammary tumours.     

The prognostic implications of DSM-IV abuse criteria in drinking adolescents

BACKGROUND: The validity of the DSM-IV diagnostic criteria for alcohol abuse has been questioned, and additional issues have been raised regarding the performance of this label in adolescents. While future diagnostic manuals might alter the approach to abuse, it is worthwhile to evaluate the implications of the current definition that has been in place since 1994. METHODS: Six hundred and sixteen 12-19-year-old subjects (mean 16.5 years) were offspring identified in the Collaborative Study on the Genetics of Alcoholism (COGA) protocol who had ever consumed a full drink and who were followed up 5 years later using age-appropriate semi-structured interviews. Following the guidelines for evaluating the utility of the diagnostic labels of Robins and Guze [Robins, E., Guze, S.B., 1970. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am. J. Psychiat. 126, 983-987], the subjects with alcohol abuse were compared with other groups regarding clinical validators and clinical course. RESULTS: At initial interview, the pattern of most alcohol use and problem variables were least severe for teenagers with no diagnosis, intermediate for those with abuse, and the highest for individuals with alcohol dependence. At follow-up, 50% of those with initial abuse maintained that diagnosis, 19% developed dependence, and 31% had no DSM-IV diagnosis. Baseline alcohol abuse predicted follow-up diagnosis even when evaluated along with initial demographic and substance use characteristics. CONCLUSIONS: These results support some assets for the DSM-IV alcohol abuse criteria in these adolescents, including indications of both cross-sectional and predictive validities. Additional studies will need to compare the current abuse label with other possible approaches.     

Oesophageal ulcerations and plasma levels of different alprenolol salts: potential implications for the clinic

The ulcerogenic effect of five different salts of alprenolol were tested against placebo in a porcine oesophageal test model. The salts with high water solubility, such as the hydrochloride and the fumarate, gave rise to the highest plasma concentrations of alprenolol and evoked serious oesophageal lesions, while the salts with low solubility-the benzoate, maleate and sebacate-had no irritative effect on the oesophagus. The plasma levels of alprenolol were much higher following administration of alprenolol hydrochloride in the oesophagus than after an identical intraduodenal dose of the same salt possibly because of the avoidance of the first-pass degradation during oesophageal absorption.     

Prevalence of hepatitis B and C infection in a methadone clinic population: implications for hepatitis B vaccination

AIMS: To examine the HBV and HCV markers of injecting drug users on methadone maintenance, and the feasibility of vaccination at the drug clinic. METHODS: Systematic serological testing of patients for hepatitis B and C was undertaken, and free hepatitis B vaccination was offered via arranged clinic appointments. RESULTS: Hepatitis B serology was obtained in 163 of the 220 clinic patients. 85 (52.1%) patients had evidence of hepatitis B exposure, and 3 (1.8%), of previous vaccination. Positive hepatitis B markers were associated with increasing age (p=0.004), and the duration of injecting prior to treatment (p=0.008). Hepatitis B and C serology was obtained for 153 patients, with 76 (49.7%) having evidence of dual exposure. 164 (84.1%) of 195 patients were positive for antibody to hepatitis C. Completion of the vaccine course was lower than anticipated (36.5% of HBV negative patients). CONCLUSIONS: The high rates of hepatitis B exposure in injecting drug users on methadone treatment confirm the need for hepatitis B vaccination, particularly in view of their endemic hepatitis C infection. Monitoring of this group for the development of chronic liver disease and hepatocellular carcinoma is recommended. Routine cost-free vaccination of patients on entering drug treatment, using a rapid vaccination schedule, may improve compliance.     

麝甲消痛膏治疗乳腺增生症疗效观察

目的 观察外用贴敷麝甲消痛膏治疗乳腺增生的临床疗效.方法 将76例乳腺增生症患者随机分为两组,麝甲消痛膏组40例(观察组),口服乳癖消对照组36例.结果 观察组痊愈18例,显效15例,有效7例,总有效率为100%;对照组痊愈2例,显效3例,有效26例,无效5例,总有效率为86.2%;两组差异有显著性(P<0.05).结论 麝甲消痛膏治疗乳腺增生症疗效好于口服乳癖消组.     

Dry eye in allergic conjunctivitis: role of inflammatory infiltrate

Dry-eye associated symptoms are frequently present in patients affected with allergic conjunctivitis. We evaluated the relationship between ocular inflammation and the tear film parameters in patients affected with chronic allergic conjunctivitis. Eighty-two subjects (age 23.00 ± 7.61: range 10-40) affected with chronic allergic conjunctivitis and thirty age- and sex matched healthy controls were enrolled. In all patients tear film qualitative and quantitative tests were performed. To determine the immune activation state, conjunctival biopsies were obtained from the inferior conjunctival fornix. Immunocytochemical markers for CD45RO, CD8, CD20 and EG2 (monoclonal antibody binding eosinophil cationic protein) were evaluated semiquantitatively. All tear film tests were found altered. They were reduced in allergic patients (p<0.001). In conjunctival biopsies of allergic patients a very high number of CD45RO+ and EG2+ cells were found (p<0.001): a lower number of CD45RO+ cells and no EG2+ cells in control biopsies were found. Multivariate analysis showed a significant relationship between tear tests and conjunctival infiltrate (CD45RO+ and EG2+): The tear film alterations are strictly related to the conjunctival immune infiltration. In particular, the reduction of the mucin-related component of tear film can be related to the toxic effect of the granule cationic proteins released by the conjunctival activated eosinophils (EG2+ cells).     

Induction of mammary gland and skin tumours in female rats by the feeding of benzyl violet 4B

A group of 35 female Sprague-Dawley rats was fed a diet containing 5% Benzyl Violet 4B for 12 months. Another group of 35 rats served as controls. In the experimental group growth was significantly depressed and only 2 animals survived the entire experimental period. Tumours developed externally in 22 out of 35 animals of the experimental group, which included 11 animals with mammary gland carcinoma, 4 animals with squamous cell carcinoma of the skin and 7 animals with both types of tumours. Though the majority of the squamous cell carcinomas developed in the ear-duct, they also appeared in the buccal and axillary regions. The mammary gland carcinomas appeared earlier than the squamous cell carcinomas of the skin. No external tumour was observed in the control group.     

Influence of strain and age on the induction of mammary tumours by diethylstilboestrol in C3H mice

C3H/HeJ and C3H/HeN female mice were fed diets containing targeted concentrations of 320 or 640 ppb diethylstilboestrol (DES) starting at 7 or 11 wk of age and continuing throughout their remaining lifespan. Regardless of the DES concentration there was a faster rate of development and higher final incidence of mammary adenocarcinomas among the C3H/HeN mice than among the C3H/HeJ mice. In C3H/HeN mice started on DES when 11 wk old, mammary tumours developed more rapidly than when treatment was started at 7 wk of age. This was also true for C3H/HeJ mice given 320 ppb DES but not for those treated with 640 ppb DES. Both age at the start of treatment and strain of C3H mice are important factors to be considered in designing experiments to study the tumorigenic activity of oestrogens such as DES.     

Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications

Abstract

Objective:

Hyponatremia is the most frequent ionic disorder among ambulatory and hospitalized populations. The aim of the study is to describe the profile of patients admitted to internal medicine departments of Spanish hospitals with a diagnostic codification of hyponatremia in their discharge sheets.     

MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy

The human homologue of the mouse double minute 2 (MDM2) oncogene is overexpressed in more than forty different types of malignancies, including solid tumors, sarcomas and leukemias. Because of its prevalent expression and its interactions with p53 and other signaling molecules, MDM2 plays a central role in cancer development and progression. The expression of this oncoprotein is being studied by researchers world-wide, and the amount of data published about it is increasing exponentially. Although there are some conflicting data about the effects of MDM2 expression in individual cancers, the overall evidence is convincing, indicating that increased MDM2 expression is related to a worse clinical prognosis. There is an increased likelihood of distant metastases, as well as a decreased response to therapeutic intervention in MDM2-positive cancers. MDM2 may also serve as a diagnostic marker, not only for cancer stage, but to differentiate between similar cancers. MDM2 may also be associated with drug resistance in cancer chemotherapy. These findings make studying the oncoprotein necessary to aid in our understanding of cancer development, to identify novel cancer drug targets, and to increase the efficacy of cancer therapy.