Robyn Hannigan

Testicular Cancer Survivorship: Research Strategies and Recommendations

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.

Aqueous toxicity and food chain transfer of Quantum DOTs in freshwater algae and Ceriodaphnia dubia.

Innovative research and diagnostic techniques for biological testing have advanced during recent years because of the development of semiconductor nanocrystals. Although these commercially available, fluorescent nanocrystals have a protective organic coating, the inner core contains cadmium and selenium. Because these metals have the potential for detrimental environmental effects, concerns have been raised over our lack of understanding about the environmental fate of these products. U.S. Environmental Protection Agency test protocol and fluorescence microscopy were used to determine the fate and effect of quantum dots (QDs; Qdot 545 ITK Carboxyl Quantum Dots [Fisher Scientific, Fisher part Q21391MP; Invitrogen Molecular Probes, Eugene, OR, USA]) using standard aquatic test organisms. No lethality was measured following 48-h exposure of Ceriodaphnia dubia to QD suspensions as high as 110 ppb, but the 96-h median lethal concentration to Pseudokirchneriella subcapitata was measured at 37.1 ppb. Transfer of QDs from dosed algae to C. dubia was verified with fluorescence microscopy. These results indicate that coatings present on nanocrystals provide protection from metal toxicity during laboratory exposures but that the transfer of core metals from intact nanocrystals may occur at levels well above toxic threshold values, indicating the potential exposure of higher trophic levels. Studies regarding the fate and effects of nanoparticles can be incorporated into models for predictive toxicology of these emerging contaminants.

Can otolith chemistry be used for identifying essential seagrass habitats for juvenile spotted seatrout, Cynoscion nebulosus, in Chesapeake Bay?

We investigated the variability of otolith chemistry in juvenile spotted seatrout from Chesapeake Bay seagrass habitats in 1998 and 2001, to assess whether otolith elemental and isotopic composition could be used to identify the most essential seagrass habitats for those juvenile fish. Otolith chemistry (Ca, Mn, Sr, Ba, and La; δ13C, δ18O) of juvenile fish collected in the five major seagrass habitats (Potomac, Rappahannock, York, Island, and Pocomoke Sound) showed significant variability within and between years. Although the ability of trace elements to allocate individual fish may vary between years, in combination with stable isotopes, they achieve high classification accuracy averaging 80–82% in the Pocomoke Sound and the Island, and 95–100% in the York and the Potomac habitats. The trace elements (Mn, Ba, and La) provided the best discrimination in 2001, a year of lower freshwater discharge than 1998. This is the first application of a rare earth element measured in otoliths (La) to discriminate habitats, and identify seagrass habitats for juvenile spotted seatrout at spatial scales of 15 km. Such fine spatial scale discrimination of habitats has not been previously achieved in estuaries and will distinguish fish born in individual seagrass beds in the Bay.

A model for continental crust genesis by arc accretion: rare earth element evidence from the Irish Caledonides

Abstract The formation of continental crust is a complex problem with a paradox at its center: continental material is believed to form by arc magmatism, a model that does not reconcile the bulk mafic and light rare earth element (LREE)-depleted composition of intra-oceanic arcs with the andesitic, LREE-enriched composition of continents. We present evidence supporting an arc origin for continental crust by demonstrating significant changes in magmatic chemistry during arc–continent collision. We use as an example the Connemara region of the western Irish Caledonides, where metamorphism and orogenesis of Dalradian sedimentary sequences record the collision of the oceanic Lough Nafooey Arc with the passive margin of Laurentia at ∼475 Ma (Arenig). This arc was mafic and LREE-depleted during its oceanic activity. During collision, rhyolites more LREE-enriched than the surrounding continental crust were erupted, while the mid-crust was intruded by similarly LREE-enriched gabbro and diorite. Crystal fractionation caused LREE enrichment to exceed that expected by assimilation of continental crust alone. We propose that subsequent loss of the corresponding lower crustal cumulates into the mantle removed this LREE-depleted material from the net crust added to the continent. The combined processes of crystal fractionation and lower crustal loss during arc–continent collision drive the average bulk arc composition toward that of average continental crust.

Laurentian crustal recycling in the Ordovician Grampian Orogeny: Nd isotopic evidence from western Ireland

Because magmatism associated with subduction is thought to be the principal source for continental crust generation, assessing the relative contribution of pre-existing (subducted and assimilated) continental material to arc magmatism in accreted arcs is important to understanding the origin of continental crust. We present a detailed Nd isotopic stratigraphy for volcanic and volcaniclastic formations from the South Mayo Trough, an accreted oceanic arc exposed in the western Irish Caledonides. These units span an arc-continent collision event, the Grampian (Taconic) Orogeny, in which an intra-oceanic island arc was accreted onto the passive continental margin of Laurentia starting at ∼ 475 Ma (Arenig). The stratigraphy corresponding to pre-, syn- and post- collisional volcanism reveals a progression of eNd(t) from strongly positive values, consistent with melt derivation almost exclusively from oceanic mantle beneath the arc, to strongly negative values, indicating incorporation of continental material into the melt. Using eNd(t) values of meta-sediments that represent the Laurentian passive margin and accretionary prism, we are able to quantify the relative proportions of continent-derived melt at various stages of arc formation and accretion. Mass balance calculations show that mantle-derived magmatism contributes substantially to melt production during all stages of arc-continent collision, never accounting for less than 21 % of the total. This implies that a significant addition of new, rather than recycled, continental crust can accompany arc-continent collision and continental arc magmatism.

Stock Identification of Walleye via Otolith Chemistry in the Eleven Point River, Arkansas

Abstract Otolith chemistry was used to identify two hatchery stocks (Missouri State Hatchery and Arkansas Federal Hatchery) and a possible wild stock of walleye Sander vitreus in the Eleven Point River in northeastern Arkansas. Previous population estimates by the Arkansas Game and Fish Commission using traditional tag-and-release techniques failed to identify the relative survival of these stocks or their spatial and temporal persistence. Using chemical analysis of otoliths combined with a priori knowledge of the hatchery source, we identified otolith chemical signatures unique to each stock. We collected 51 walleyes that bore the physical tag of a known hatchery, along with 46 nontagged walleyes. The efficacy of otolith chemistry in classifying walleyes to known stocks was assessed by analyzing unknowns via discriminant function analysis. Fish were classified to their respective stocks based on otolith chemistry, and 92% were assigned to known stocks. Fishery managers can assess the persistence of indiv...

Otolith Chemistry Discriminates among Hatchery-Reared and Tributary-Spawned Salmonines in a Tailwater System

Abstract The Little Red River tailwater (LRRT) system in Arkansas supports a naturally reproducing population of brown trout Salmo trutta and an economically valuable fishery. Natural reproduction by stocked brook trout Salvelinus fontinalis and rainbow trout Oncorhynchus mykiss is unknown but assumed to be negligible. An artificial tributary to the LRRT was constructed to provide a spawning and nursery refuge for stocked trouts, and shortly thereafter we observed spawning adults and emergent fry in the tributary. As a first step in determining the relative contributions of hatchery- and tributary-produced brook and rainbow trouts recruiting to the LRRT fishery, we distinguished hatchery-reared fry from tributary-spawned fry via otolith chemistry. We used laser ablation inductively coupled plasma mass spectrometry to measure the abundances of cations in otoliths. Significant differences between hatchery and wild stocks were found for six element : Ca ratios. A five-variable (Mg, Mn, Zn, Sr, and Ba) discri...

Zinc regulates the ability of Cdc25C to activate MPF/cdk1

Zn2+ is an essential micronutrient for the growth and development of multicellular organisms, as Zn2+ deficiencies lead to growth retardation and congenital malformations (Vallee, BL, Falchuk, KH. 1993. Physiol Rev., 73:79–118). At the cellular level Zn2+ depravation results in proliferation defects in many cell types (Vallee, BL, Falchuk, KH. 1993. Physiol Rev., 73:79–118), however the molecular pathways involved remain poorly defined. Here we show that the transition metal chelator TPEN (N,N,N′,N′‐tetrakis(2‐pyridylmethyl) ethylene diamine) blocks the G2/M transition of the meiotic cell cycle by inhibiting Cdc25C‐cdk1 activation. ICP‐MS analyses reveal that Cdc25C is a Zn2+‐binding metalloprotein, and that TPEN effectively strips Zn2+ away from the enzyme. Interestingly, although apo‐Cdc25C (Zn2+‐deficient) remains fully catalytically active, it is compromised in its ability to dephosphorylate and activate MPF/cdk1. Thus, Zn2+ is an important regulator of Cdc25C function in vivo. Because of the conserved essential role of the Cdc25C‐cdk1 module in the eukaryotic cell cycle, these studies provide fundamental insights into cell cycle regulation. J. Cell. Physiol. 213: 98–104, 2007.

Effects of acid-volatile sulfide on metal bioavailability and toxicity to midge (Chironomus tentans) larvae in black shale sediments.

Metal bioavailability and toxicity to aquatic organisms are greatly affected by variables such as pH, hardness, organic matter, and sediment acid-volatile sulfide (AVS). Sediment AVS, which reduces metal bioavailability and toxicity by binding and immobilizing metals as insoluble sulfides, has been studied intensely in recent years. Few studies, however, have determined the spatial variability of AVS and its interaction with simultaneously extracted metals (SEM) in sediments containing elevated concentrations of metals resulting from natural geochemical processes, such as weathering of black shales. We collected four sediment samples from each of four headwater bedrock streams in northcentral Arkansa (USA; three black shale-draining streams and one limestone-draining stream). We conducted 10-d acute whole-sediment toxicity tests using the midge Chironomus tentans and performed analyses for AVS, total metals, SEMs, and organic carbon. Most of the sediments from shale-draining streams had similar total metal and SEM concentrations but considerable differences in organic carbon and AVS. Zinc was the leading contributor to the SEM molar sum, averaging between 68 and 74%, whereas lead and cadmium contributed less than 3%. The AVS concentration was very low in all but two samples from one of the shale streams, and the sum of the SEM concentrations was in molar excess of AVS for all shale stream sediments. No significant differences in mean AVS concentrations between sediments collected from shale-draining or limestone-draining sites were noted (p > 0.05). Midge survival and growth in black shale-derived sediments were significantly less (p < 0.001) than that of limestone-derived sediments. On the whole, either SEM alone or SEM-AVS explained the total variation in midge survival and growth about equally well. However, survival and growth were significantly greater (p < 0.05) in the two sediment samples that contained measurable AVS compared with the two sediments from the same stream that contained negligible AVS.

Variations in otolith elemental compositions of two clupeid species, Stolothrissa tanganicae and Limnothrissa miodon in Lake Tanganyika

Lake Tanganyika in East Africa has two primary basins (Northern and Southern) and borders four sovereign countries. Effective management of the fisheries of this lake requires sound biological understanding of the various fish stocks. The feasibility of fish stock identification within different basins and sub-basins of this lake was attempted through otolith elemental composition analysis. Element ratio signatures of whole sagittal otoliths (Mg/Ca, Sr/Ca and Ba/Ca) of two commercially important clupeid species (Stolothrissa tanganicae, n=18; Limnothrissa miodon, n=32) were used to classify individual fish to their resident basins. No element ratios in L. miodon otoliths were significantly different between Southern sub-basins, yet Ba/Ca and Sr/Ca ratios were significantly different for individuals from the Northern and Southern basins. Sr/Ca and Ba/Ca ratios were also significantly different between otoliths of sympatric L. miodon and S. tanganicae in the Northern Bujumbura Sub-basin. Species differences may be due to ontogenetic and environmental variables. Sr/Ca and Ba/Ca element concentration ratios contributed greatly to basin classification of individual fish. Canonical discriminant analysis correctly classified 91% of L. miodon and 83.3% of S. tanganicae to the Bujumbura sub-basin, compared to 59.9% of L. miodon collected from the Southern Basin that were correctly classified to this basin. These classification rates are similar to those found for estuarine species. Our results of a limited study suggest that otolith element compositions can be used as a natural tag to identify fish stocks in Lake Tanganyika and assist in the implementation of a multi-national fisheries best management plan.