Ianus Bifrons: The Two Faces of Metformin.

The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open?

Identification of a novel mutation in exon 1 of androgen receptor gene in an azoospermic patient with mild androgen insensitivity syndrome: case report and literature review.

OBJECTIVE: To report a case of an azoospermic subject with mild androgen insensitivity syndrome (MAIS) and review the relevant literature. DESIGN: Case report. SETTING: Academic research hospital. PATIENT(S): A 49-year-old man with undermasculinized features and a history of cryptorchidism and azoospermia. INTERVENTION(S): Hormonal evaluation and genetic testing of the androgen receptor gene (AR). MAIN OUTCOME MEASURE(S): Hormonal levels and sequence chromatogram of the proband and his mother. RESULT(S): We found total T in the normal range and high levels of gonadotropins. Karyotype was 46,XY. Genetic testing identified a novel mutation of exon 1 of AR, which resulted in an alanine to serine substitution in the transactivation domain at codon 240 (A240S). Fourteen other mutations of exon 1 of AR have been associated with MAIS to date. CONCLUSION(S): The novel mutation A240S of AR is involved in MAIS, a syndrome associated with azoospermia.

Role of dopamine receptors in normal and tumoral pituitary corticotropic cells and adrenal cells.

The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing's syndrome (CS) has renewed the debate about the dopamine control on pituitary-adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D(2)R), together with different SSTR subtypes (ssts), in particular sst(5). In vitro, activation of D(2)R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D(2)R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS.

Euclidean and fractal geometry of microvascular networks in normal and neoplastic pituitary tissue.

In geometrical terms, tumour vascularity is an exemplary anatomical system that irregularly fills a three-dimensional Euclidean space. This physical characteristic and the highly variable shapes of the vessels lead to considerable spatial and temporal heterogeneity in the delivery of oxygen, nutrients and drugs, and the removal of metabolites. Although these biological characteristics are well known, quantitative analyses of newly formed vessels in two-dimensional histological sections still fail to view their architecture as a non-Euclidean geometrical entity, thus leading to errors in visual interpretation and discordant results from different laboratories concerning the same tumour. We here review the literature concerning microvessel density estimates (a Euclidean-based approach quantifying vascularity in normal and neoplastic pituitary tissues) and compare the results. We also discuss the limitations of Euclidean quantitative analyses of vascularity and the helpfulness of a fractal geometry-based approach as a better means of quantifying normal and neoplastic pituitary microvasculature.

Treatment of a pituitary metastasis from a neuroendocrine tumour: case report and literature review.

Herein we report a rare case of a pituitary metastasis from a neuroendocrine tumour mimicking an adenoma. Moreover, starting from this unusual case, the relevant literature concerning the diagnosis and management of patients with metastasis at pituitary level is reviewed. A 69-year-old woman was admitted to our Unit for severe headache, diplopia, and critical visual field impairment. MRI showed a large pituitary mass compressing the optic chiasm and infiltrating the cavernous sinus. Trans-sphenoidal biopsy revealed a pituitary metastasis from a neuroendocrine tumour, in line with the multiple liver lesions that were already considered metastases from an ileal primary neuroendocrine tumour. In vitro receptor characterisation of both pituitary and liver tissues by immunohistochemistry showed a heterogeneous somatostatin receptor subtype pattern, with a predominant expression of sst(2) within the pituitary lesion. However, the liver metastasis receptor profile was completely different from the pituitary. Octreotide LAR was administered first, followed by receptor radiometabolic therapy with radiolabelled somatostatin analogues ((90)Y-DOTATOC and (177)Lu-DOTATATE). After 16 months, MRI showed a significant shrinkage of the sellar mass. Moreover, disappearance of diplopia and visual defects, together with a considerable improvement in quality of life were gradually recorded. To our knowledge, this is the first case of combined treatment using "cold" and radiolabelled octreotide in a pituitary metastasis from a neuroendocrine tumour.

Neuroendocrine-immune interactions: the role of cortistatin/somatostatin system.

Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst(1-5)). Neuronal and accessory cells, so-called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti-inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system.

Partial visual recovery from radiation-induced optic neuropathy after hyperbaric oxygen therapy in a patient with Cushing disease.

Here we describe the case of a 41-year-old woman with a history of Cushing disease who had previously undergone unsuccessful neurosurgery, followed by stereotactic radiosurgery. More than 4 years after this treatment, she presented severe visual impairment, which started in the left eye and was documented by neuro-ophthalmic evaluation. Radiological assessment by contrast-enhanced magnetic resonance (MR) imaging initially suggested the diagnosis of glioma of the optic nerve and the patient started corticosteroid treatment (first with prednisone, 80 mg/day, followed by dexamethasone, 8 mg/day). Despite the therapy, vision in the left eye rapidly worsened until light was no longer perceptible; similar symptoms and signs also developed in the right eye, evolving to complete temporal hemianopsia. The clinical evidence was confirmed by the rapid progression of the MR picture, which showed homogeneous enhancement of the chiasm and optic nerves. On the basis of these findings, the original diagnosis of glioma was excluded, and radiation-induced optic neuropathy was diagnosed. As corticosteroids had proved inefficacious, hyperbaric oxygen (HBO) therapy was promptly instituted and vision steadily started to improve. This improvement was documented and confirmed by the progressive recovery of the visual field in the right eye and the changes in the sequential follow-up MR scanning. Optic neuropathy is an infrequent but dramatic complication of radiation therapy. Symptoms develop, on average, 12 months after treatment, and the onset may be acute and characterized by the progressive loss of vision in one or both eyes. HBO has already been used to treat this complication, but its efficacy is still controversial. Here, in addition to describing this particular case, which presented a significantly delayed radiation injury of the optic pathways, we provide a brief literature review and discuss some important points.

Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function.

293 kidney embryonic cells feature very low levels of the anti-apoptotic protein PED. In these cells, expression of PED to levels comparable with those occurring in normal adult cells inhibits apoptosis induced by growth factor deprivation and by exposure to H(2)O(2) or anisomycin. In PED-expressing 293 cells (293(PED)), inhibition of apoptosis upon growth factor deprivation was paralleled by decreased phosphorylation of JNK1/2. In 293(PED) cells, decreased apoptosis induced by anisomycin and H(2)O(2) was also accompanied by block of JNK1/2 and p38 phosphorylations, respectively. Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation. At variance with JNK1/2 and p38, PED expression increased basal and growth factor-stimulated Ras-Raf-1 co-precipitation and MAPK phosphorylation and activity. Treatment of 293(PED) cells with the MEK inhibitor PD98059 blocked ERK1/2 phosphorylations with no effect on inhibition of JNK1/2 and p38 activities. Complete rescue of JNK and p38 functions in 293(PED) cells by overexpressing JNK1 or p38, respectively, enabled only partial recovery of apoptotic response to growth factor deprivation and anisomycin. However, simultaneous rescue of JNK and p38 activities accompanied by block of ERK1/2 fully restored these responses. Thus, PED controls activity of the ERK, JNK, and p38 subfamilies of MAPKs. PED anti-apoptotic function in the 293 cells requires PED simultaneous activation of ERK1/2 and inhibition of the JNK/p38 signaling systems by PED.