A. Umran Dogan

Germline BAP1 mutations predispose to malignant mesothelioma

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.

A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes

In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government.

BASELINE STUDIES OF THE CLAY MINERALS SOCIETY SOURCE CLAYS: SPECIFIC SURFACE AREA BY THE BRUNAUER EMMETT TELLER (BET) METHOD

Specific surface area measurements of The Clay Minerals Society source clays were made by the Brunauer, Emmett and Teller (BET) method of adsorption of nitrogen gas. Two replicate measurements of specific surface area were performed for each source clay. All pair values were within 3%, which is very good agreement for this type of measurement.

Erionite exposure in North Dakota and Turkish villages with mesothelioma

Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted.

Black Sea-Marmara Sea Quaternary connections: new data from the Bosphorus, Istanbul, Turkey

Abstract Previous studies concluded that the Bosphorus Strait was formed during the Quaternary by fluvial incision of a valley between the Black Sea, to the north, and the Marmara Sea in the south. Hitherto, however, few details of the evolution of this connection have been elucidated from the sediments deposited within the Bosphorus itself. We report here details of sedimentological and palaeontological evidence relating to this history, obtained from five boreholes drilled into the unconsolidated sediment fill in the north-central sector of the Bosphorus, together with nearby geophysical profiles. The Quaternary fill of this part of the Bosphorus comprises two major facies associations. Yellow arkosic sands dominate the lower Facies Association A: these are assigned a Middle to Late Pleistocene age and the contained faunas have a lagoonal to lacustrine character and a Black Sea provenance (Paratethyan affinities). The abruptly succeeding units of Facies Association B comprise fining and coarsening upwards units of coarse to fine shelly and clayey sands that alternate with shell-bearing green clays. These sediments were formed in a range of marine and coastal settings and biostratigraphic evidence and absolute dating demonstrate the Mid–Late Holocene age of this upper unit. Initially brackish faunal assemblages in this upper unit show an upward increase in marine and Mediterranean affinities. Integrating these new data with previously published observations from coeval deposits in the southern Bosphorus and Izmit Bay (NE Marmara Sea) we conclude that during the Late Pleistocene and Early Holocene a topographic barrier existed in the south-central sector of the Bosphorus, on both sides of which estuarine and lagoonal sediments accumulated, with distinctive Black Sea and Mediterranean faunas. During a significant rise in sea level, between 7000 and 5300 years ago, this barrier was finally submerged, permitting interchange of marine waters between the Mediterranean and the Black Sea and creating the present oceanographic situation. This evolution conflicts with the cataclysmic role of the Bosphorus in the early Holocene as postulated in the ‘Catastrophic Flood’ hypothesis of Ryan et al. [Mar. Geol. 138 (1997) 119–126; Annu. Rev. Earth Planet. Sci. 31 (2003) 525–554]. It also contrasts with the history recorded from the Gulf of Izmit, where intermittent connection between these two bodies of water throughout much of the Quaternary is evident.

Consensus Report of the 2015 Weinman International Conference on Mesothelioma

ABSTRACT On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the groups efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos‐like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA‐exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin‐3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

Crystal structure and iron topochemistry of erionite-K from Rome, Oregon, U.S.A.

Abstract A complete crystal-chemical characterization of erionite-K from Rome, Oregon, was obtained by combining field emission scanning electron microscopy, laboratory parallel-beam transmission powder diffraction, and 57Fe Mössbauer spectroscopy. Rietveld refinement results evidenced that the most striking difference in comparison with the structure of erionite-Ca is significant K at a K2 site (½, 0, 0), which is empty in erionite-Ca. In addition, site Ca1 shows low occupancy and Ca3 is vacant. The oxidation and coordination state of Fe, whose occurrence was revealed by chemical analysis, have been clarified by exploiting room- and low-temperature 57Fe Mössbauer spectroscopy. The majority of Fe (95%) was attributed to Fe3+-bearing, superparamagnetic, oxide-like nanoparticles with dimensions between 1 and 9 nm, and the remaining 5% was attributed to hematite particles with size ≥10 nm, both located on the crystal surface.

Re-evaluation and re-classification of erionite series minerals.

Governments and industries have introduced regulatory measures requiring safety controls to limit asbestos exposure of the general public and asbestos workers. Although erionite is a more potent health hazard mineral than asbestos, it has received far less attention. Precise definition of erionite, types of these fibrous minerals, and most importantly, characterization requirements still raise questions and often lead to arguments and even legal disputes. Many bulk erionite samples used in animal and cell experiments for carcinogenicity are not mineralogically pure. To test this hypothesis, we characterized two erionite standards from Rome, Oregon, and Pine Valley, Nevada, USA. These standards were characterized quantitatively using modern analytical techniques, and one of them, the erionite standard from Rome, Oregon, passed the required tests for positive identification, but the other, the erionite standard from Pine Valley, Nevada, did not. Furthermore, we observed ambiguous definitions, incorrect identifications, and inaccurate reporting of clinical investigations. To address this problem, we established characterization guidelines for positive identification of erionite using a modified balance error formula, and we re-evaluated and re-classified published erionite data from the literature as erionite-Ca, erionite-Na, and erionite-K. If data did not pass either the E% or Mg-content test, then we propose that reference to them in the literature be disregarded. Erionite requires special attention from the mineralogical community to help establish its true carcinogenetic properties. We believe that the characterization guidelines established in this paper will contribute to setting up rules and regulations for evaluation of erionite by regulatory agencies.

Morpho-chemical characterization and surface properties of carcinogenic zeolite fibers.

Erionite belonging to the zeolite family is a human health-hazard, since it was demonstrated to be carcinogenic. Conversely, offretite family zeolites were suspected carcinogenic. Mineralogical, morphological, chemical, and surface characterizations were performed on two erionites (GF1, MD8) and one offretite (BV12) fibrous samples and, for comparison, one scolecite (SC1) sample. The specific surface area analysis indicated a larger availability of surface sites for the adsorption onto GF1, while SC1 shows the lowest one and the presence of large pores in the poorly fibrous zeolite aggregates. Selected spin probes revealed a high adsorption capacity of GF1 compared to the other zeolites, but the polar/charged interacting sites were well distributed, intercalated by less polar sites (Si-O-Si). MD8 surface is less homogeneous and the polar/charged sites are more interacting and closer to each other compared to GF1. The interacting ability of BV12 surface is much lower than that found for GF1 and MD8 and the probes are trapped in small pores into the fibrous aggregates. In comparison with the other zeolites, the non-carcinogenic SC1 shows a poor interacting ability and a lower surface polarity. These results helped to clarify the chemical properties and the surface interacting ability of these zeolite fibers which may be related to their carcinogenicity.

Mesothelioma in Cappadocian Villages

Volcanic tuffs in the Cappadocian region of Turkey have weathered into a dramatic landscape. The soft rock of which they are composed is easily quarried and excavated and has long provided both caves and building material for homes. Studying the complex geology of Cappadocia has shown the presence of zeolitic rocks in some areas which contain respirable fibres of the zeolite group mineral erionite. In 1975, a high incidence of malignant pleural mesothelioma (MPM) was observed in several villages of this region. MPM is a quickly progressing lethal disease with very poor prognosis. Clinical and experimental studies suggested that the disease was linked to the erionite mineral. Extensive studies have since confirmed that it is the erionite, rather than any of the asbestos types known to cause MPM, that is the major cause of this epidemic in the study area. In addition to the three erionite villages of Cappadocia (Tuzköy, Karain and Sar| h| d| r), the list has now been extended to include the villages of Karacaoren, Boyali, Cokek and Yesiloz. The high potential of erionite to induce MPM has now received further confirmation from both epidemiological and other recent experimental work.