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Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.

Extensive evidence implicates the urokinase plasminogen activator receptor (uPAR) in tumor growth, invasion, and metastasis. Recent studies have substantiated the importance of the interaction between uPAR and the extracellular matrix protein vitronectin (VN) for the signaling activity of the receptor in vitro, however, the possible relevance of this interaction for the activity of uPAR in tumor growth and metastasis has not been assessed. We generated a panel of HEK293 cell lines expressing mouse uPAR (muPARWT), an uPAR mutant specifically deficient in VN binding (muPARW32A), and a truncation variant (muPARΔD1) deficient in both VN and uPA binding. In vitro cells expressing muPARWTdisplay increased cell adhesion, spreading, migration, and proliferation associated with increased p130Cas and MAPK signaling. Disruption of VN binding or ablation of both VN and uPA binding specifically abrogates these activities of uPAR. When xenografted into SCID (severe combined immunodeficiency) mice, the expression of muPARWT, but not muPARW32Aor muPARΔD1, accelerates tumor development, demonstrating that VN binding is responsible for the tumor-promoting activity of uPAR in vivo. In an orthotopic xenograft model using MDA-MB-231 cells in RAG1−/−/VN−/−mice, we document that host deficiency in VN strongly impairs tumor formation. These 2 lines of in vivo experimentation independently demonstrate an important role for VN in tumor growth even if the uPAR dependence of the effect in the MDA-MB-231 model remains to be ascertained.

Many pharmacogenomic biomarkers (PGBM) were identified and translated into clinical practice, affecting the usage of drugs via label updates. In this context, abacavir is one of the most brilliant examples of pharmacogenetic studies translated into clinical practice. Pharmacogenetic studies have revealed that abacavir HSRs are highly associated with the major histocompatibility complex class I. Large studies established the effectiveness of prospective HLA-B57:01 screening to prevent HSRs to abacavir. Accordingly to these results the abacavir label has been modified: the European Medicines Agency (EMA) and the FDA recommend/suggested that the administration of abacavir must be preceded by a specific genotyping test. The HLA locus is extremely polymorphic, exhibiting many closely related alleles, making it difficult to discriminate HLA-B57:01 from other related alleles, and a number of different molecular techniques have been developed recently to detect the presence of HLA-B57:01. In this review, we provide a summary of the available techniques used by laboratories to genotype HLA-B57:01, outlining the scientific and pharmacoeconomics pros and cons.

Background:Congenital adrenal hyperplasia (CAH) is mainly caused by the deficiency of the 21-hydroxylase enzyme coded by the CYP21A2gene. However, some alleles in the non-classical form (NC-CAH) remain without identified mutations, suggesting the involvement of regulatory regions. Aim:Our objective was to study an allele carrying the variant *13 G>A in the 3’UTR of the CYP21A2gene identified in some patients with a mild form of NC-CAH in order to verify the possible implication of this variation with the phenotype observed. Subjects and methods:Among all the subjects in whom the CYP21A2gene was analyzed, 14 patients and 7 relatives heterozygous or homozygous for the *13 G>A substitution in 3’UTR were selected. Sequencing of DNA, genotyping, multiplex ligation-dependent probe amplification (MLPA), in vitrostudies and bioinformatic analysis were performed. Results:The haplotype of the *13 G>A allele was identical in all the subjects with a monomodular structure composed by one C4Agene and one CYP21A2gene without a second module with the CYP21A1Ppseudogene. No other concomitant mutations were found in the region extending from 3 kb in the promoter and encompassing the polyadenylation signal. Both bioinformatic analysis and in vitrostudies predicted an alteration of the RNA folding and expression, but no miRNA target sequences were found in this region. Conclusions:The identification of a substitution in the 3’UTR of the gene associated with a mild form of NC-CAH suggests the importance of analyzing the CYP21A2 untranslated regions to better characterize and treat this subgroup of patients.

Detailed mapping of coastline around Theologos area revealed the existence of well developed permanently submerged notches 75 ± 10 cm below present mean sea level. The regional occurrence of well preserved submerged tidal notches suggests their coseismic origin. The submergence of this Holocene shoreline possibly occurred at 1894 AD. Average submergence rate of 6.08 mm/yr may be estimated by a well preserved recumbent U-shaped notch. The retreating point depth suggests that the developing period of the notch might have been of the order of as much as three thousand years. Several non in situ large rock blocks, containing marine fossils (Lithophaga, Vermetids, Serpulids) in growth position, seem to have been projected on the coast by a tsunami wave, which might have been caused by the same coseismic episode.

Extreme sea levels with various return periods are estimated to rise from the present situation to higher levels during the next half a century at seventeen tide-gauge stations of the English Channel. The possible increase is ascribed to local/regional relative sea-level rise, to global sea-level rise, and to an increase in maximum surge height. This would produce more frequently sea-level events greatly exceeding the present level of highest astronomical tide, with increased risk of coastal flooding and erosion. The area potentially more at risk seems located in the central part of the English coast, between Weymouth and Portsmouth. French L'étude des niveaux marins extrêmes, avec des périodes de retour variées, dans 17 stations marégraphiques de la Manche, laisse prévoir une élévation, par rapport à la situation actuelle, au cours du prochain demi-siècle. Cette possible augmentation peut être attribuée à une montée du niveau relatif de la mer à l'échelle locale ou régionale, à l'échelle globale et enfin à un accroissement des surcotes maximales. Les hauteurs d'eau dépassant nettement l'actuel niveau de la plus haute marée astronomique deviendraient de ce fait plus fréquentes, avec une augmentation du risque de submersion littorale et d'érosion. La région la plus à risque semble localisée dans la partie centrale de la côte anglaise, entre Weymouth et Portsmouth.

AbstractBackground:Persistentmüllerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. Aim:We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. Results:Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. Conclusions:The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate.Copyright © 2008 S. Karger AG, Basel

This study summarizes preliminary results obtained in the framework of the DISCOBOLE Project, that aims at estimating the long-term evolution of certain consequences of climate change, in order to improve the design and the management of maritime constructions. The mean sea level tends to increase more or less everywhere along the French Atlantic coasts. However, the rise is greater than average at Saint-Jean-de-Luz, Sables-d?Olonne and Le Conquet, suggesting the occurrence of subsidence phenomena. Nevertheless, the recent climatic evolution is not unfavourable, since surge-related winds tend to decrease in frequency and speed, or to remain almost stable. The duration of low atmospheric pressure occurrences tends also to decrease. The most significant among the trends that are liable to contribute to the coastal flooding risk are summarized graphically. For other results of the project, see on the internet?: http?://discobole.cetmef.equipement.gouv.fr/discobole/

Objective: Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course.Design: The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor.Methods: The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing.Results: Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents.Conclusions: We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand–receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.

Behrendt, Lothar (2004): Das Quartär der südwestlichen Niederlausitz (Raum Senftenberg – Lauchhammer – Bad Liebenwerda) – eine Dokumentation. – Altenburger Naturwissensch. Forsch., H. 14, Bundesrepublik Deutschland, Nationalatlas, Part 3: Hrsg. v. Institut für Länderkunde, Leipzig, Dongus, H. (2003): Das Relief der Alpen, Heine, K. & Pfeffer, K.-H. (Hrsg.) (2001): Angewandte Geomorphologie in verschiedenen Geoökosystemen. Beiträge der Symposien der Kommission für Geomorphologie der Bayerischen Akademie der Wissenschaften: „Fließgewässer und Flußauen“ und „Tropische Geomorphologie“, Hess, Harro (2003): Haack TaschenAtlas. Vulkane und Erdbeben, Katzung, Gerhard (Hrsg.) (2004): Geologie von Mecklenburg-Vorpommern, Marzolff, I., Ries, J. B., De la Riva, J. & Seeger, M. (Eds.) (2003): Landnutzungswandel und Landdegradation in Spanien – El cambio en el uso del suelo y la degradación del territorio en España, Niller, H.-P. (1998): Prähistorische Landschaften im Lößgebiet bei Regensburg – Kolluvien, Auenlehme und Böden als Archive der Paläoumwelt. –Regensburger Geograph. Schriften, H. 31, Press, Frank & Siever, Raymond (2003): Allgemeine Geologie. Einführung in das System Erde. 3. Aufl., Spektrum Lehrbuch, Schneider, G. (ed.) (2004): The Roadside Geology of Namibia, Slim, H., Trousset, P., Paskoff, R. & Oueslati, A. (2004): Le littoral de la Tunisie: Etude géoarchéologique et historique.

AbstractBackground: Testis enlargement in McCune-Albright syndrome (MAS) is generally bilateral and associated with clinical and biochemical manifestations of sexual precocity. Case Report: We describe for the first time an unreported clinical expression of MAS in a 4.6-year-old boy presenting with monolateral testis enlargement and no signs of sexual precocity or other clinical manifestations of MAS at the time of presenting with macroorchidism. Both testosterone and LHRH-stimulated gonadotropin levels were in the prepubertal range. Serum inhibin B was increased to a pubertal level indicating Sertoli cell activation. The histological and immunocytochemical evaluation of the enlarged testis revealed Sertoli cell hyperplasia with no mature Leydig cells. Mutation R201C of GNAS1 gene, classically responsible for MAS, was identified in DNA samples from the right testis biopsy and leukocytes. Conclusions: (a) MAS should be taken into consideration in the clinicopathological approach to a boy with monolateral macroorchidism; (b) testicular enlargement may be only the presenting clinical manifestation of MAS and is not necessarily linked to manifestations of peripheral precocious puberty; (c) testicular autonomous hyperfunction in MAS may be restricted to Sertoli cells, as also demonstrated previously by others.Copyright © 2006 S. Karger AG, Basel

AbstractMild insulin resistance appears to be an early metabolic defect in girls with Turner syndrome (TS). Impaired glucose tolerance has been reported in 10–34% of patients with TS, and type 2 diabetes mellitus is 2–4 times more common and occurs at a younger age in girls with TS than in the general population. In a mixed longitudinal and cross-sectional study, we analysed carbohydrate tolerance and insulin sensitivity in 46 children and adolescents with TS who reached their final height after long-term treatment (mean 6.3 ± 2.5 years) with growth hormone (GH: 0.33 mg/kg/week [0.05 mg/kg/day]), and in 36 of these patients who were followed-up after the cessation of GH therapy (mean follow-up, 2.6 ± 2.5 years; range, 1–9.5 years). Patients with TS were compared with an age-matched female control group. Insulin sensitivity appeared to be lower in patients with TS than in controls, even before the start of GH therapy. As in controls, insulin sensitivity decreased with age in patients with TS, and levels were lower in those aged >12 years than in those aged <12 years. GH therapy resulted in good catch-up growth in patients with TS, with final height significantly higher than projected height evaluated before the initiation of GH therapy. Insulin sensitivity increased after 7–8 years of therapy and, on the cessation of GH therapy, returned to pre-treatment levels. The increase in insulin sensitivity seen on the cessation of GH therapy appeared to be influenced negatively by body mass index and triglyceride levels, and correlated positively with the number of years since cessation of GH therapy. As in the general population, excess weight and an abnormal lipid profile, in particular excess triglyceride levels, worsened insulin sensitivity. In conclusion, our study confirms that GH therapy reduces insulin sensitivity, but at its cessation there is a return to pre-therapy values. We therefore report a progressive improvement in carbohydrate tolerance and insulin function in patients with TS, despite an increase in age.Copyright © 2005 S. Karger AG, Basel

The drill core of Funafuti Atoll, collected by The Royal Society Coral Reef Expedition in 1896–1898, has been dated using high–precision 14C and Sr isotope measurements determined by mass spectrometry. The core top is a Holocene reef deposit, reflecting 26.4 m of reef growth since 8 ka, and is underlaid by Pleistocene reef–lagoonal deposits separated by a series of inferred hiatuses at 26.4 m, ca.30 m, ca.65 m and ca.80 m (ca.0.1 Ma, ca.0.2 Ma, ca.0.3 Ma and ca.0.6 Ma, respectively), reflecting atoll carbonate deposits associated with late Quaternary sea–level changes. In turn, the underlying sequence below ca.80 m comprises an upper section of additional Pleistocene reef–lagoonal deposits, having a high accumulation rate greater than 100 m Ma−1, and a heavily dolomitized lower section. Sr isotope data in the lower section provide maximum (oldest) ages for dolomite formation and, depending on the extent of the isotopic memory from precursor CaCO3, reflect ongoing diagenetic alteration from ca.2.3 Ma (i.e. the oldest dolomite) or in one or more discrete diagenetic events at ca.1 Ma, and possibly at ca.2 Ma. This sequence reflects interaction between atoll carbonate sedimentation, tectonic subsidence and eustatic sea–level change.

Jaesche, P. (1999): Bodenfrost und Solifluktionsdynamik in einem alpinen Periglazialgebiet (Hohe Tauern, Osttirol). - Bayreuther Geowissenschaftliche Arbeiten, Bd. 20; Pain, C. F. (ed.): Weathering and soils. Proceedings of the Fourth International Conference on Geomorphology, Bologna 1997, Volume IV. - Zeitschrift fur Geomorphologie, Supplementband 119; Paskoff, R. (2001): L'élévation du niveau de la mer et les espaces côtiers. - 191 p., 72 Fig., 4 Tables, glossary, index. Institut oceanographique, Paris;Pfeffer, K.-H. (ed.): Holocene Geomorphology. Zeitschrift für Geomorphologie, Supplement­ band 122. 282 S., 120 Abbildungen und 30 Tabellen, € 86.-, Gebr. Borntraeger, Berlin, Stuttgart, 2000.

At least three raised shorelines, micro-benches and notches, spanning a distance of more than 10km and marked by a well-preserved marine fauna have been identified along the NW coast of Samos Island, Aegean Sea, and area hitherto assumed to be characterised by a Holocene marine transgression. These fossil shorelines are nearly horizontal, approximately 0.6, 1.1 and 2.3m above sea level, and can be assigned to hitherto unnoticed earthquakes, which occurred approximately 500, 3600–3900 and possibly 1500 years ago. Some evidence of Quaternary and longer-term uplift has been found as well. The observed uplift may be related to a zone of intense seismicity and faulting following the Great Meander (Buyuk Menderes) River graben in Western Anatolia, but its structural explanation is not clear. New evidence indicates that the geomorphological evolution of Samos Island and of the wider Eastern Aegean is not simply a result of marine transgression and of regional-scale tectonics, but also of earthquakes, and that local-scale tectonics are responsible for the evolution and present-day morphology of at least a part of the coast of Samos Island, as well as of other Aegean coasts.

Marine bioerosion marks and radiocarbon AMS dating give evidence of a two-phase sequence of coseismic vertical displacements which occurred during the Late Holocene in the Livanates-Arkitsa area (south coast of the Euboea Gulf). Morphological and biological arguments suggest that both the displacements were superimposed on a gradual relative sea-level rise. The earlier coseismic movement (a subsidence of 0.9 m max.) is possibly related to a tsunami wave, dated between 1380 and 965 B.C., which swept at 16 m in altitude the nearby archaeological site of Homeric Kynos. The later coseismic movement, between 360 B.C. and A.D. 210, was an uplift greater than 1.4 m.

• OBJECTIVE. —To determine the effects of 18-Gy cranial irradiation on growth, growth hormone (GH) secretion, and pituitary magnetic resonance imaging in children who underwent previous irradiation for treatment of acute lymphoblastic leukemia. DESIGN. —Clinical survey. SETTING. —Department of Pediatrics of the University of Bologna (Italy). PATIENTS. —Ten boys and 18 girls who were treated for acute lymphoblastic leukemia; median age at diagnosis was 3.1 years and at the end of follow-up was 11.5 years. MEASUREMENTS AND RESULTS. —Height was periodically measured from diagnosis until the end of follow-up, when GH secretion study and magnetic resonance imaging were performed. The mean height SD score was significantly lower than at diagnosis only at the end of treatment. Nocturnal mean GH concentration and GH response to pharmacological tests (arginine and levodopa [L-dopa]) were pathological in 22 cases (81.5%) and 18 cases (64.3%), respectively. Sixteen cases (59.2%) had a blunted GH release to the three tests. Mean pituitary anterior lobe height was reduced and seven subjects (25%) showed an empty sella. CONCLUSIONS. —Cranial irradiation with 18 Gy does not seem to influence the growth pattern of most children who are treated for acute lymphoblastic leukemia, despite severe impairment of GH secretion and morphological abnormalities of the sellar area. However, a follow-up until final height is necessary.(AJDC. 1992;146:1343-1348)

• To evaluate the effects of two different doses of cranial irradiation on growth and growth hormone (GH) release, we studied 61 children with acute lymphocytic leukemia who had survived at least five years in continuous complete remission. Forty-three children received 24 Gy (group 1) and 18 children received 18 Gy (group 2). Height was evaluated at diagnosis, at the end of treatment, and 6, 12, and 24 months later. Growth hormone release was evaluated by arginine and levodopa tests after the end of treatment. After diagnosis, the height SD score decreased significantly in both groups; two years after the end of treatment, only group 1 showed an SD score for height that was still significantly lower than at diagnosis. Group 1 showed impaired GH responses to the tests and, compared with controls, group 1 in fact included a percentage of subjects with a normal response to levodopa (ie, >8 μg/L) that was significantly lower (56.4% vs 83.3%) and a percentage of nonresponders to both tests that was significantly higher (21.6% vs 0%). These data indicate that only patients treated with lower cranial irradiation dosage (18 Gy) had complete growth recovery and normal GH responses to pharmacologic tests.(AJDC 1988;142:1199-1202)