Aβ leads to Ca²⁺ signaling alterations and transcriptional changes in glial cells.

The pathogenesis of Alzheimer's disease includes accumulation of toxic amyloid beta (Aβ) peptides. A recently developed cell-permeable peptide, termed Tat-Pro, disrupts the complex between synapse-associated protein 97 (SAP97) and the α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), thereby leading to an alteration of the trafficking of the enzyme, which is important for nonamyloidogenic processing of amyloid precursor protein (APP). We report that Tat-Pro treatment, as well as the treatment with exogenous Aβ, deregulates Ca(2+) homeostasis specifically in astrocytes through increased expression of key components of Ca(2+) signaling, metabotropic glutamate receptor-5 and inositol 1,4,5-trisphosphate receptor-1.

Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, polycystic ovaries at ultrasound evaluation, and quite frequently by insulin resistance or compensatory hyperinsulinemia. Attention has been given to the role of inositol-phosphoglycan (IPG) mediators of insulin action and growing evidences suggest that a deficiency of D-chiro-inositol (DCI) containing IPG might be at the basis of insulin resistance, frequent in PCOS patients. On such basis, we investigated the efficacy on insulin sensitivity and hormonal parameters of 8 weeks treatment with myo-inositol (MYO) (Inofert, ItalPharmaco, Milano, Italy) at the dosage of 2 g day in a group (n = 42) of obese PCOS patients,.

The NAMPT inhibitor FK866 reverts the damage in spinal cord injury.

Background: Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.

Nitric oxide and pro-inflammatory cytokine serum levels in postmenopausal women with the metabolic syndrome.

Background: The metabolic syndrome (METS) increases after the menopause which may enhance cardiovascular risk in part explained by a pro-inflammatory state.

Objective: Measure nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) serum levels in postmenopausal women with and without the METS (Adult Treatment Panel III criteria).

Methods: Analyte levels were compared among those with and without the syndrome and each of its diagnostic components.

Bazedoxifene: literature data and clinical evidence.

A Multidisciplinary National Panel of Experts in the management of Menopause and Postmenopausal Osteoporosis was created to determine the specific positioning of Bazedoxifene acetate (BZA), a third-generation selective estrogen receptor modulator (SERM), in the field of available therapeutic options in prevention and treatment of postmenopausal osteoporosis.There are various therapeutic options in prevention and treatment for postmenopausal osteoporosis, but nevertheless the problem of osteoporosis and osteoporosis-related fractures is not yet resolved today.In view of this unmet medical need, to have new treatments with efficacy and safety profile so good to therapeutically manage even larger groups of population is the conceptual basis to reduce the devastating impact of this disease on individual's morbidity and mortality, and on public health expense.

Polycystic ovary syndrome: brain-derived neurotrophic factor (BDNF) plasma and follicular fluid levels.

Polycystic ovary syndrome is one of the most common endocrine disorders in women of reproductive age. Features of PCOS are hyperandrogenism, chronic anovulation and polycystic ovaries on ultrasonography. Follicle development is a complex and carefully orchestrated phenomenon, involving gonadotropins and a rapidly expanding list of other intraovarian regulators, such as brain-derived neurotrophic factor (BDNF).

Estrogen regulates endothelial migration via plasminogen activator inhibitor (PAI-1).

Endothelial plasminogen activator inhibitor (PAI-1) controls vascular remodeling, angiogenesis and fibrinolysis. PAI-1 blood levels in women are related to estrogen. The aim of this study was to characterize the signaling pathways through which estrogen regulates PAI-1 in endothelial cells.

Calcium signaling in closely related protozoan groups (Alveolata): non-parasitic ciliates (Paramecium, Tetrahymena) vs. parasitic Apicomplexa (Plasmodium, Toxoplasma).

The importance of Ca2+-signaling for many subcellular processes is well established in higher eukaryotes, whereas information about protozoa is restricted. Recent genome analyses have stimulated such work also with Alveolates, such as ciliates (Paramecium, Tetrahymena) and their pathogenic close relatives, the Apicomplexa (Plasmodium, Toxoplasma). Here we compare Ca2+ signaling in the two closely related groups.

Evaluation of brain-derived neurotrophic factor in menstrual blood and its identification in human endometrium.

The presence of high-affinity brain-derived neurotrophic factor receptor Trk B in mouse and in human fetal oocytes, together with the presence of neurotrophins in human follicular fluid suggests a paracrine role for brain-derived neurotrophic factor (BDNF) in female biology. This study aims to evaluate if BDNF is present and quantitatively determined in human menstrual blood and endometrium. Twenty-one women were studied and subdivided in two groups: A, 11 fertile women (27 ± 2 days cycle length) and B, 10 anovulatory women and/or women with inadequate luteal phase (36 ± 2 days cycle length).

Benign breast diseases, contraception and hormone replacement therapy.

The term benign breast disease includes a wide and heterogenous spectrum of lesions different for histology and natural history. Approximately 70% of women who undergo a biopsy for benign breast disease have non-proliferative lesions with no increased risk of breast cancer, 26% have typical hyperplasia which is associated with a two-fold increased risk, and only 4% have atypical hyperplasia which is associated with a five-fold increased risk. The data on the effect of steroid hormones on benign breast disease come from observational studies with several potential bias.

New insights on the pathogenesis of ovarian carcinoma: molecular basis and clinical implications.

Ovarian carcinoma can be subdivided into two categories termed type I and type II. Type I tumours, usually having an indolent clinical behaviour, are often detected in early stage, and rarely harbour p53 gene mutations. Each histological type has a distinct molecular profile with mutations of genes involved in different signalling transduction pathways, such as KRAS, BRAF, CTNNB1, PTEN, PIK3CA and ARID1A.

Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery.

Purpose: To evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms (XRCC1, TP53, MSH2, MSH3, XPD), oxidative stress response (GSTP1, GSTA1, eNOS, SOD2) and fibroblast proliferation (TGFβ1) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy.

Material And Methods: Skin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery. Genotyping was conducted by PCR-RFLP analysis and real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood.

Analysis of failures in patients with FIGO stage IIIc1-IIIc2 endometrial cancer.

Aim: To assess the pattern of failures in patients with FIGO stage IIIc(1)-IIIc(2) endometrial cancer.

Patients And Methods: Data were retrospectively analyzed for 34 patients with this malignancy who underwent extra-fascial total hysterectomy, bilateral salpingo-oophorectomy and pelvic/para-aortic node dissection. Postoperative treatment consisted of radiotherapy in 5 patients, 6 cycles of chemotherapy in 9, and 3-4 cycles of chemotherapy followed by radiotherapy in 20.

N-arylbenzamides: extremely simple scaffolds for the development of novel estrogen receptor agonists.

The research of estrogen receptor (ER) ligands has benefited in the last decade from the implementation of combinatorial chemistry. The general pharmacophore has been identified and subsequently a multitude of compounds have been synthesized. Surprisingly, up to now simple amides have not been taken into consideration.

Estimation of instantaneous secretory rates and intrinsic characteristics of luteinizing hormone secretion in women with Kallmann syndrome before and after estriol administration.

Three Kallmann syndrome (KS) patients were examined to assess characteristics of LH response to GnRH bolus, with and without GnRH sensitization using Instantaneous Secretory Rate (ISR) computation before and after estriol treatment (60 days, 2 mg/day). Six healthy women were enrolled as controls and underwent GnRH bolus during the early follicular phase (days 3-5 of the menstrual cycle). After estriol treatment, the KS patients showed a higher LH response to GnRH bolus and similar LH pulse duration to healthy controls.

Estriol administration modulates luteinizing hormone secretion in women with functional hypothalamic amenorrhea.

Objective: To evaluate the influence of estriol administration on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA).

Design: Controlled clinical study.

Setting: Patients with FHA in a clinical research environment.

Actin cytoskeleton remodelling by sex steroids in neurones.

Cell morphology and its interaction with the extracellular environment are integrated processes involving a number of intracellular controllers orchestrating cytoskeletal proteins and their interaction with the cell membrane and anchorage proteins. Sex steroids are effective regulators of cell morphology and tissue organisation, and recent evidence indicates that this is obtained through the regulation of the actin cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through the rapid, nonclassical signalling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis.

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation.

Purpose: The aim of this study was to evaluate the effect of different clinical covariates on tacrolimus dose requirements in adult kidney transplant patients with a specific focus on drug interactions.

Patients: Tacrolimus dosing requirement, normalized by drug levels and expressed as the concentration/dose (C/D) ratio as a surrogate index of tacrolimus bioavailability, was employed to identify four categories of tacrolimus dosing requirement, namely, very high, high, small, and very-small, in very fast, fast, slow, and very slow metabolizers, respectively. Steroid weight-based doses were analyzed instead of fixed doses, and genetic analysis of cytochrome P450 (CYP) 3A5*1/*3 and multi-drug resistance 1 (MDR1) C3435T and C1236T polymorphisms were performed

Results: Multivariate analysis on 450 adult transplant patients identified six risk factors for being slow metabolizers and therefore requiring small tacrolimus doses: male sex (OR 1.

Common variants of GSTP1, GSTA1, and TGFβ1 are associated with the risk of radiation-induced fibrosis in breast cancer patients.

Purpose: To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFβ1 C-509T, and TGFβ1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery.

Methods And Materials: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue--Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction--restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood.

Identification of novel antitubulin agents by using a virtual screening approach based on a 7-point pharmacophore model of the tubulin colchi-site.

Tubulin inhibition represents an established target in the field of anticancer research, and over the last 20 years, an intensive search for new antimicrotubule agents has occurred. Indeed, in silico models have been presented that might aid the discovery of novel agents. Among these, a 7-point pharmacophore model has been recently proposed.

Clinico-pathological and biological prognostic variables in squamous cell carcinoma of the vulva.

Several clinical-pathological parameters have been related to survival of patients with invasive squamous cell carcinoma of the vulva, whereas few studies have investigated the ability of biological variables to predict the clinical outcome of these patients. The present paper reviews the literature data on the prognostic relevance of lymph node-related parameters, primary tumor-related parameters, FIGO stage, blood variables, and tissue biological variables. Regarding these latter, the paper takes into account the analysis of DNA content, cell cycle-regulatory proteins, apoptosis-related proteins, epidermal growth factor receptor [EGFR], and proteins that are involved in tumor invasiveness, metastasis and angiogenesis.

Dydrogesterone exerts endothelial anti-inflammatory actions decreasing expression of leukocyte adhesion molecules.

Clinical observations and basic studies show that progesterone and progestins have a variable influence on endothelial function. Dydrogesterone (DG) is a widely used progestin, but its endothelial actions have not been thoroughly assessed. In this study, we investigated the effects of DG and its metabolite 20-α-dihydro-dydrogesterone (DHD), natural progesterone as well as medroxyprogesterone acetate, on the expression of leukocyte adhesion molecules in human endothelial cells using an in vitro experimental endothelial inflammation system.

Patterns of failures in endometrial cancer: clinicopathological variables predictive of the risk of local, distant and retroperitoneal failure.

Unlabelled: The aim of this study was to assess the pattern of failure and the outcome of endometrial cancer patients and to analyze the variables predictive of the risk of local, distant and retroperitoneal lymph node disease recurrence.

Patients And Methods: The authors assessed 511 patients who underwent primary surgery. The median follow-up of survivors was 74 months.

Neurosteroids in clinical practice: implications for women's health.

The steroidogenic endocrine glands and local synthesis both contribute to the pool of steroids present in the central nervous system (CNS) and peripheral nervous system (PNS). Although the synthesis of neurosteroids in the nervous system is now well established, the spectrum of respective functions in regulating neuronal and glial functions remains to be fully elucidated. From the concept of neurosteroids derives another therapeutical strategy: the use of pharmaceutical agents that increase the synthesis of endogenous neurosteroids within the nervous system.