ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC

Challenges in Pediatric Endocrinology

As the Section Editor-in-Chief, it is my pleasure to introduce the new section of Children devoted to pediatric endocrinology [...

The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency. Hormones 7

ABSTRACT Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population

Patients with Laron syndrome are protected from development of cancer even if treated with IGF-I

In accordance with the link between increased GH and IGF-I secretion and cancer, we found that homozygous patients with Laron syndrome (severe GH insensitivity) and low to undetectable serum IGF-I are protected from developing cancer even if treated with IGF-I to enhance linear growth

The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer

Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology

Long Term Experience with a Superactive GnRH Analog in the Treatment of Precocious Puberty

Since 1960 we have treated in our Institute 209 children with central (true) precocious puberty (CPP). Out of these only 2 male patients had CNS tumors (optic nerve glioma and glioblastoma), in the others the process was idiopathic. Depending upon the time period, the drugs used varied (Table 1). The results obtained TABLE 1 Drugs employed in the treatment of 209 children (149 girls, 60 boys) with central precocious puberty Year Drug Patients Girls Treated Boys 1960–1967 Medroxyprogesterone acetate inj. (Upjohn) 4 1 1967–1980 Cyproterone acetate p.o. (Schering) 100 53 1980–1987 Gn-RH analog ([D-Trp6-LHRH)a Aqueous daily s.c. inj.b (Schally) 21 4 Depot monthly i.m. inj. (Ferring) 36 1 a 15 patients were previously treated with cyproterone acetate b 7 patients were switched from daily to monthly injections. with medroxyprogesterone acetate (Depo-Provera, Upjohn) were not satisfactory [1]. The first drug which seemed to have long-term effects in suppressing the precocious gonadotropin secretion, slowing the rate of skeletal maturation and thus prolonging the period of growth, was cyproterone acetate (Androcur, Schering) [2]. However, with increasing experience it was observed that on prolonged administration, “escape phenomena” occurred and that an improved final height was often not achieved. In 1980, trying in children with hypogonadotropic hypogonadism the long-term stimulatory activity of a superactive GnRH analog ([D-Trp6] LHRH) we observed that the stimulatory phase was followed by a blocking effect [3], therefore, immediately tried to find out whether this property of paradoxical refractoriness of the gonadotropic cells induced by long-term use of a GnRH agonist could be exploited in the treatment of precocious puberty