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THIS NEWS RELEASE IS NOT FOR DISTRIBUTION TO U.S. NEWS WIRE SERVICES OR FOR THE DISSEMINATION IN THE UNITED STATES West Melville Metals Inc. ("West Melville" or the "Company") (TSX VENTURE:WMM) is pleased to announce the completion and filing of a National Instrument 43-101 compliant independent technical report, dated September 6, 2016 (Revised October 6, 2016), on the Wels Gold property (the "Technical Report"). The Technical Report entitled "Technical Report on the Wels Gold Property, Whitehorse Mining District, Yukon, Canada" was prepared by R. Allan Doherty, P.Geo. of Aurum Geological Consultants Inc., and has been filed under the Company's profile on SEDAR (www.sedar.com) and the West Melville website (www.westmelville.com). The Company's option agreement with Gorilla Minerals Corp. ("Gorilla") to acquire a 90% joint venture interest (subject to an existing 3% NSR) in the Wels Gold property, first announced on August 15, 2016 has now been accepted by the TSX Venture Exchange, and the Company closed the related $2.0 million financing. John Robins Chairman of West Melville states, "The Wels gold project is an exciting opportunity for West Melville and affords the Company a platform to leverage off Kaminak's recent success and experience in the Yukon". The Property is located in the Traditional Territory of White River First Nation (the "WRFN"), and is approximately 50km east of Beaver Creek and 180 km south of Dawson City, west central, Yukon. The area comprises 229 contiguous 'quartz claims' covering an area of approximately 4,788 hectares. The Property is a new discovery in an area not previously recognized to host the potential for gold. The Property was staked in 2011 and to date only 1 km by 1km of the Property has undergone some exploration (soil, trench-rock sampling and diamond drilling). The remainder of the Property has undergone little or no exploration or has only been subjected to airborne geophysics (2.5km x 2.5km grid flown for magnetics and radiometrics). The Property is located within the prolific Tintina Gold Province that stretches over 1,500km from western Alaska to eastern Yukon and is host to a variety of styles of gold and base metal mineralization. The local geology is interpreted as IRGS type with 'Tombstone Belt' rock-type affiliations similar to the Dublin Gulch-Eagle and Fort Knox gold mines, both multi-million ounce deposits. Gorilla Minerals Corp, the Property vendors, collected 1658 soil samples (2011, 2012 and 2014), undertook 155m of trenching and rock sampling (104 trench samples plus 28 rock samples) and undertook 442M of diamond drilling (300 samples) in addition to a small airborne magnetic and radiometric survey. The area of exploratory investigation to date only covers approximately 2km by 4km. The property was staked in 2011 based on 2 slightly anomalous soil sample values (36 ppb Au and 57 ppb Au) collected from a 2002 regional Yukon Government program. In 2011 a 2km x 1km soil grid was established over the central area of the claims. Soils taken over the Property identified 3 anomalous zones (values above 120ppb), now termed the Saddle zone, North Zone and Southwest Spur. The Saddle Zone in particular returned very high values including 5204 ppb Au, 3740 ppb Au and 1984 ppb Au and subsequently became the main focus of attention in 2012 (sample set was 88 samples, 16 of which returned values above 122 ppb Au and only 26 returned < 5.4ppb Au) Infill soil sampling was completed over all 3 zones. The results of both programs show that 102 samples (7.6%) were above 63.3ppb Au and of those 48 (3.6%) were above 122 ppb. In 2012 one hand trench (Trench A) was dug to fractured bedrock (1.5m depth) and a single representative rock sample returned 149.5 g/t Au (the "Discovery sample"). Due to unforeseen circumstances at the end of the field season in 2012 the high grade results were only followed up with one small rock sampling program in 2013 which returned an average of 15.25 g/t Au from 5 rock trench samples 2kg to 3kg in weight from the same location as the Discovery sample. In 2014 a much more expansive trenching program (155m) returned the following results: To view the figure associated with this press release, please visit the following link: http://media3.marketwire.com/docs/1074230a.pdf An airborne magnetic and radiometric survey flown in 2015 was unsuccessful in providing drill targets or valuable technical information due to the lack of lithological contrast between the intrusive granitoid rocks and the siliceous country rocks. A 442 metre diamond drilling program was completed in June 2015. The drill was set up on 2 platforms and because parallel mineralized trends were suspected the holes were either drilled in a northerly or southerly direction at various angles of inclination. DDH01/02/03 were drilled from one platform and DDH 04 and 05 from a second platform 50m west of DDH01/02/03. DDH01/DDH02 and DDH04 were drilled in a due north direction and DDH03 and DDH05 in a due south direction. The exploration to date demonstrates that IRGS mineralization of the Fort Knox style hosting high grade gold exists outside of the traditionally recognized Tombstone Belt districts in the Yukon and Alaska. The drilling shows that mineralization extends to at least 80m true depth but the extent and orientation of the mineralization is still largely unknown over the area that is only partially explored to date. Local geological interpretation suggests that the mineralization profile is preserved and much more work is required to understand the size, depth, lateral extent and economic potential of this exciting new discovery. Consistent with the recommendations in the Technical Report, the Company expects to undertake a follow-up program of VTEM geophysics and more groundwork, including drilling, to be applied for the 2016-2017 exploration season. Updates on the Company's exploration plans for the Property will be provided as additional information becomes available. In conjunction with the Wels property transaction, the Company has completed its previously announced non-brokered private placement of 8.0 million units (the "Units") at a price of $0.25 per Unit, for gross proceeds of $2.0 million (the "Offering"). Each Unit consists of one common share of the Company (a "Share") and one-half of one non-transferable common share purchase warrant (a "Warrant"). Each whole Warrant entitles the holder to purchase one additional Share at an exercise price of $0.35 per Share for a period of 18 months from the closing, subject to an acceleration provision under which, if at any time after February 28, 2017, its common shares close at a price at or above $0.50 per share for more than 10 consecutive trading days, West Melville may give notice (the "Notice") to the holders of the Warrants, and issue a press release, advising that the Warrants will expire on the date which is 30 calendar days after the date of the Notice. In connection with the Offering, West Melville entered into finder's fee agreements with six arm's length finders, Canaccord Genuity Corp., Richardson GMP Ltd., Mackie Research Capital Corporation, PI Financial Corp., Haywood Securities Inc., and Leede Jones Gable Inc., pursuant to which West Melville issued 136,200 warrants ("Finder's Warrants"). Each Finder's Warrant has the same terms as the Warrants issued under the Offering. As certain insiders of the Company participated in the Offering, it constituted a related party transaction pursuant to TSX Venture Exchange Policy 5.9 and Multilateral Instrument 61-101 - Protection of Minority Security Holders in Special Transactions ("MI 61-101"). The Company relied on section 5.5(a) of MI 61-101 for an exemption from the formal valuation requirement and section 5.7(1)(a) of MI 61-101 for an exemption from the minority shareholder approval requirement of MI 61-101 as the fair market value of the transaction did not exceed 25% of the Company's market capitalization. The net proceeds from the Offering will be used by West Melville principally to advance its exploration plans and payment commitments on the Wels Gold property, and also to expand the project portfolio by possible new acquisitions, and for general working capital purposes. All securities issued in connection with the Offering will be subject to a hold period expiring February 28, 2017. R. Allan Doherty, P.Geo., author of the Technical Report is the Qualified Person, in accordance with NI 43-101 of the Canadian Securities Administrators, and is responsible for the technical content of this press release. On behalf of the Board of Directors, This news release contains forward-looking statements that are not historical facts. Forward-looking statements involve risks, uncertainties and other factors that could cause actual results, performance, prospects and opportunities to differ materially from those expressed or implied by such forward-looking statements, including statements regarding the mineral potential of the Wels Gold Property, future exploration plans and consultations with the WRFN. Factors that could cause actual results to differ materially from these forward-looking statements include, but are not limited to, variations in the nature, quality and quantity of any mineral deposits that may be located, the Company's inability to reach satisfactory agreements with the WRFN to facilitate its exploration and development plans for the Wels Gold Property, the Company's inability to obtain any necessary permits, consents or authorizations required for its planned activities, and the Company's inability to raise the necessary capital or to be fully able to implement its business strategies. The reader is referred to the Company's public disclosure record which is available on SEDAR (www.sedar.com). Although the Company believes that the assumptions and factors used in preparing the forward-looking statements are reasonable, undue reliance should not be placed on these statements, which only apply as of the date of this news release, and no assurance can be given that such events will occur in the disclosed time frames or at all. Except as required by securities laws and the policies of the TSX Venture Exchange, the Company disclaims any intention or obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise. This news release does not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of any of the securities in any jurisdiction in which such offer, solicitation or sale would be unlawful, including any of the securities in the United States of America. No securities of the Company have been or will, in the foreseeable future, be registered under the United States Securities Act of 1933 (the "1933 Act") or any state securities laws and may not be offered or sold within the United States or to, or for account or benefit of, U.S. Persons (as defined in Regulation S under the 1933 Act) unless registered under the 1933 Act and applicable state securities laws, or an exemption from such registration requirements is available. NEITHER TSX VENTURE EXCHANGE NOR ITS REGULATION SERVICES PROVIDER (AS THAT TERM IS DEFINED IN POLICIES OF THE TSX VENTURE EXCHANGE) ACCEPTS RESPONSIBILITY FOR THE ADEQUACY OR ACCURACY OF THIS RELEASE.


WCB Resources Ltd. (TSX VENTURE:WCB) and GBM Resources Ltd. (ASX:GBZ) are pleased to jointly announce that they have executed a binding HOA to merge the two companies which is to be structured as an Arrangement Agreement under Canadian law . Each WCB shareholder at the record date will receive 8 ordinary shares of GBM for each common share of WCB they hold in consideration for the transfer of those WCB shares to GBM (Merger). The Merger will allow the companies to create a new Australasian focussed gold development and exploration group. Upon completion of the Merger, WCB shareholders will hold 36% and GBM shareholders will hold approximately 64% of the merged entity. Both companies have major shareholder support and the directors of both companies unanimously support the Merger in the absence of a superior proposal. The Boards of GBM and WCB consider that the combination of the two companies will provide significant strategic and financial benefits to both sets of shareholders. "The complementary nature of the two companies' projects creates a strong platform for both companies' shareholders to benefit from a substantial value uplift from a significant increase in combined gold resources at Misima and Mt Coolon, and the ability to step up exploration within the group's extensive landholding. GBM's board believes that this transaction is in the best interest of GBM and unanimously recommends it to our shareholders, in the absence of a superior proposal. We also look forward to welcoming WCB President and CEO, Mr Cameron Switzer to the Board of the combined entity as an Executive Director, where his strong, long-term understanding of the Misima Gold Mine will prove invaluable." "The Board of WCB considers this merger to be an outstanding opportunity for existing shareholders. The attractiveness regarding the focus on near term production and cash flow from Mt Coolon underpins the group moving forward. The significant exploration upside identified at both the Misima and Mt Coolon project has the potential to ensure that the merged company has an exciting future with significant growth optionality moving forward". The Merger is subject to both Australian and Canadian regulatory approvals. In Canada the Arrangement Agreement is a statutory process under Division 5 of Part 9 of the Business Corporations Act (British Columbia) which will involve WCB shareholder and Canadian court approval. In Australia shareholder approval will be required for the Merger transaction. The HOA includes a commitment by WCB not to solicit alternative transactions to the Merger. Each of the directors of WCB have agreed to vote in favour of the Merger, in the absence of a superior proposal. Major shareholder of WCB, Sandfire Resources NL (holds 38%) has also indicated their support of the Merger in the absence of a superior proposal. On satisfying the condition precedents under the HOA and the formal Arrangement Agreement being executed, a full copy of the Arrangement Agreement will be filed in accordance with applicable securities laws and will be found on the WCB profile on SEDAR at www.sedar.com. Following completion of the Merger, Mr Cameron Switzer (the current WCB President and CEO) will join the merged entity as Executive Director - Misima Gold Project. Cameron Switzer was previously one of the founding directors' of GBM. The non-executive directors of WCB will retire on completion of the Merger. Once GBM has secured the required debt funding of AUD$8.5million, then WCB and GBM will execute the Arrangement Agreement. In addition to other customary conditions and regulatory approvals, the Arrangement Agreement is conditional upon GBM obtaining all necessary shareholder and regulatory approvals. The Merger is subject to the approval of both GBM and WCB shareholders. Pursuant to the Business Corporations Act (British Columbia), the Merger will require the approval of 66 2/35 of the votes cast by WCB shareholders. A special shareholder meeting for each company to vote on the Merger is likely to be held in May 2017 with the completion of the Merger expected in June 2017, at which time WCB would be delisted from the TSX-V. Further information regarding the Merger for holders of GBM ordinary shares will be contained in a notice of meeting that GBM will prepare and mail to its shareholders in connection with the meeting of GBM shareholders to be held to consider matters in connection with the Merger. In due course, WCB's shareholders will receive a comprehensive Information Circular that will contain full details of the proposed Merger, including the basis for the WCB board's recommendation that WCB shareholders approve the proposed Merger. Upon signing the HOA GBM will advance AUD$150,000 to WCB. If the conditions precedent to the HOA are not satisfied before 31 March 2017 then the HOA will terminate and shall be deemed to be at an end. If the HOA is terminated then the Parties have agreed that the AUD$150,000 will be converted into fully paid common shares of WCB at a conversion price of CAD0.05, subject to approval of the TSX-V. The Company was incorporated under the Business Corporations Act (British Columbia) on March 2, 2007 and was listed on the TSX-V and called to trade on October 10, 2007. The Company completed its Qualifying Transaction under the policies of the TSX Venture Exchange on April 8, 2010. As a result, the Company is a Tier 2 mining issuer on the TSX-V. Misima is a large bulk mineable disseminated gold (Au) and silver (Ag) deposit spatially related to a potentially significant porphyry copper (Cu) gold (Au) system at depth. Placer Pacific (owned by Placer Dome) commissioned the Misima Gold Mine in 1988 and was operated by Misima Mines Pty Ltd (MMPL), a subsidiary of Placer to 2004. The mine produced 3.7 Moz Au and 22.2 Moz Ag during this 14 year period. Historic production prior to this period was estimated at 240,000 ounces. WCB signed a farm-in JV Agreement with Pan Pacific to test for Cu and explore Au on Misima in 2011. PPC is a global mining, smelting, refining and international copper producer. Under the terms and conditions of the Agreement, WCB can obtain up to a 70% interest in EL1747 Misima and currently has earned 49%. Systematic exploration completed by WCB resulted in the completion of a series of deep drill holes up to 800m in depth targeting the porphyry Cu Au mineralisation whist also understanding the upside and potential of the superimposed Au Ag base metal mineralisation. An initial inferred resource was completed in 2013 and further upgraded to inferred / indicated in 2015 over the Umuna region where the majority of the historic mining activity has been completed. All resources are quoted within optimised pit shells. Key Strategy is to move to a 70% interest in the Misima Project by 2018 and complete mining feasibility studies by end calendar year 2019. The disclosure of the Indicated and Inferred Mineral Resource estimate has been reviewed and approved by Mr Peter Stoker an Honorary Fellow of the Australasian Institute of Mining and Metallurgy and a Chartered Professional, and full time employee of AMC Consultants Pty Ltd who is a "qualified person" as defined by the National Instrument 43-101. GBM Resources Ltd (ASX:GBZ) is an Australian resource company that listed on the ASX in 2007, headquartered in Perth WA, with exploration operations in Victoria and Queensland and holds equity in a Malaysia gold company listed on the Singapore exchange. The Company's primary focus is the development of key gold and copper-gold assets in Australia. GBM is on track to become a gold producer in 2017 with the Company's flagship Mount Coolon Gold Project. GBM tenements cover an area greater than 2,600 square kilometres in eight major project areas in Queensland and Victoria. The Mount Coolon Gold Project is located within Queensland's Drummond Basin, a prolific Gold Province which has an identified gold endowment in excess of 7.5million ounces. Deposits already identified and exploited in this province include examples of high grade vein style and large tonnage stockwork epithermal gold systems. GBM's tenement package has three identified deposits with published gold resources. In addition, the project hosts a number of advanced exploration targets including; Bimurra, Conway, Verbena Sinter and South East silica Zone, each of which will be further investigated with a high probability of significantly adding to the already growing resource base. A summary of key points relating to the known deposits is provided below. For further detail the reader is referred to the GBM Annual Report 2016 and company announcements. To view the Mount Coolon Resource Table, please visit the following link: http://media3.marketwire.com/docs/Mount-Coolon-Resource-Table.jpg. Mineral Resources are calculated on information compiled by Kerrin Allwood who is a member of the Australasian Institute of Mining and Metallurgy and The Australian Institute of Geoscientists. Mr Allwood is a full time employee of Geomodeling Limited. Mr Allwood has sufficient experience which is relevant to the style of mineralisation and type of deposit under consideration and to the activity which he is undertaking to qualify as a Competent Person as defined in the 2012 Edition of the Australasian Code for Reporting of Exploration Results, Mineral Resources and Ore Reserves. Mr Allwood consents to the inclusion in the report of the matters based in his information in the form and context in which it appears. The Project assessments of these deposits are well advanced and it is planned that Koala, Glen Eva and the Eugenia heap leach will commence gold production in sequence by the end of 2017. The Company is targeting end March 2017 to commence feasibility studies on these deposits. Anchor Resources Limited - Lubuk Mandi Gold Project (Malaysia) GBM has an investment in value Singapore Stock Exchange Listed Anchor Resources Limited (Anchor). Anchor's principal asset is the Lubik Mandi Gold Project located in Malaysia. GBM's equity holding is 35 million shares in Anchor which represents 12.5% of that company's issued capital. Mount Morgan Copper Gold Project (Queensland, Australia): Consists of 11 granted leases with targets identified associated with significant geochemical anomalism. Brightlands and Milo Iron -Oxide Copper -Gold (IOCG) and REE Project (Queensland, Australia): Consists of an IOCG breccia pipe system in the Mt Isa Inlier with an inferred resource containing 97,000 tonnes of copper, 14 million pounds of U3O8 and 108,000 tonnes of TREEYO (ASX:GBZ 29th February 2012) with significant exploration upside. Malmsbury Gold Project (Victoria, Australia): Large intrusive related Gold System (IRGS) with 104,000 ounces of gold in historic inferred resources with significant exploration upside (ASX:GBZ 19th January 2009). Mr. Cameron Switzer, BSc (Hons), MAIG (3384), MAUSIMM (112798), President and Chief Executive Officer of WCB Resources, is a qualified person as defined by National Instrument 43-101. He is responsible for quality control of exploration undertaken by WCB. Mr. Switzer has reviewed and approved the technical information in this release. Neither TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release. Forward Looking Statements: This news release includes certain statements that may be deemed "forward-looking statements". All statements in this release, other than statements of historical facts, including, without limitation, statements potential mineralization, the estimation of mineral resources, the realization of mineral resource estimates, interpretation of prior exploration and potential exploration results, the timing and success of exploration activities generally, the timing and results of future resource estimates, permitting time lines, metal prices and currency exchange rates, availability of capital, government regulation of exploration operations, environmental risks, reclamation, title, and future plans and objectives of the company are forward-looking statements that involve various risks and uncertainties. Although the Company believes the expectations expressed in such forward-looking statements are based on reasonable assumptions, such statements are not guarantees of future performance and actual results or developments may differ materially from those in the forward-looking statements. Forward-looking statements are based on a number of material factors and assumptions. Factors that could cause actual results to differ materially from those in forward-looking statements include failure to obtain necessary approvals in respect of a transaction, unsuccessful exploration results, changes in project parameters as plans continue to be refined, results of future resource estimates, future metal prices, availability of capital and financing on acceptable terms, general economic, market or business conditions, risks associated with operating in foreign jurisdictions, uninsured risks, regulatory changes, defects in title, availability of personnel, materials and equipment on a timely basis, accidents or equipment breakdowns, delays in receiving government approvals, unanticipated environmental impacts on operations and costs to remedy same, and other exploration or other risks detailed herein and from time to time in the filings made by the company with securities regulators. Mineral exploration and development of mines is an inherently risky business. Accordingly the actual events may differ materially from those projected in the forward-looking statements. For more information on the Company, investors should review their annual filings that are available at www.sedar.com. Neither TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release. The Company relies on litigation protection for "forward looking" statements. Actual results could differ materially from those described in the news release as a result of numerous factors, some of which are outside the control of the Company.


PubMed | STAB VIDA Investigacao e Servicos em Ciencias Biologicas, IRGS, University of Sannio, CNR Institute Experimental Endocrinology and Oncology Gaetano Salvatore and University of Naples Federico II
Type: | Journal: Cell death & disease | Year: 2015

Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 10(-9)M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-B pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-B activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions.


PubMed | Helmholtz Center Munich, IRGS, Sahlgrenska University Hospital, Columbia University and 2 more.
Type: Journal Article | Journal: Development (Cambridge, England) | Year: 2015

Current understanding infers a neural crest origin of thyroid C cells, the major source of calcitonin in mammals and ancestors to neuroendocrine thyroid tumors. The concept is primarily based on investigations in quail-chick chimeras involving fate mapping of neural crest cells to the ultimobranchial glands that regulate Ca(2+) homeostasis in birds, reptiles, amphibians and fishes, but whether mammalian C cell development involves a homologous ontogenetic trajectory has not been experimentally verified. With lineage tracing, we now provide direct evidence that Sox17+ anterior endoderm is the only source of differentiated C cells and their progenitors in mice. Like many gut endoderm derivatives, embryonic C cells were found to coexpress pioneer factors forkhead box (Fox) a1 and Foxa2 before neuroendocrine differentiation takes place. In the ultimobranchial body epithelium emerging from pharyngeal pouch endoderm in early organogenesis, differential Foxa1/Foxa2 expression distinguished two spatially separated pools of C cell precursors with different growth properties. A similar expression pattern was recapitulated in medullary thyroid carcinoma cells in vivo, consistent with a growth-promoting role of Foxa1. In contrast to embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment downregulated Foxa2, foregoing epithelial-to-mesenchymal transition designated by loss of E-cadherin; both Foxa2 and E-cadherin were re-expressed at metastatic sites. These findings revise mammalian C cell ontogeny, expand the neuroendocrine repertoire of endoderm and redefine the boundaries of neural crest diversification. The data further underpin distinct functions of Foxa1 and Foxa2 in both embryonic and tumor development.


PubMed | IRGS, University of Verona, University of Naples Federico II, CNR Institute Experimental Endocrinology and Oncology Gaetano Salvatore and 2 more.
Type: | Journal: Scientific reports | Year: 2016

In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.


PubMed | The Second University of Naples, IRGS, University of Trieste, University of Sannio and University of Naples Federico II
Type: Journal Article | Journal: PloS one | Year: 2016

Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity.


Di Gennaro A.,IRGS | Spadaro O.,IRGS | Baratta M.G.,University of Naples Federico II | De Felice M.,IRGS | And 3 more authors.
Thyroid | Year: 2013

Background: Organogenesis of the thyroid gland requires the Pax8 protein. Absence or reduction of Pax8 results in congenital hypothyroidism in animal models and humans, respectively. This study aims at elucidating the regulatory mechanism leading to the expression of Pax8 in thyroid cells. Methods: The murine Pax8 gene promoter was functionally dissected by mutagenesis and transfection in the thyroid cell line FRTL-5. Nuclear factors important for thyroid-specific gene expression were identified by DNA-binding assays. Results: We show that Pax8 binds to and controls the expression of its own promoter. Furthermore, we identify a novel, thyroid-specific, DNA-binding activity (denominated nTTF [for novel Thyroid Transcription Factor]) that recognizes a specific region of the Pax8 promoter. Conclusions: The Pax8 promoter appears to be autoregulated, a feature that might be responsible for the haploinsufficiency displayed by this gene. © Copyright 2013, Mary Ann Liebert, Inc. 2013.


Silberschmidt D.,Stazione Zoologica Anton Dohrn | Rodriguez-Mallon A.,Stazione Zoologica Anton Dohrn | Mithboakar P.,IRGS | Cal G.,University of Naples Federico II | And 10 more authors.
BMC Developmental Biology | Year: 2011

Background: The transcription factor Nkx2-1 (also known as TTF-1, Titf1 or T/EBP) contains two apparently redundant activation domains and is post-translationally modified by phosphorylation. We have generated mouse mutant strains to assess the roles of the two activation domains and of phosphorylation in mouse development and differentiation. Results: Mouse strains expressing variants of the transcription factor Nkx2-1 deleted of either activation domain have been constructed. Phenotypic analysis shows for each mutant a distinct set of defects demonstrating that distinct portions of the protein endow diverse developmental functions of Nkx2-1. Furthermore, a mouse strain expressing a Nkx2-1 protein mutated in the phosphorylation sites shows a thyroid gland with deranged follicular organization and gene expression profile demonstrating the functional role of phosphorylation in Nkx2-1. Conclusions: The pleiotropic functions of Nkx2-1 are not all due to the protein as a whole since some of them can be assigned to separate domains of the protein or to specific post-translational modifications. These results have implication for the evolutionary role of mutations in transcription factors. © 2011 Silberschmidt et al; licensee BioMed Central Ltd.


Porreca I.,IRGS | Porreca I.,Stazione Zoologica Anton Dohrn | Porreca I.,University of Naples Federico II | De Felice E.,Stazione Zoologica Anton Dohrn | And 5 more authors.
Developmental Biology | Year: 2012

Regulated cell death, defined in morphological terms as apoptosis, is crucial for organ morphogenesis. While differentiation of the thyroid gland has been extensively studied, nothing is yet known about the survival mechanisms involved in the development of this endocrine gland. Using the zebrafish model system, we aim to understand whether genes belonging to the Bcl-2 family that control apoptosis are implicated in regulation of cell survival during thyroid development. Evidence of strong Bcl-2 gene expression in mouse thyroid precursors prompted us to investigate the functions played by its zebrafish homologs during thyroid development. We show that the bcl2-like (bcl2l) gene is expressed in the zebrafish thyroid primordium. Morpholino-mediated knockdown and mutant analyses revealed that bcl2l is crucial for thyroid cell survival and that this function is tightly modulated by the transcription factors pax2a, nk2.1a and hhex. Also, the bcl2l gene appears to control a caspase-3-dependent apoptotic mechanism during thyroid development. Thyroid precursor cells require an actively maintained survival mechanism to properly proceed through development. The bcl2l gene operates in the inhibition of cell death under direct regulation of a thyroid specific set of transcription factors. This is the first demonstration of an active mechanism to ensure survival of the thyroid primordium during morphogenesis. © 2012 Elsevier Inc.


Cephalopod mollusks possess a number of anatomical traits that often parallel vertebrates in morphological complexity, including a centralized nervous system with sophisticated cognitive functionality. Very little is known about the genetic mechanisms underlying patterning of the cephalopod embryo to arrive at this anatomical structure. Homeodomain (HD) genes are transcription factors that regulate transcription of downstream genes through DNA binding, and as such are integral parts of gene regulatory networks controlling the specification and patterning of body parts across lineages. We have used a degenerate primer strategy to isolate homeobox genes active during late-organogenesis from the European cuttlefish Sepia officinalis. With this approach we have isolated fourteen HD gene fragments and examine the expression profiles of five of these genes during late stage (E24-28) embryonic development (Sof-Gbx, Sof-Hox3, Sof-Arx, Sof-Lhx3/4, Sof-Vsx). All five genes are expressed within the developing central nervous system in spatially restricted and largely nonoverlapping domains. Our data provide a first glimpse into the diversity of HD genes in one of the largest, yet least studied, metazoan clades and illustrate how HD gene expression patterns reflect the functional partitioning of the cephalopod brain. © 2014 Focareta et al.

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