AN EMPIRICAL ESTIMATION OF MEDICAL AND NON-MEDICAL INPUTS IN THE PRODUCTION OF CARDIO-RESPIRATORY PHYSICAL HEALTH STATUS

The purpose of this study was to examine, in the context of an economic model of health production, the relationship between inputs (health influencing activities) and fitness.^ Primary data were collected from 204 employees of a large insurance company at the time of their enrollment in an industrially-based health promotion program. The inputs of production included medical care use, exercise, smoking, drinking, eating, coronary disease history, and obesity. The variables of age, gender and education known to affect the production process were also examined. Two estimates of fitness were used; self-report and a physiologic estimate based on exercise treadmill performance. Ordinary least squares and two-stage least squares regression analyses were used to estimate the fitness production functions.^ In the production of self-reported fitness status the coefficients for the exercise, smoking, eating, and drinking production inputs, and the control variable of gender were statistically significant and possessed theoretically correct signs. In the production of physiologic fitness exercise, smoking and gender were statistically significant. Exercise and gender were theoretically consistent while smoking was not. Results are compared with previous analyses of health production. ^

Bayesian adaptive designs for drug combinations in early phase clinical trials

Treating patients with combined agents is a growing trend in cancer clinical trials. Evaluating the synergism of multiple drugs is often the primary motivation for such drug-combination studies. Focusing on the drug combination study in the early phase clinical trials, our research is composed of three parts: (1) We conduct a comprehensive comparison of four dose-finding designs in the two-dimensional toxicity probability space and propose using the Bayesian model averaging method to overcome the arbitrariness of the model specification and enhance the robustness of the design; (2) Motivated by a recent drug-combination trial at MD Anderson Cancer Center with a continuous-dose standard of care agent and a discrete-dose investigational agent, we propose a two-stage Bayesian adaptive dose-finding design based on an extended continual reassessment method; (3) By combining phase I and phase II clinical trials, we propose an extension of a single agent dose-finding design. We model the time-to-event toxicity and efficacy to direct dose finding in two-dimensional drug-combination studies. We conduct extensive simulation studies to examine the operating characteristics of the aforementioned designs and demonstrate the designs' good performances in various practical scenarios.^

Genetic Predictors of Clinical Outcomes in Non-Small Cell Lung Cancer Patients

Lung cancer is the leading cause of cancer-related mortality in the US. Emerging evidence has shown that host genetic factors can interact with environmental exposures to influence patient susceptibility to the diseases as well as clinical outcomes, such as survival and recurrence. We aimed to identify genetic prognostic markers for non-small cell lung cancer (NSCLC), a major (85%) subtype of lung cancer, and also in other subgroups. With the fast evolution of genotyping technology, genetic association studies have went through candidate gene approach, to pathway-based approach, to the genome wide association study (GWAS). Even in the era of GWAS, pathway-based approach has its own advantages on studying cancer clinical outcomes: it is cost-effective, requiring a smaller sample size than GWAS easier to identify a validation population and explore gene-gene interactions. In the current study, we adopted pathway-based approach focusing on two critical pathways - miRNA and inflammation pathways. MicroRNAs (miRNA) post-transcriptionally regulate around 30% of human genes. Polymorphisms within miRNA processing pathways and binding sites may influence patients’ prognosis through altered gene regulation. Inflammation plays an important role in cancer initiation and progression, and also has shown to impact patients’ clinical outcomes. We first evaluated 240 single nucleotide polymorphisms (SNPs) in miRNA biogenesis genes and predicted binding sites in NSCLC patients to determine associations with clinical outcomes in early-stage (stage I and II) and late-stage (stage III and IV) lung cancer patients, respectively. First, in 535 early-stage patients, after correcting multiple comparisons, FZD4:rs713065 (hazard ratio [HR]:0.46, 95% confidence interval [CI]:0.32-0.65) showed a significant inverse association with survival in early stage surgery-only patients. SP1:rs17695156 (HR:2.22, 95% CI:1.44-3.41) and DROSHA:rs6886834 (HR:6.38, 95% CI:2.49-16.31) conferred increased risk of progression in the all patients and surgery-only populations, respectively. FAS:rs2234978 was significantly associated with improved survival in all patients (HR:0.59, 95% CI:0.44-0.77) and in the surgery plus chemotherapy populations (HR:0.19, 95% CI:0.07-0.46).. Functional genomics analysis demonstrated that this variant creates a miR-651 binding site resulting in altered miRNA regulation of FAS, providing biological plausibility for the observed association. We then analyzed these associations in 598 late-stage patients. After multiple comparison corrections, no SNPs remained significant in the late stage group, while the top SNP NAT1:rs15561 (HR=1.98, 96%CI=1.32-2.94) conferred a significantly increased risk of death in the chemotherapy subgroup. To test the hypothesis that genetic variants in the inflammation-related pathways may be associated with survival in NSCLC patients, we first conducted a three-stage study. In the discovery phase, we investigated a comprehensive panel of 11,930 inflammation-related SNPs in three independent lung cancer populations. A missense SNP (rs2071554) in HLA-DOB was significantly associated with poor survival in the discovery population (HR: 1.46, 95% CI: 1.02-2.09), internal validation population (HR: 1.51, 95% CI: 1.02-2.25), and external validation (HR: 1.52, 95% CI: 1.01-2.29) population. Rs2900420 in KLRK1 was significantly associated with a reduced risk for death in the discovery (HR: 0.76, 95% CI: 0.60-0.96) and internal validation (HR: 0.77, 95% CI: 0.61-0.99) populations, and the association reached borderline significance in the external validation population (HR: 0.80, 95% CI: 0.63-1.02). We also evaluated these inflammation-related SNPs in NSCLC patients in never smokers. Lung cancer in never smokers has been increasingly recognized as distinct disease from that in ever-smokers. A two-stage study was performed using a discovery population from MD Anderson (411 patients) and a validation population from Mayo Clinic (311 patients). Three SNPs (IL17RA:rs879576, BMP8A:rs698141, and STK:rs290229) that were significantly associated with survival were validated (pCD74:rs1056400 and CD38:rs10805347) were borderline significant (p=0.08) in the Mayo Clinic population. In the combined analysis, IL17RA:rs879576 resulted in a 40% reduction in the risk for death (p=4.1 × 10-5 [p=0.61, heterogeneity test]). We also validated a survival tree created in MD Anderson population in the Mayo Clinic population. In conclusion, our results provided strong evidence that genetic variations in specific pathways that examined (miRNA and inflammation pathways) influenced clinical outcomes in NSCLC patients, and with further functional studies, the novel loci have potential to be translated into clinical use.

ROLE OF STAT3 IN KERATINOCYTE STEM CELLS DURING SKIN TUMORIGENESIS

STATs play crucial roles in a wide variety of biological functions, including development, proliferation, differentiation, migration and in cancer development. In the present study, we examined the impact of Stat3 deletion or activation on behavior of keratinocytes, including keratinocyte stem cells (KSCs). Deletion of Stat3 specifically in the bulge region of the hair follicle using K15.CrePR1 X Stat3fl/fl mice led to decreased tumor development by altering survival of bulge region KSCs. To further understand the role of KSCs in skin tumorigenesis, K5.Stat3C transgenic (Tg) mice which express a constitutively active/dimerized form of Stat3 called Stat3C via the bovine keratin 5 (K5) promoter were studied. The number of CD34 and α6 integrin positive cells was significantly reduced in Tg mice as compared to non-transgenic (NTg) littermates. There was a concomitant increase in the progenitor populations (Lgr-6, Lrig-1 and Sca-1) in the Tg mice vs. the stem cell population (CD34 and Keratin15). To investigate the mechanism underlying the increase in the progenitor population at the expense of bulge region KSCs we examined if Stat3C expression was involved in inducing migration of the bulge region KSCs. There was altered β-catenin and α6-integrin expression in the hair follicles of Tg mice, which may have contributed to reduced adhesive interactions between the epithelial cells and the basement membrane facilitating migration out of the niche. To further study the effect of Stat3 on differentiation of keratinocytes we analyzed the epidermal keratinocytes in K5.Cre X Stat3fl/fl mice. There was an increase in the expression of epidermal differentiation markers in the Stat3 knockout mice. These data suggest that deletion of Stat3 in the epidermis and hair follicle induced differentiation in these cells. Preliminary studies done with the BK5.Stat3C mouse model suggests that multiple hair follicle stem/progenitor populations may be involved in skin tumor development and progression in this model of skin tumorigenesis. Overall, these data suggest that Stat3 plays an important role in differentiation as well as migration of keratinocytes and that these effects may play a role during epithelial carcinogenesis.

Targeting AKT/mTOR Signaling Pathways During Murine Skin Tumor Promotion and the Impact of Dietary Energy Balance Manipulation

The prevalence of obesity has continued to rise over the last several decades in the United States lending to overall increases in risk for chronic diseases including many types of cancer. In contrast, reduction in energy consumption via calorie restriction (CR) has been shown to be a potent inhibitor of carcinogenesis across a broad range of species and tumor types. Previous data has demonstrated differential signaling through Akt and mTOR via the IGF-1R and other growth factor receptors across the diet-induced obesity (DIO)/CR spectrum. Furthermore, mTORC1 is known to be regulated directly via nutrient availability, supporting its role in the link between epithelial carcinogenesis and diet-induced obesity. In an effort to better understand the importance of mTORC1 in the context of both positive and negative energy balance during epithelial carcinogenesis, we have employed the use of specific pharmacological inhibitors, rapamycin (mTORC1 inhibitor) and metformin (AMPK activator) to target mTORC1 or various components of this pathway during skin tumor promotion. Two-stage skin carcinogenesis studies demonstrated that mTORC1 inhibition via rapamycin, metformin or combination treatments greatly inhibited skin tumor development in normal, overweight and obese mice. Furthermore, mechanisms by which these chemopreventive agents may be exerting their anti-tumor effects were explored. In addition, the effect of these compounds on the epidermal proliferative response was analyzed and drastic decreases in epidermal hyperproliferation and hyperplasia were found. Rapamycin also inhibited dermal inflammatory cell infiltration in a dose-dependent manner. Both compounds also blocked or attenuated TPA-induced signaling through epidermal mTORC1 as well as several downstream targets. In addition, inhibition of this pathway by metformin appeared to be, at least in part, dependent on AMPK activation in the skin. Overall, the data indicate that pharmacological strategies targeting this pathway offset the tumor-enhancing effects of DIO and may serve as possible CR mimetics. They suggest that mTORC1 contributes significantly to the process of skin tumor promotion, specifically during dietary energy balance effects. Exploiting the mechanistic information underlying dietary energy balance responsive pathways will help translate decades of research into effective strategies for prevention of epithelial carcinogenesis.

Adaptive clinical trial design for targeted therapy development

The development of targeted therapy involve many challenges. Our study will address some of the key issues involved in biomarker identification and clinical trial design. In our study, we propose two biomarker selection methods, and then apply them in two different clinical trial designs for targeted therapy development. In particular, we propose a Bayesian two-step lasso procedure for biomarker selection in the proportional hazards model in Chapter 2. In the first step of this strategy, we use the Bayesian group lasso to identify the important marker groups, wherein each group contains the main effect of a single marker and its interactions with treatments. In the second step, we zoom in to select each individual marker and the interactions between markers and treatments in order to identify prognostic or predictive markers using the Bayesian adaptive lasso. In Chapter 3, we propose a Bayesian two-stage adaptive design for targeted therapy development while implementing the variable selection method given in Chapter 2. In Chapter 4, we proposed an alternate frequentist adaptive randomization strategy for situations where a large number of biomarkers need to be incorporated in the study design. We also propose a new adaptive randomization rule, which takes into account the variations associated with the point estimates of survival times. In all of our designs, we seek to identify the key markers that are either prognostic or predictive with respect to treatment. We are going to use extensive simulation to evaluate the operating characteristics of our methods.^

Instrumental variable method for the causal relationship between soluble receptor for advanced glycation end-products (sRAGE) and risk of pancreatic cancer

This thesis project is motivated by the potential problem of using observational data to draw inferences about a causal relationship in observational epidemiology research when controlled randomization is not applicable. Instrumental variable (IV) method is one of the statistical tools to overcome this problem. Mendelian randomization study uses genetic variants as IVs in genetic association study. In this thesis, the IV method, as well as standard logistic and linear regression models, is used to investigate the causal association between risk of pancreatic cancer and the circulating levels of soluble receptor for advanced glycation end-products (sRAGE). Higher levels of serum sRAGE were found to be associated with a lower risk of pancreatic cancer in a previous observational study (255 cases and 485 controls). However, such a novel association may be biased by unknown confounding factors. In a case-control study, we aimed to use the IV approach to confirm or refute this observation in a subset of study subjects for whom the genotyping data were available (178 cases and 177 controls). Two-stage IV method using generalized method of moments-structural mean models (GMM-SMM) was conducted and the relative risk (RR) was calculated. In the first stage analysis, we found that the single nucleotide polymorphism (SNP) rs2070600 of the receptor for advanced glycation end-products (AGER) gene meets all three general assumptions for a genetic IV in examining the causal association between sRAGE and risk of pancreatic cancer. The variant allele of SNP rs2070600 of the AGER gene was associated with lower levels of sRAGE, and it was neither associated with risk of pancreatic cancer, nor with the confounding factors. It was a potential strong IV (F statistic = 29.2). However, in the second stage analysis, the GMM-SMM model failed to converge due to non- concaveness probably because of the small sample size. Therefore, the IV analysis could not support the causality of the association between serum sRAGE levels and risk of pancreatic cancer. Nevertheless, these analyses suggest that rs2070600 was a potentially good genetic IV for testing the causality between the risk of pancreatic cancer and sRAGE levels. A larger sample size is required to conduct a credible IV analysis.^

Modulation of cytochrome P450 enzyme activity and PAH -induced skin carcinogenesis by naturally occurring coumarins

The present study was designed to determine the potential anticarcinogenic activity of naturally occurring coumarins and their mechanism of action. The results indicated that several naturally occurring coumarins including bergamottin, coriandrin, imperatorin, isopimpinellin, and ostruthin, to which humans are routinely exposed in the diet, were effective inhibitors and/or inactivators of CYP1A1-mediated ethoxyresorufin-O-dealkylase (EROD) or CYP2B1-mediated pentoxyresorufin-O-dealkylase (PROD) in mouse liver microsomes. In addition, bergamottin and corandrin were also found to be inhibitors of purified human P450 1A1 in vitro. Further studies with coriandrin revealed that this compound was a mechanism-based inactivator of P450 1A1 and covalently bound to the P450 1A1 apoprotein. In cultured mouse keratinocytes, bergamottin and coriandrin effectively inhibited the B(a) P metabolism and significantly decreased covalent binding of B(a) P and DMBA to keratinocyte DNA and anti-diol-epoxide-DNA adducts derived from both B(a) P and DMBA in keratinocytes. The data from in vivo experiments showed that bergamottin and coriandrin were potent inhibitors of covalent binding of B (a) P to epidermal DNA and the formation of (+) anti BPDE-DNA adduct, whereas imperatorin and isopimpinellin were more potent inhibitors of covalent binding of DMBA to epidermal DNA. The ability of coumarins to inhibit covalent binding of B (a) P to DNA in mouse epidermis was positively correlated with their inhibitory effect P450 1A1 in vitro, while the inhibitory effect of coumarins on covalent binding of DMBA to epidermal DNA was positively correlated with their inhibitory effects on P450 2B1 and negatively to their inhibitory activity toward P450 1A1. The data from tumor experiments indicated that bergamottin, ostruthin, and coriandrin inhibited tumor initiation by B (a) P in a two-stage carcinogenesis protocol. Bergamottin was most effective in this regard and produced a dose dependent inhibition of papilloma formation in these experiments. In addition, imperatorin was an effective inhibitor of skin tumorigenesis induced by DMBA in SENCAR mouse skin using both a two-stage and a complete carcinogenesis protocol. At dose levels higher than those effective against DMBA, imperatorin also inhibited tumor initiation by B (a) P. The results to date demonstrate that several naturally occurring coumarins possess the ability to block tumor initiation and tumorigenesis by PAHs such as B (a) P and DMBA through inhibition of the P450s involved in the metabolic activation of these hydrocarbons. A working model for the involvement of specific P450s in the metabolic activation of these two PAHs was proposed. ^

Proceedings of the Nineteenth Annual Biochemical Engineering Symposium

The nineteenth symposium was held at the University of Missouri–Columbia on April 22, 1989. A total of eighteen papers were scheduled for presentation, of which nine were in poster session. Finally, fifteen papers were presented and sixteen were submitted for this proceedings. It was attended by 53 participants from five institutions. A sixth group (from Colorado State University) was kept from attending the symposium due to mechanical problems on the road and we missed them. Since they worked hard at their presentations, I requested CSU-group to submit their papers for the proceedings and I am happy that they did. ContentsMathematical modelling of a flour milling system. K. Takahashi, Y. Chen, J. Hosokoschi, and L. T. Fan. Kansas State University A novel solution to the problem of plasmid segregation in continuous bacterial fermentations. K.L. Henry, R. H. Davis, and A. L. Taylor. University of Colorado Modelling of embryonic growth in avian and reptile Eggs. C.L. Krause, R. C. Seagrave, and R. A. Ackerman. Iowa State University Mathematical modeling of in situ biodegradation processes. J.C. Wu, L. T. Fan, and L. E. Erickson. Kansas State University Effect of molecular changes on starch viscosity. C.H. Rosane and V. G. Murphy. Colorado State University Analysis of two stage recombinant bacterial fermentations using a structured kinetic model. F. Miao and D. S. Kampala. University of Colorado Lactic acid fermentation from enzyme-thinned starch by Lactobacillus amylovorus. P.S. Cheng, E. L. Iannotti, R. K. Bajpai, R. Mueller, and s. Yaeger. University of Missouri–Columbia Solubilization of preoxidized Texas lignite by cell-free broths of Penicillium strains. R. Moolick, M. N. Karim, J. C. Linden, and B. L. Burback. Colorado State University Separation of proteins from polyelectrolytes by ultrafiltration. A.G. Bazzano and C. E. Glatz. Iowa State University Growth estimation and modelling of Rhizopus oligosporus in solid state fermentations. D.-H. Ryoo, V. G. Murphy, M. N. Karim, and R. P. Tengerdy. Colorado State University Simulation of ethanol fermentations from sugars in cheese whey. C.J. Wang and R. K. Bajpai. University of Missouri–Columbia Studies on protoplast fusion of B. licheniformis. B. Shi, Kansas State University Cell separations of non-dividing and dividing yeasts using an inclined settler. C.-Y. Lee, R. H. Davis, and R. A. Sclafani. University of Colorado Effect of·serum upon local hydrodynamics within an airlift column. G.T. Jones, L. E. Erickson, and L. A. Glasgow. Kansas State University Optimization of heterologous protein secretion in continuous culture. A. Chatterjee, W. F. Remirez, and R. H. Davis. University of Colorado An improved model for lactic acid fermentation. P. Yeh, R. K. Bajpai, and E. L. Iannotti. University of Missouri–Columbia

Mineralogy and structural specification of ODP Leg 125 peridotite samples

Abundant serpentinite seamounts are found along the outer high of the Mariana forearc at the top of the inner slope of the trench. One of them, Conical Seamount, was drilled at Sites 778, 779, and 780 during Leg 125. The rocks recovered at Holes 779A and 780C, respectively, on the flanks and at the summit of the seamount, include moderately serpentinized depleted harzburgites and some dunites. These rocks exhibit evidence of resorption of the orthopyroxene, when present, and the local presence of very calcic-rich diopside in veins oblique to the main high-temperature foliation of the rock. The peridotites, initially well-foliated with locally poikiloblastic textures, show overprints of a two-stage deformation history: (1) a high-temperature (>1000°C), low-stress (0.02 GPa), homogeneous deformation that has led to the present Porphyroclastic textures displayed by the rocks and (2) heterogeneous ductile shearing at a much higher stress (0.05 GPa). This heterogeneous shearing probably describes a single tectonic event because it began at high temperatures, producing dynamic recrystallization of olivine in the shear zone, and ended at low temperatures in the stability field of chlorite and serpentine. In a few samples, olivine shows evidence of quasi-hydrostatic recrystallization at a very high temperature. Here, we propose that this recrystallization was related to fluid/magma percolation, a process that can also account for the resorption of the orthopyroxene and for the late crystallization of diopside veins in the rock. The impregnation by fluid or magma, development of the main high-temperature, low-stress deformation, and subsequent migration recrystallization of olivine probably occurred in a mantle fragment involved in the arc formation. In addition, this mantle has preserved structures that may have formed earlier in the oceanic lithosphere upon which the arc formed. Heterogeneous ductile shear zones in the peridotites may have developed during uplift. The "cold" deformation may have taken place during diapiric rise of hot mantle that underwent subsequent serpentinization or gliding along normal faults associated with the extension of the eastern margin of the forearc.

Nd and Sr isotopic composition of Cretaceous MORB

Chemical and isotopic (Nd and Sr) compositions have been determined for 12 Cretaceous basaltic samples (108 Ma old) from Holes 417D and 418A of Legs 51,52 and 53. We have found that: (1) The chemical compositions are typical of MORB. They do not vary systematically with the stratigraphic positions of the analyzed samples; thus, the chemical evolution is independent of the eruption sequence that occurred at this Cretaceous ridge. (2) REE patterns for all rocks are characterized by a strong LREE depletion with (La/Sm)N = 0.38-0.50; no significant Eu anomalies are found; HREE are nearly flat or slightly depleted towards Yb-Lu and have 12-18 * chondritic abundances. Combining the results of previous studies, it suggests that no significant temporal and spatial variation in magma chemistry (especially for LIL elements) has occurred in the 'normal' ridge segments over the last 150 Ma. (3) lsotopically, 143Nd/144Nd ratios vary from 0.513026 to 0.513154, corresponding to epsilon-Nd(0) = +7.5 to +10, and they fall in the typical range of MORB. However, these rocks have unexpectedly high 87Sr/86Sr ratios (0.70355-0.70470) which are attributed to the result of seawater-rock interaction. (4) The Nd model ages (Tin), ranging from 1.53 to 2.47 (average 2.06) AE, suggest that the upper mantle source(s) underwent a large scale chemical differentiation leading to LREE and other LIL element depletion about 2 AE ago, assuming a simple two-stage model. More realistically, the variation in Tm(Nd) or epsilon-Nd could be derived from mixing of heterogeneous mantle sources that were a consequence of continuous mantle differentiation and continental formation. (5) Because of the low mg values (0.52-0.63), the analyzed basaltic rocks do not represent primary liquids of mantle melting. The variation in La/Sm ratios and TiO2 are not compatible with a model in which all rocks are genetically related by a simple fractional crystallization. Rather, it is proposed that the basaltic rocks might have been derived from some heterogeneous upper mantle source with or without later magmatic mixing, and followed by some shallow-level fraetionations.

Heat flow in the Central Basin of the Indian Ocean and the northern part of the Afanasy Nikitin Rise

Heat flux data obtained during Cruise 20 of R/V Akademik Mstislav Keldysh in the Central Basin of the Indian Ocean and northern part of the Afanasy Nikitin Rise are presented. Thermal conditions on the rise are not associated with an anomalous zone of the large tectonic deformation block north of it. Geothermal data indicate that the Afanasy Nikitin Rise has formed near an ancient spreading axis. Distribution of measured heat flux values indicates an additional source of heat in the Central Basin resulting from dissipative heating of the crust in the two-stage plate tectonics model.

Isotopic geochemistry of granitoids in the Jinshajiang suture zone, SW China

The Jinshajiang suture zone, located in the eastern part of the Tethyan tectonic domain, is noticeable for a large-scale distribution of Late Jurassic to Triassic granitoids. These granitoids were genetically related to the evolution of the Paleo-Tethys Ocean. The Beiwu, Linong and Lunong granitoids occur in the middle zone of the Jinshajiang Suture Zone, and possess similar geochemical features, indicating they share a common magma source. SIMS zircon U-Pb dating reveals the Beiwu, Linong and Lunong granitic intrusions were emplaced at 233.9±1.4 Ma (2 sigma), 233.1 ±1.4 Ma (2 sigma) and 231.0±1.6 Ma (2 sigma), respectively. All of these granitoids are enriched in abundances of Si (SiO2 =65.2-73.5 wt.%), and large-ion-lithophile-elements (LILEs), but depleted in high-field-strength-elements contents (HFSEs, e.g., Nb, Ta, Ti). In addition, they have low P2O5 contents (0.06-0.11 wt.%), A/CNK values ([molecular Al2O3/(CaO+Na2O+K2O)], mostly<1.1) and 10000Ga/Al ratios (1.7-2.2), consistent with the characteristics of I-type granites. In terms of isotopic compositions, these granitoids have high initial 87Sr/86Sr ratios (0.7078-0.7148), Pb isotopic compositions [(206Pb/204Pb)t=18.213-18.598, (207Pb/204Pb)t=15.637-15.730 and (208Pb/204Pb)t=38.323-38.791], zircon d18O values (7. per mil-9.3 per mil) and negative eNd(t) values (-5.1 to -6.7), suggesting they were predominantly derived from the continental crust. Their Nb/Ta ratios (average value=8.6) are consistent with those of the lower continental crust (LCC). However, variable ?Hf(t) values (-8.6 to +2.8) and the occurrences of mafic microgranular enclaves (MMEs) suggest that mantle-derived melts and lower crustal magmas were involved in the generation of these granitoids. Moreover, the high Pb isotopic ratios and elevated zircon d18O values of these rocks indicate a significant contribution of the upper crustal composition. We propose a model in which the Beiwu, Linong and Lunong granitoids were generated under a late collisional or post-collisional setting. It is possible that this collision was completed before Late Triassic. Decompression induced mantle-derived magmas underplated and provided the heat for the anatexis of the crust. Hybrid melts including mantle-derived and the lower crustal magmas were then generated. The hybrid melts thereafter ascended to a shallow depth and resulted in some degree of sedimentary rocks assimilation. Such three-component mixing magmas source and subsequent fractional crystallization could be responsible for the formation of the Beiwu, Linong and Lunong granitoids.

Geochemistry of lavas from the Lau-Tonga arc and back-arc system

Detailed comparison of mineralogy, and major and trace geochemistry are presented for the modern Lau Basin spreading centers, the Sites 834-839 lavas, the modern Tonga-Kermadec arc volcanics, the northern Tongan boninites, and the Lau Ridge volcanics. The data clearly confirm the variations from near normal mid-ocean-ridge basalt (N-MORB) chemistries (e.g., Site 834, Central Lau Spreading Center) to strongly arc-like (e.g., Site 839, Valu Fa), the latter closely comparable to the modern arc volcanoes. Sites 835 and 836 and the East Lau Spreading Center represent transitional chemistries. Bulk compositions range from andesitic to basaltic, but lavas from Sites 834 and 836 and the Central Lau Spreading Center extend toward more silica-undersaturated compositions. The Valu Fa and modern Tonga-Kermadec arc lavas, in contrast, are dominated by basaltic andesites. The phenocryst and groundmass mineralogies show the strong arc-like affinities of the Site 839 lavas, which are also characterized by the existence of very magnesian olivines (up to Fo90-92) and Cr-rich spinels in Units 3 and 6, and highly anorthitic plagioclases in Units 2 and 9. The regional patterns of mineralogical and geochemical variations are interpreted in terms of two competing processes affecting the inferred magma sources: (1) mantle depletion processes, caused by previous melt extractions linked to backarc magmatism, and (2) enrichment in large-ion-lithophile elements, caused by a subduction contribution. A general trend of increasing depletion is inferred both eastward across the Lau Basin toward the modern arc, and northward along the Tongan (and Kermadec) Arc. Numerical modeling suggests that multistage magma extraction can explain the low abundances (relative to N-MORB) of elements such as Nb, Ta, and Ti, known to be characteristic of island arc magmas. It is further suggested that a subduction jump following prolonged slab rollback could account for the initiation of the Lau Basin opening, plausibly allowing a later influx of new mantle, as required by the recognition of a two-stage opening of the Lau Basin.