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Background The Health Counselor of Sicily in Italy, appointed the “Forum Meridiano Sanità” 2020 dedicated to Health Tourism (HT). Sicily is a member of the Italian network “Mattone internazionale salute” that focus the development of Health Tourism aiming at: Establish the state of art on HT;Defining a strategy to give visibility of the services targeting health tourists;Defining joint actions/projects to strengthen Italy's attractiveness and the action plan to promote/valorize health performances and the touristic services offered. Sicily, making use of its cultural/environmental characteristics, landscapes, climate, food traditions and its Mediterranean diet, wants to be accounted for a destination on health/wellness tourism. Target groups are seniors, disabled people and people affected by particular pathologies Contribution of Sicilian Region (Sicilian Health Government and CEFPAS) and of the European program 2021-2027 are promoting in Sicily the implementation of such in the development of the “Health and Wellness Tourism”. In order for this to be integrated in a broader framework a discussion on the first European Charter on Health Tourism will be developed with participants. Results The “working table” has elaborated a document “Framework on health and tourism - the interregional point of view” containing the definitions of Health tourism, a state of art of the national/European legislative framework and a mapping of the touristic flow and the needs of seniors. The Regional Health Government is also starting articulations with other Regional Governments (e.g. Tourism/Environment). Strategic alliances/resources able to transform the tourism sector, should focus a strategic policy agenda for health prevention/promotion linked to a wider concept of general wellness. Key message Promote health/wellness tourism targeting seniors and people with disabilities/pathologic diseases is considered worth the investment.

The purpose of this study is to explore the relationship between Emotional Intelligence (EI) and burnout in health care professionals. More specifically, this survey has the purpose of demonstrating the role of EI as a protective factor against the risk of burnout. Health professionals (doctors, nurses, and other caregivers) composed the sample. Health care professionals were invited to complete the following tests: Self Report Emotional Intelligence Test (Schutte et al., 1998; it. ad. Craparo, et al.[35]); Link Burnout Questionnaire,LBQ; Other variables, such as gender, lenght of service (years of professional experience) and organizational department. Major results of this survey underline the relationship between EI and burnout. More specifically, there is a negative and significant correlation between burnout and Emotional Intelligence. Moreover, burnout varies depending on length of service: burnout increases between 5 and 10 years of experience and decreases over 10 years. Indeed, burnout is differently expressed amongst healthcare professionals: more specifically, Psycho-physical exhaustion, Detriment of the relationships and Burnout (total score) impact physician (doctors) more than other investigated health professionals. These findings seem to suggest the opportunity to improve Emotional Intelligence abilities through specific training programs, useful to promote the ability to cope with stress and to enrich the relationships in the workplace. Key messages Burnout is more diffuse among health professionals working in emergency departments. Emotional intelligence has the role to cope with burnout.

In December 2013 the European Commission approved the project promoted by CEFPAS, The Centre for Training and Research in Public Health within the programme PROGRESS, “Improving the operational skills of health personnel working in the emergency departments. A useful tool to give concrete answers to EU policies on patients’ safety and to create new working opportunities”. This project aimed to combine the need to find innovative solutions in the field of healthcare with the objective of increasing the safety of patients in emergency departments, while also covering the need to promote worker mobility within the European Union. The key tool for implementing this goal is the exchange of experience and best practices. The project partners included: the Edinburgh University of Medicine, the Napier University (again in Edinburgh), the Dresden University of Technology, the Herlev Hospital (in Copenhagen) through the DIMS or the Danish Institute for Medical Simulation at the University of Copenhagen, as well as ISMETT and CREAM (the Research Centre of the University of Medicine) in Palermo. Every partner, during the planning, has provided the know how developed in the area of emergency. Specifically it has been analyzed the possibility to compare and visit the simulation Centres of Edinburgh, Dresden and Palermo, and to study the use, in each country, of innovative methodology during the training of the health personnel. The partner, during the planning of the project, studied also how to help people to find easier jobs opportunities in the health sector (so they thought to create a specific data base of the emergency departments operating in Italy, Scotland and Germany where to find a job or a chance for an internship). The project has lasted for one year and has provided research activities and the exchange of experience and best practices. Key messages There is a huge difference regarding the way in which the emergency system is organized within single countries around Europe. Comparing high-level organisations we have benefited in terms of ideas, projects and potential objectives to be set in order to improve our work and to improve results for patients.

A potent series of inhibitors against the B-RafV600E kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.

Oregano spice is widely used in the Mediterranean diet, which is associated with a low risk for colon cancer. Although the medicinal benefits of oregano, such as the anti-inflammatory and antimicrobial activities, are well known; nonetheless, only few data are available on its effect in cancer prevention, especially concerning the mechanism of action. Here, we investigated the effect of Origanum vulgare ethanolic extracts on redox balance, cell proliferation, and cell death in colon adenocarcinoma Caco2 cells. Oregano extract leads to growth arrest and cell death in a dose- and time-dependent manner. Changes in glutathione content, as well as the increase in its oxidized form, may be involved in oregano-triggered death. Both extrinsic and intrinsic apoptotic pathways appear to be activated by spice extract. Our findings suggest that oregano amounts found in the Mediterranean diet can exert proapoptotic effects, which are selective for cancer cells. Moreover, whole extract, instead of a specific component, can be responsible for the observed cytotoxic effects.

Heat shock protein (Hsp)90 is emerging as an important therapeutic target for the treatment of cancer. Two analogues of the Hsp90 inhibitor geldanamycin are currently in clinical trials. Geldanamycin (GA) and its analogues have been reported to bind purified Hsp90 with low micromolar potency, in stark contrast to their low nanomolar antiproliferative activity in cell culture and their potent antitumor activity in animal models. Several models have been proposed to account for the ≈100-fold-greater potency in cell culture, including that GA analogues bind with greater affinity to a five-protein Hsp90 complex than to Hsp90 alone. We have determined that GA and the fluorescent analogue BODIPY-GA (BDGA) both demonstrate slow, tight binding to purified Hsp90. BDGA, used to characterize the kinetics of ligand–Hsp90 interactions, was found to bind Hsp90α with k off = 2.5 × 10 −3 min −1 , t 1/2 = 4.6 h, and K i * = 10 nM. It was found that BDGA binds to a functional multiprotein Hsp90 complex with kinetics and affinity identical to that of Hsp90 alone. Also, BDGA binds to Hsp90 from multiple cell lysates in a time-dependent manner with similar kinetics. Therefore, our results indicate that the high potency of GA in cell culture and in vivo can be accounted for by its time-dependent, tight binding to Hsp90 alone. In the broader context, these studies highlight the essentiality of detailed biochemical characterization of drug–target interactions for the effective translation of in vitro pharmacology to cellular and in vivo efficacy.

The MMP-11 proteinase, also known as stromelysin-3, probably plays an important role in human cancer because MMP-11 is frequently overexpressed in human tumors and MMP-11 levels affect tumorogenesis in mice. Unlike other MMPs, however, human MMP-11 does not cleave extracellular matrix proteins, such as collagen, laminin, fibronectin, and elastin. To help identify physiologic MMP-11 substrates, a phage display library was used to find peptide substrates for MMP-11. One class of peptides containing 26 members had the consensus sequence A(A/Q)(N/A) downward arrow (L/Y)(T/V/M/R)(R/K), where downward arrow denotes the cleavage site. This consensus sequence was similar to that for other MMPs, which also cleave peptides containing Ala in position 3, Ala in position 1, and Leu/Tyr in position 1', but differed from most other MMP substrates in that proline was rarely found in position 3 and Asn was frequently found in position 1. A second class of peptides containing four members had the consensus sequence G(G/A)E downward arrow LR. Although other MMPs also cleave peptides with these residues, other MMPs prefer proline at position 3 in this sequence. In vitro assays with MMP-11 and representative peptides from both classes yielded modest kcat/Km values relative to values found for other MMPs with their preferred peptide substrates. These reactions also showed that peptides with proline in position 3 were poor substrates for MMP-11. A structural basis for the lower kcat/Km values of human MMP-11, relative to other MMPs, and poor cleavage of position 3 proline substrates by MMP-11 is provided. Taken together, these findings explain why MMP-11 does not cleave most other MMP substrates and predict that MMP-11 has unique substrates that may contribute to human cancer.

Clastogenicity is frequently observed following treatment of mammalian cells with new chemical entities. This clastogenicity, unless proven otherwise, is assumed to result from the imperfect repair of DNA lesions produced from covalent chemical/DNA interaction. However, clastogenicity can also arise via other mechanisms such as non-covalent chemical intercalation into DNA resulting in poisoning of cellular DNA topoisomerase II (topo II) and stabilization of DNA double strand breaks. We have recently reported modifications to the V79 in vitro micronucleus assay which allow an indirect evaluation of both the intercalative and topoisomerase-interactive activities of chemical agents. In the present studies we have used these modified assays to further assess the validity of this approach in an evaluation of a number of intercalating and non-intercalating polycyclic compounds. It is shown that intercalating agents may be catalytic topo II inhibitors (e.g. chloroquine (CHL), tacrine (TAC), 9-aminoacridine (9AA), ethidium bromide (EB)) or topo II poisons (e.g. proflavine (PROF), auramine O (AUR) and curcumin (CURC)). Still other intercalators are shown to lack detectable topo II-interactions, (e.g. imipramine (IMP), quinacrine (QUIN), 2-aminoanthracene (AA), iminostilbene (IMN) and promethazine (PHE)). It is concluded that (1) the clastogenicity of three agents, PROF (a typical DNA intercalating agent), and AUR and CURC (both structurally atypical intercalating agents, with unknown clastogenic mechanisms), may be due to topo II poisoning; (2) other intercalating agents may either act as catalytic topo II inhibitors or exhibit no functional topo II interaction; (3) The use of these cell-based approaches may provide a logical first step in determining if unexpected clastogenicity associated with test article exposure is due to a topo II interaction.

The understanding of phytoplankton dynamics in the Gulf of the Saint Lawrence (GSL) is critical for managing major fisheries off the Canadian East coast. In this study, the accuracy of two atmospheric correction techniques (NASA standard algorithm, SA, and Kuchinke's spectral optimization, KU) and three ocean color inversion models (Carder's empirical for SeaWiFS (Sea-viewing Wide Field-of-View Sensor), EC, Lee's quasi-analytical, QAA, and Garver- Siegel-Maritorena semi-empirical, GSM) for estimating the phytoplankton absorption coefficient at 443 nm (aph(443)) and the chlorophyll concentration (chl) in the GSL is examined. Each model was validated based on SeaWiFS images and shipboard measurements obtained during May of 2000 and April 2001. In general, aph(443) estimates derived from coupling KU and QAA models presented the smallest differences with respect to in situ determinations as measured by High Pressure liquid Chromatography measurements (median absolute bias per cruise up to 0.005, RMSE up to 0.013). A change on the inversion approach used for estimating aph(443) values produced up to 43.4% increase on prediction error as inferred from the median relative bias per cruise. Likewise, the impact of applying different atmospheric correction schemes was secondary and represented an additive error of up to 24.3%. By using SeaDAS (SeaWiFS Data Analysis System) default values for the optical cross section of phytoplankton (i.e., aph(443) = aph(443)/chl = 0.056 m2mg−1), the median relative bias of our chl estimates as derived from the most accurate spaceborne aph(443) retrievals and with respect to in situ determinations increased up to 29%.

Objective: This community study assessed the prevalence of post-traumatic stress disorder (PTSD) and the psychosocial consequences of the landslide which occurred in Sarno, Southern Italy, in May 1998. Method: A random sample (n=272) of the population living in the highest risk area of Sarno, and a control group recruited in a small town situated near the disaster area, but not affected by the event, were assessed 1 year after the disaster by standardized instruments. Results: Of the subjects recruited in Sarno, 27.6% met DSM-IV criteria for PTSD; 59% subjects recruited in Sarno and 35% of the control group were identified as ‘probable cases’ by the GHQ-30 (P

Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.

Gonadotrophin-releasing hormone (GnRH) agonists have become irreplaceable addition to gonadotrophins in ovulation induction for assisted reproduction. Of the several schemes currently employed, long regimens appear to be maximally effective to optimize patient scheduling and to improve clinical results.

Pulsatile GnRH (pGnRH) was administered to 292 anovulatory patients in 600 consecutive cycles between February 1984 and February 1993. This represents the largest single pGnRH series ever reported. Patients were divided into the following groups: primary hypogonadotropic amenorrhea (PHA), 73 patients, 161 cycles; other hypogonadotropic hypogonadisms (OHH), 57 patients 107 cycles; multifollicular ovary (MFO), 39 patients 75 cycles; polycystic ovary (PCO), 85 patients 172 cycles; and other hyperandrogenic anovulations (OHA), 38 patients 85 cycles. GnRH was administered iv at a dose of 1.25-20.0 micrograms every 30-120 min; most cycles (505) were performed with a regimen of 2.5-5.0 micrograms GnRH every 60-90 min. In 228 cycles of MFO, PCO, and OHA patients, pGnRH was preceded by GnRH agonist (GnRH-A) suppression. Ovulatory rates were 75%, and pregnancy occurred in 105 cycles (pregnancy rate of 18%/treatment cycle and 23%/ovulatory cycle). Ovulatory and pregnancy rates were higher in PHA, OHH, and MFO and lower in PCO and OHA. Only 4 multiple pregnancies occurred (3.8%), none after GnRH-A suppression. The abortion rate was 30% and was highest in PCO (45%). GnRH-A pretreatment improved ovulatory rates only in PCO (from 49% to 71%; P < 0.001), whereas it had no significant effect on pregnancy and abortion rates in any group. Higher weight and insulin were associated with lower ovulatory and pregnancy rates; higher LH and testosterone were associated with lower ovulatory rates only. We conclude that 1) pGnRH is a highly effective ovulation induction method; 2) pGnRH does not cause ovarian hyperstimulation; 3) low dose pGnRH is associated with a remarkably low incidence of multiple pregnancy; 4) GnRH-A pretreatment improves pGnRH outcome in PCO and further lowers the incidence of multiple pregnancy; 5) pGnRH is associated with relatively elevated abortion rates, particularly in PCO; and 6) pGnRH is less successful in overweight patients and when high baseline LH, testosterone, and insulin levels are present.

The pattern of episodic gonadotrophin releasing hormone (GnRH)-driven luteinizing hormone (LH) secretion changes dynamically across the human menstrual cycle. Adherence to a specific regimen of pulse amplitude and frequency is critical for normal ovulation, menstrual cyclicity and reproductive function. Derangements of episodic LH secretion are associated with anovulation. We have shown that in the human slowing of GnRH-induced LH pulses results in lower ovulatory rates and dysfunctions of the mid-cycle LH surge. This information is relevant for the understanding of the endocrine dynamics of the menstrual cycle both in normal and anovulatory subjects.

Different depot GnRH analogs (GnRH-A) are currently used for the reversible suppression of the pituitary-ovarian axis in several reproductive and neoplastic disorders in women. In spite of anecdotal reports of incomplete suppression by some depot GnRH-A, this issue has never been systematically investigated in adult women. Thus, we elected to study 40 normally cycling women with male-related infertility or benign reproductive disorders; each group of 10 subjects received a different GnRH-A for 3 months: buserelin (group B; 300 micrograms, sc, every 12 h, as a control), goserelin (group G; 3.6 mg, sc, every 28 days), leuprorelin (group L; 3.75 mg, im, every 28 days), and triptorelin (group T; 3.75 mg, im, every 28 days). Depot GnRH-A was administered by one of the investigators. GnRH tests (100 micrograms, iv) were performed before treatment (cycle day 7; test A) and on treatment days 57 (i.e. 1 day after the third depot GnRH-A; test B) and 84 (i.e. 28 days after the third depot GnRH-A; test C). Immunoreactive (i) LH levels were measured with an ultrasensitive immunochemiluminometric assay. Profound suppression of the iLH response to the GnRH test occurred in all subjects during treatment. Conversely, FSH levels in the third month of treatment tended to be higher in the depot GnRH-A groups than in group B, and this difference achieved statistical significance (P < 0.05) in groups G and L during test C. In GnRH test B, while the mean estradiol (E2) level was less than 75 pmol/L (< 20 pg/mL) in all group B subjects, individual E2 levels were greater than 75 pmol/L in five patients receiving depot GnRH-A (two in group G, one in L, and two in T). Finally, individual E2 levels during test C were greater than 75 pmol/L in only two patients of group G, who also reported vaginal spotting. Thus, we conclude that in adult women, 1) iLH was profoundly suppressed in the third month of administration of all GnRH-A tested; 2) FSH suppression with depot GnRH-A was less marked than that with high-dose short-acting sc buserelin; and 3) signs of an incomplete block of ovarian function can be present in the third month of depot GnRH-A administration, particularly when goserelin is employed.

We trace the first steps in the organization of the International League against Epilepsy, the great initial impetus for which came from an Italian savant, Prof. Tamburini, among others. The League came into being because of the need to differentiate epilepsy from insanity and to channel into a single institution all research into the etiopathogenesis, new therapies and principles of care to ensure their rapid diffusion all over the world.

By modulating the cellular redox state, the plasma membrane electron transport (PMET) is important in platelet biology; indeed, the oxidant/antioxidant balance plays a central role during activation of the coagulation pathway. None the less, in human platelets, the PMET system has not yet been fully characterized and the molecular identities of most components are unknown. Here, for the first time, the presence of the plasma membrane hydroquinone (NADH) oxidase Ecto-NOX1 in human platelets has been described. We found that Ecto-NOX1 expression is modulated by capsaicin: Indeed, it is positively regulated through a mechanism requiring binding of capsaicin to its receptor, namely the transient receptor potential vanilloid subtype 1 (TRPV1). Ligand-receptor interaction triggers a signalling cascade leading to ROS production, which in turn enhances expression and activity of Ecto-NOX1. Redox regulation of Ecto-NOX1 may be important to platelet recruitment and activation during inflammatory diseases.

Reactive oxygen species (ROS) and redox state have emerged as physiological mediators, controlling blood coagulation and thrombosis. The redox balance is obviously linked to the presence of antioxidants; in particular, vitamin C appears to be a key modulator of platelet oxidative state, since these cells physiologically accumulate ascorbic acid and, moreover, platelet ascorbate plays a role during aggregation. Here, we showed that platelets could compensate for fluctuations in ascorbate levels by modulating the expression of the Na+-dependent transporter SVCT2. Furthermore, the use of anucleated cells demonstrated, for the first time, that SVCT2 expression could be regulated at the translational level. The control of ascorbic acid uptake, through regulation of its carrier, was not only related to substrate availability, but it also occurred during platelet activation, which was accompanied by vitamin C deprivation and alteration in the redox state. Finally, we showed that changes in intracellular ascorbic acid content had physiological relevance, since they modulate the surface sulfhydryl content and the thrombus viscoelastic properties. Beside its role during aggregation, vitamin C may also have important effects during postaggregatory events.

Experimental work on the correlation of optical coefficients to laser backscatter have been performed to provide a foundation for the development of laser based optical oceanographic instrumentation. Results of these ccsrrelations with the beam attenuation, ablsorption, scattering , and diffuse at.tenuation coefficients will be presented. Also, a comparison of the experimental data with salient models is gi.ven.

Ovarian hyperstimulation (OHS) and multiple pregnancy are dreaded complications of ovulation induction. The use of pulsatile GnRH permits to prevent the occurrence of OHS and results in few multiple pregnancies. Low-dose GnRH administration, avoidance of preovulatory hCG, patient selection, and the use of GnRH agonist pituitary desensitization in selected patients permits to limit multiple conceptions to a level comparable with the occurrence of this complication in normal unstimulated women.

Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC(50)s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-ray diffraction studies on a later derivative bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in approximately 100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.

This paper describes the history of the Italian Society of Neurology (Societa Italiana di Neurologia, SIN), originally an offshoot of the Societa Freniatrica Italiana, whose origins go back to Aversa in 1861, when Biagio Gioacchino Miraglia founded the Societa Frenopatica, the first neuropsychiatric organisation for Italian scientists. The “Societa Freniatrica” was founded in Rome in 1873 and was to bring together neurologists and psychiatrists until 1907, when the SIN was founded with its own Articles of Association (subsequently modified in 1971) and the two specialisations of neurology and psychiatry were recognised as being distinct entities. The first SIN Congress was held in Naples in 1908, and an analysis of its themes and those of subsequent Congresses highlights the fact that, right from the start, the interests of neurologists covered the whole range of the neurosciences: neuroanatomy, histology, physiopathology and clinical neurology. Over the years, special Groups have been established to enable the more profound study of specialised aspects, and the Society of Hospital Neurologists founded.

Objectives To clarify the endocrine mechanisms underlying the outcome of different ovulation induction regimens with gonadotropins and GnRH agonists (GnRH-a). Design Prospective study. Setting Reproductive Endocrinology Center, University of Bologna. Patients Forty eumenorrheic women randomly assigned to four groups of 10 subjects each. Interventions Ovulation induction regimens: group A, purified FSH only; group B, purified FSH and flare-up GnRH-a; group C, purified FSH and long GnRH-a; and group D, hMG and long GnRH-a. Main Outcome Measures Pelvic ultrasound and hormone levels in daily serum samples and in follicular fluid drawn immediately before hCG administration. Results Exogenous gonadotropin dose did not differ among groups. Group B had fewer preovulatory follicles than group C. Group B had higher serum LH, FSH, E 2 , P, T, and follicular fluid LH, E 2 , T, and α-inhibin than groups C and/or D. Groups C and D did not differ. Conclusions Long GnRH-a regimens improved follicle yield and the endocrine milieu in spite of comparable exogenous gonadotropin dose and lower serum FSH and thus appear to be preferable in assisted reproduction. Reduced folliculogenesis found in flare-up GnRH-a regimens could be mediated by the atretic effects of high intraovarian androgens. Efficacy of purified FSH and hMG was comparable.

Objective To assess the oral glucose tolerance test (OGTT)-stimulated insulin secretion and its relation to pulsatile GnRH ovulation induction outcome in patients with multifollicular or polycystic ovaries (PCOs). Design Prospective study. Setting Reproductive Endocrinology Center, University of Bologna, Bologna, Italy. Patients Eight normal and 29 anovulatory women (8 with multifollicular ovaries and 21 with PCOs). Intervention A standard OGTT was performed in all subjects. In all anovulatory patients, ovulation was induced with pulsatile GnRH (5 μ g IV every 60minutes). In multifollicular ovary patients, pulsatile GnRH was administered alone, whereas in PCOs it was preceded by GnRH agonist (GnRH-a) suppression. Main Outcome Measures Glucose, insulin, and C-peptide response to the OGTT, expressed as area under the curve (AUC). Ovulatory rates in response to pulsatile GnRH. Results Insulin and C-peptide AUC were greater than controls in both multifollicular ovary and PCO patients. Insulin AUC was positively correlated to ovarian volume. Ovulation was achieved in 88% and 57% of multifollicular ovary and PCO patients, respectively. Body mass index and glucose AUC but not insulin and C-peptide AUC were significantly greater in the anovulatory PCO. Conclusions [1] Insulin AUC was increased in both multifollicular ovary and PCO patients; [2] derangements of insulin secretion may be present in a greater variety of anovulatory patients than previously thought; [3] insulin levels during the OGTT did not predict a response to pulsatile GnRH in PCOs, suggesting complex insulin interactions at the ovarian level; [4] given the in vitro stimulatory properties of insulin on granulosa cells synergistic with FSH we propose that excessive insulin levels may contribute to the ovarian enlargement often found in multifollicular ovary and PCO patients.

In this paper, the authors pay tribute to Jean Martin Charcot in the centenary of his death (16th August 1893), concentrating on his artistic sense and drawing ability. The authors give some examples of the drawings Charcot used to illustrate his Tuesday Lessons at Salpetriere, together with his highly precise clinical and semiological descriptions.

Background: GSK2118436 is a potent inhibitor of B-Raf, a signal transduction kinase in the MAPK pathway that can be mutated to become an oncogenic driver in several human cancers, including melanomas (70%). GSK2118436 inhibits in a dose dependant manner phoshorylation of ERK (pERK) in cell lines encoding B-RafV600E mutation leading to inhibition of cell proliferation and tumor regression. Purpose: To predict clinical relevant doses based on exposure-response relationship from preclinical pERK inhibition tumor xenograft data and exposure observed in first-time-in-human (FTIH) study. Methods: Tumor pERK and tumor volume measurements from nude mouse xenograft models, including colon carcinoma and melanoma encoding B-RafV600E mutation, were pooled for the analysis. GSK2118436 was administered using a wide range of oral (0.1 to 300 mg/kg QD, 5 to 300 mg/kg BID) and continuous IV (3 to 100 mg/kg/day) doses. Tumor pERK inhibition was characterized as a function of GSK2118436 concentration using an inhibitory Emax model. For tumor regression, tumor volume was described using a linear growth model with tumor death rate expressed as a function of GSK2118436 concentration. The analyses were conducted using nonlinear mixed effects modeling. To extrapolate to clinical exposure, GSK2118436 concentrations in mouse were corrected for blood:plasma ratio. Results: The relationship between preclinical tumor pERK inhibition and exposure was described using a mean (90% CI) plasma IC50 of 18.5 (4.3-32.4) ng/mL (35.5nM). In preclinical models, tumor regression was observed at 30mg/kg QD orally and 3mg/kg IV and was dependent on dosing regimen. Based on exposure observed in IV studies, tumor regression was associated with >70% pERK inhibition. Tumor growth was characterized with a mean rate of 1.04 mm3/hr and was inhibited by GSK2118436 with a mean (90% CI) plasma IC50 of 28 (5.9-50.4) ng/mL (53.8nM) for tumor death rate. The model was successful in describing data observed with different modes of administration. In the FTIH study, inhibition of tumor pERK was exposure-related with >80% inhibition predicted at doses ≥100 mg BID. Consistent with target inhibition, administration of the recommended Phase 2 dose of 150 mg BID resulted in clinical activity in subjects with B-Raf-mutant melanoma. Mean exposure at trough exceeded 100 ng/mL (192nM), which is >3-fold the target exposure for tumor growth inhibition (53.8nM) based on the preclinical model. Conclusions: The exposure-response models developed using preclinical tumor pERK inhibition and mouse xenograft data translated well to the clinical biomarker and efficacy data observed with GSK2118436 and support 150 mg BID as a clinically effective dose. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5035. doi:10.1158/1538-7445.AM2011-5035

Activation of the Ras-Raf-MEK-ERK pathway has been implicated in a large range of human cancers. Growth factor receptor stimulation by extracellular ligands activates Ras, which then sets in motion a signal transduction cascade through the Raf, MEK and ERK serine/threonine kinases. Mutation of the B-Raf kinase constitutively activates MAPK signalling, thus bypassing the need for upstream stimuli. This has been genetically associated with several human cancers, especially occurrence of the B-RafV600E mutant and its high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. The ability to selectively and potently inhibit B-Raf should provide a potential therapy for patients with mutant B-Raf tumors, for which addictive dependency on this pathway is observed. We have identified a novel, potent, and selective Raf kinase inhibitor that is capable of inhibiting the kinase activity of wild-type B-Raf, B-RafV600E and c-Raf with IC50 values of 3.2, 0.8, and 5.0 nM, respectively. Kinase panel screening for over 270 kinases has indicated that this inhibitor is selective for Raf kinase, with ∼400 fold selectivity towards B-Raf over 91% of the other kinases tested. Specific cellular inhibition of B-RafV600E kinase by this inhibitor leads to decreased ERK phosphorylation and inhibition of cell proliferation by an initial arrest in the G1 phase of the cell cycle, followed by cell death. This inhibition is selective for cancer cells that specifically encode the mutation for B-RafV600E. Oral compound administration inhibits the growth of B-RafV600E mutant melanoma (A375P) and colon cancer (Colo205) human tumor xenografts, growing subcutaneously in immuno-compromised mice. This cell-specific B-RafV600E inhibitor is currently being evaluated in a human Phase I clinical trial. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B88.