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Highlights • High-dose RT upregulated pDCs within the tumor microenvironment. • The administration of intratumoral TLR9 agonist (CMP-001) after stereotactic RT significantly enhanced the anti-tumor immune response both locally and at secondary tumor site. • CMP-001 Post-RT delayed the abscopal tumor growth and extended the survival rate via increasing the percentages of activated CD4+ and CD8+ T-cells within the tumor microenvironment. • The treatment proved efficacious in both lung adenocarcinoma and colon carcinoma syngeneic models used., Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b+ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4+ and CD8+ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease., Graphical Abstract Image, graphical abstract

In-memory Key-Value (KV) stores are widely deployed in modern data centers. These systems generally use DRAM as their storage medium, causing huge hardware costs. The emerging persistent memory (PMEM) is a potential substitute for DRAM, which has a lower price and larger capacity, but lower access speed and bandwidth. Many prior studies strive to build hybrid memory systems to retain both the advantages of DRAM and PMEM. However, they are either application agnostic or simply take DRAM as a cache, which are both not efficient for in-memory KV stores. In this paper, we propose SwapKV, a well-designed in-memory KV store for hybrid DRAM-PMEM system. SwapKV has several promising properties. First, SwapKV combines DRAM and PMEM to a uniform memory pool and only stores one copy of data, which maximizes capacity utilization. Second, SwapKV maps all writing operations to DRAM and migrates data to PMEM with large blocks asynchronously, which mitigates the intrinsic inefficiency of PMEM for writing operations. Third, SwapKV maintains the hot data in DRAM through an efficient hotness filtering and data swapping mechanism, which ensures high system throughput and responsiveness. We implement SwapKV and evaluate it under various workload patterns. The results demonstrate that SwapKV improves the throughput by 11\% $\sim$ 41\% compared to the state-of-the-art alternatives.

A series of injectable in situ cross-linking hyaluronic acid/carboxymethyl cellulose based hydrogels (HA/CMC) was prepared via disulfide bonds by the oxidation of dissolved oxygen. The results showed that HA/CMC hydrogels exhibited tunable gelling time, appropriate rheology properties, high swelling ratio, good stability, and sustained drug release ability. The gelling time of HA/CMC hydrogels ranged from 1.4 to 7.0 min, and the values of the storage modulus, complex shear modulus, dynamic viscosity, and yield stress of HA3/CMC3 hydrogel were about 5869 Pa, 5870 Pa, 587 Pa·s, and 1969 Pa, respectively. The degradation percentage of HA1/CMC1, HA2/CMC2, and HA3/CMC3 hydrogels were about 60, 49, and 41% after incubating 42 days, and the in vitro cumulative release percentage of BSA from HA1/CMC1, HA2/CMC2, and HA3/CMC3 drug-loaded hydrogels were about 99, 91, and 82% after 30 days. The series of injectable in situ cross-linking HA/CMC hydrogels exhibited good comprehensive performance, signifying that these hydrogels could be potentially used in the fields of short- and medium-term controlled drug release, cell encapsulation, regenerative medicine, and tissue engineering.

PURPOSE/OBJECTIVE(S) Although radiation is beneficial in killing tumor cells, it also causes accumulation of senescent cells in tumors and in the surrounding healthy tissue. Senescent tumor cells can recover by acquiring a senescence-associated secretory phenotype (SASP), which leads to undesired tumor cell proliferation. We hypothesize that the clearance of RT-induced senescence by a senolytic cocktail Dasatinib + Quercetin (DQ), may enhance the radio-sensitivity to RT in melanoma. Here, we present data on the effect of DQ and RT on tumor cells and senescence in a radio-resistant melanoma model in vitro and in vivo. MATERIALS/METHODS Exponentially growing melanoma cells (B16F10) were irradiated with 2 Gy, 6 Gy or 12 Gy X-rays at room temperature. Following irradiation, cells were cultured for 2, 3, 5 and 8 days and markers for senescence were determined. In an in vivo study, C57BL/6 mice were injected with 0.5 × 106 B16F10 cells subcutaneously in the right leg. Mice were irradiated with three fractions of 10 Gy, and Dasatinib (5 mg/kg) + Quercetin (50 mg/kg) was given daily by oral gavage beginning from either 1 day after RT (early stage) or 7 days after RT (later stage) for total of 5 doses. Tumor volumes and survival were recorded. Tumor cell senescence was determined by the cells' morphology. Expression of biomarkers for senescence in tumor tissues were determined by senescence associated β-galactosidase (SA-β-Gal) assay, DNA damage (53BP1/ γ-H2AX foci), and qRT-PCR analysis for p21 and p16 genes, and SASP including IL-1b, IL-6, IL-8, TGF-b, TNF-a, and CXCL10. RESULTS In vitro, RT increased signals for SA-β-Gal and volume of tumor cells in a dose dependent fashion: 0 Gy (0%) vs. 2 Gy (10%) vs. 6 Gy (50%) vs. 12 Gy (85%). QRT-PCR showed a time and dose-dependent increase of expression for CXCL10 and p21, which was higher at 12 Gy after 8 days compared to other doses and time points (all P < 0.05). In B16F10 tumor bearing mice treatment with RT + DQ (7 days post RT, late stage) reduced tumor volumes and extended survival compared to controls and groups treated with RT or DQ only. In contrast, the combination of RT + DQ on day 1 post RT (early stage) failed to enhance antitumor effects and survival. Analysis of biomarkers for senescence in irradiated tumors showed reduced expression of TGF-b and p21 in RT + DQ (7 days post RT, later stage) vs. RT alone. SA-β-Gal staining was reduced in the 53BP1/ γ-H2AX positive area in the RT + DQ (later stage) group compared to RT alone. CONCLUSION The combination of senescence-inducing RT and a senolytic cocktail DQ enhanced the antitumor effects in a mouse model for melanoma in a time-dependent fashion. Further studies are ongoing to assess a potential mechanism of clearance of RT-induced senescence to validate clinical studies.

PURPOSE/OBJECTIVE(S) To report updated findings from a prospective phase II trial of salvage high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer (NCT02710253). MATERIALS/METHODS Eligible patients had metastatic disease that progressed on immunotherapy within the prior 6 months. Patients were given either HD-RT (20-70Gy total; 3-12.5Gy/fraction), or HD-RT and LD-RT to separate lesions (LD-RT comprised of < 2Gy/fraction up to 10Gy total), with continued immunotherapy. Radiographic response was assessed per RECIST1.1 and Immune-Related Response Criteria (irRC). Primary endpoints were 1) 4-month disease control (complete/partial response [CR/PR] or stable disease [SD]) or an overall response (CR/PR) at any point in ≥10% of patients, and 2) dose-limiting toxicity within 3 months not exceeding 30%. Also, where applicable, biopsies pre- and post- low-dose RT were collected, FFPE slides were prepared and analyzed by Multiplex Immunofluorescence (Multi-IF) microscopy for immune-cell infiltration. RESULTS Seventy-four patients were analyzed (39 in HD-RT group and 35 in HD-RT+LD-RT group), mostly with non-small cell lung cancer (n = 38) or melanoma (n = 21). Patients received immunotherapy for a median of 7.1 months (3.7-10.6 months) before RT, and 95% maintained the same therapy after RT. The median follow-up time was 13.8 months. The site most commonly treated with HD- or LD-RT was lung/mediastinum. The primary endpoint was met for the 72 evaluable patients, with a 4-month overall disease control rate of 42% (RECIST1.1, 47% [16/34] for the HD-RT+LD-RT group and 37% [14/38] for the HD-RT only group). Three (4.2%) patients experienced grade ≥3 toxicity. LD-RT treated lesion response rates (irRC, 53%) was improved compared to nonirradiated lesions in the HD-RT+LD-RT (23%, P = 0.002) and HD-RT only (11%, P < 0.001) group. The median PFS was 7.0 months vs. 5.8 months, while median OS was 15.9 months vs. 10.5 months for the HD-RT+LD-RT group vs. HD-RT only group respectively; however, statistical significance was not reached. Furthermore, the addition of LD-RT did not significantly affect the absolute lymphocyte counts (ALC), with ALC reduction after treatment recorded as 420/μL vs. 340/μL in the HD-RT only vs. HD-RT+LD-RT groups (P = 0.44). The Multi-IF data for 3 analyzed biopsies of LD-RT lesions showed strong correlation between T cell and NK cell infiltration and clinical response rate. Lesion 1 for example (24% SD), had CD56+ NK cell numbers increase from 67 to 1837 n/mm2 post LD-RT. Lesion 2 (-80% PR) had its CD3+CD4+ T cells increase from 287 to 1233 n/mm2 and NK cells increase from 0 to 187 n/mm2; while lesion 3 (-8% SD) showed an increase from 79 to 131 n/mm2 and 3.6 to 7.3 n/mm2 in the T cell and NK cell compartments respectively. CONCLUSION Low-dose RT is an effective and safe way to enhance individual lesion-specific response rates among progressing patients with solid tumors, with the ability to improve the infiltration of effector immune cells into the tumor microenvironment.

BackgroundTIGIT and LAG3 are inhibitory receptors expressed on cytotoxic CD8+ T cells and NK cells and directly inhibit the activation and proliferation of these cells. We proposed that blockade of TIGIT and LAG3 could improve antitumor immune response in a mouse model of anti-PD1 (aPD1)-resistant mice.Methods129Sv/Ev mice were inoculated with 50,000 aPD1-resistant 344SQR cells in the right leg on day 0 (primary tumor) and with 50,000 cells in the left leg on day 4 (secondary tumor). Primary tumors were injected with NBTXR3 radioenhancer nanoparticles on day 7 and irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1, aLAG3, and aTIGIT were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. On day 21, primary tumors, secondary tumors, and blood samples were harvested and analyzed with flow cytometry to evaluate changes in immune cell populations. The RNA extracted from the tumors were also analyzed by Nanostring. Mice in which tumors were completely eradicated were re-challenged with another 50,000 344SQR cells in the right flank at least two months post radiation; no further treatment was given to these mice, and tumor growth was monitored.ResultsThe addition of aTIGIT, aLAG3, or aTIGIT+aLAG3 to NBTXR3+XRT+aPD1 therapy significantly improved control of tumors, and the addition of aTIGIT+aLAG3 also led to fewer spontaneous lung metastases. The addition of either aTIGIT or aLAG3 to NBTXR3+XRT+aPD1 extended mouse survival time relative to NBTXR3+XRT+aPD1. None of the 8 mice in either the NBTXR3+XRT+aPD1+aTIGIT group or the NBTXR3+XRT+aPD1+aLAG3 group survived more than 32 days; in contrast, 3 of the 8 mice that received NBTXR3+XRT+aPD1+aTIGIT+aLAG3 survived until the end of the experiment. These surviving mice were found to have developed memory against 344SQR cells, and no further tumor growth was observed after re-challenge. Flow cytometry analysis showed that adding aTIGIT+aLAG3 to NBTXR3+XRT+aPD1 increased the percentages of proliferating CD8+ T cells in primary tumors, secondary tumors, and blood. Furthermore, Nanostring transcriptomic analysis of cells isolated from the tumors of mice thus treated showed evidence of classical two-step immunological priming, with an elevation of innate immune genes at the primary tumor and full-blown activation of the immune system within the secondary tumor.ConclusionsBlockade of TIGIT and LAG3 with NBTXR3+XRT+aPD1 improved CD8+ T-cell proliferation, augmented the antitumor response at both irradiated and unirradiated (abscopal) tumors, and induced potent long-term antitumor memory in mice.AcknowledgementsThis work was supported by Cancer Center Support (Core) Grant CA016672 to The University of Texas MD Anderson Cancer Center; the Goodwin family research fund; the family of M. Adnan Hamed and the Orr Family Foundation to MD Anderson Cancer Center‘s Thoracic Radiation Oncology program; an MD Anderson Knowledge Gap award; Nanobiotix.

A series of oxidized hyaluronic acid (oxi-HA)/3,3′-dithiobis (propionohydrazide) (DTP) redox responsive hydrogels by Schiff base reaction under physiological conditions were designed and prepared. The influence of the concentration of oxi-HA and DTP on rheological properties, equilibrium swelling ratio, and degradation rate were investigated. All oxi-HA/DTP hydrogels exhibited good rheological properties, high equilibrium swelling ratio, low degradation rate, and sustainable drug release properties, and the comprehensive performance of oxi-HA5/DTP6 hydrogel was better than that of others. The redox responsiveness was evaluated by means of degradation and in vitro bovine serum albumin release behavior investigation with the stimulus of different concentration of dithiothreitol as reducing agent. The intelligent hydrogels could be potentially applied in the fields of drug delivery system, tissue engineering, or cell scaffold materials. Copyright © 2017 John Wiley & Sons, Ltd.

Aim: To evaluate the value of pretreatment blood biomarkers in predicting pathologic responses to neoadjuvant chemoradiotherapy (neo-CRT) in patients with locally advanced rectal cancer. Materials & methods: We conducted logistic regression analysis and receiver operating characteristic to assess the predictive value of blood biomarkers. The outcome was defined by the pathologic complete response and good response. Results: Carcinoembryonic antigen (CEA) (p

A series of injectable in situ dual-crosslinking hydrogels (HA/ALG) based on oxidized sodium alginate (oxi-ALG) and hyaluronic acid modified with thiol and hydrazide (HA-SH/CDH) were prepared via hydrazone bonds and disulfide bonds. The chemical structures, morphologies, rheological properties, gelling time, swelling ratio, degradation rate and drug release behavior of hydrogels were investigated. HA/ALG hydrogels exhibited tunable gelling time, rheological properties, swelling ratio and degradation rate with varying precursor concentrations. The gelling time of HA/ALG hydrogels ranged from 157 s to 955 s, the values of yield stress of HA2/ALG2, HA3/ALG3 and HA4/ALG4 hydrogels were 1724, 4349 and 5306 Pa, and the degradation percentage of HA2/ALG2, HA3/ALG3 and HA4/ALG4 hydrogels were about 64%, 51% and 42% after incubating 35 days, respectively. Bovine serum albumin (BSA) was used as a model drug to investigate the drug controlled release properties, and the in vitro cumulative release percentage of BSA from HA2/ALG2, HA3/ALG3 and HA4/ALG4 drug-loaded hydrogels were about 79%, 72% and 69% after 20 days. The series of injectable in situ dual-crosslinking HA/ALG hydrogels could be an attractive candidate for drug delivery system, tissue engineering and regenerative medicine. Injectable in situ dual-crosslinking hydrogels (HA/ALG) were prepared from thiol- and hydrazide-bifunctionalized hyaluronic acid (HA-SH/CDH) and oxidized alginates (oxi-ALG). Hydrogels exhibited tunable gelling time, appropriate rheology properties, high swelling ratio, low degradation percentage and sustainable controlled release properties, signifying that they could be potentially used in the fields of drug controlled release, cell encapsulation, tissue engineering and regenerative medicine.

Triple-negative breast cancer (TNBC) is a particular subtype of breast malignant tumor with poorer prognosis than other molecular subtypes. Previous studies have demonstrated that some abnormal expression of non-coding RNAs including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were closely related to tumor cell proliferation, apoptosis, invasion, migration and drug sensitivity. However, the role of non-coding RNAs in the pathogenesis of TNBC is still unclear. In order to characterize the molecular mechanism of non-coding RNAs in TNBC, we downloaded RNA data and miRNA data from the cancer genome atlas database. We successfully identified 686 message RNAs (mRNAs), 26 miRNAs and 50 lncRNAs as key molecules for high risk of TNBC. Then, we hypothesized that the lncRNA–miRNA–mRNA regulatory axis positively correlates with TNBC and constructed a competitive endogenous RNA (ceRNA) network of TNBC. Our series of analyses has shown that five molecules (TERT, TRIML2, PHBP4, mir-1-3p, mir-133a-3p) were significantly associated with the prognosis of TNBC, and there is a prognostic ceRNA sub-network between those molecules. We mapped the Kaplan–Meier curve of RNA on the sub-network and also suggested that the expression level of the selected RNA is related to the survival rate of breast cancer. Reverse transcription-quantitative polymerase chain reaction showed that the expression level of TRIML2 in TNBC cells was higher than normal. In general, our findings have implications for predicting metastasis, predicting prognosis and discovering new therapeutic targets for TNBC.

Aim To evaluate the efficacy and toxicity of vinorelbine and gemcitabine (NG) versus vinorelbine and cisplatin (NP) in anthracycline- and taxane-pretreated patients with HER2-negative advanced breast cancer. Patients and methods Patients were randomly assigned on a 1:1 schedule to receive no more than six cycles of NG or NP. Dosing for the NG group was 25 mg/m2 vinorelbine and 1,000 mg/m2 gemcitabine, given on days 1 and 8 every 3 weeks; for the NP group,25 mg/m2 vinorelbine was given on days 1 and 8, and 75 mg/m2 cisplatin was given on day 1 every 3 weeks. The primary endpoint was disease control rate (DCR). The secondary endpoints were the progression-free survival (PFS), overall survival (OS) and safety. Results The full analysis set comprised of 37 patients receiving NG and 37 receiving NP. The DCR was 70.3% with NG and 64.9% with NP (p=0.619). Median PFS were 7 months (95% CI=5.88-8.12) and 6 months (95% CI=5.29-6.71) respectively in NG and NP group [hazard ratio (HR)=1.696; 95% confidence interval (CI)=0.73-3.93; p=0.217)]. Corresponding median OS was 18 (95% CI=10.35-13.65) months and 12 (95% CI=15.83-20.17) months (HR=1.219; 95% CI=0.67-2.23; p=0.521). For adverse events, neutropenia and nausea/vomiting were milder in the NG group than in the NP group (all p Conclusion Although no significant differences were observed in terms of DCR, PFS and OS, with milder toxicity, NG appeared to be a more valuable first-line treatment regimen than NP in anthracycline- and taxane-pretreated patients with HER2-negative advanced breast cancer.

Epidermal growth factor receptor (EGFR) is over-expressed in about 50% of Triple negative breast cancers (TNBCs), but EGFR inhibitors have not been effective in treating TNBC patients. Increasing evidence supports that autophagy was related to drug resistance at present. However, the role and the mechanism of autophagy to the treatment of TNBC remain unknown. In the current study, we investigated the effect of autophagy inhibitor to gefitinib (Ge) in TNBC cells in vitro and in nude mice vivo. Our study demonstrated that inhibition of autophagy by 3-Methyladenine or bafilomycin A1 improved Ge’s sensitivity to MDA-MB-231 and MDA-MB-468 cells, as evidence from stronger inhibition of cell vitality and colony formation, higher level of G0/G1 arrest and DNA damage, and these effects were verified in nude mice vivo. Our data showed that the mitochondrial-dependent apoptosis pathway was activated in favor of promoting apoptosis in the therapy of Ge combined autophagy inhibitor, as the elevation of BAX/Bcl-2, Cytochrome C, and CASP3. These results demonstrated that targeting autophagy should be considered as an effective therapeutic strategy to enhance the sensitivity of EGFR inhibitors on TNBC.

To investigate whether genes required for synaptogenesis and synaptic function are also involved in fat storage control in Caenorhabditis elegans.Fat storage was examined in mutants of genes affecting the synaptogenesis and synaptic function. In addition, the genetic interactions of SNAREs syntaxin/unc-64 and SNAP-25/ric-4 with daf-2, daf-7, nhr-49, sbp-1 and mdt-15 in regulating fat storage were further investigated. The tissue-specific activities of unc-64 and ric-4 were investigated to study the roles of unc-64 and ric-4 in regulating fat storage in the nervous system and/or the intestine.Mutations of genes required for the formation of presynaptic neurotransmission site did not obviously influence fat storage. However, among the genes required for synaptic function, the plasma membrane-associated SNAREs syntaxin/unc-64 and SNAP-25/ric-4 genes were involved in the fat storage control. Fat storage in the intestinal cells was dramatically increased in unc-64 and ric-4 mutants as revealed by Sudan Black and Nile Red strainings, although the fat droplet size was not significantly changed. Moreover, in both the nervous system and the intestine, expression of unc-64 significantly inhibited the increase in fat storage observed in unc-64 mutant. And expression of ric-4 in the nervous system completely restored fat storage in ric-4 mutant. Genetic interaction assay further indicated that both unc-64 and ric-4 regulated fat storage independently of daf-2 [encoding an insulin-like growth factor-I (IGF-I) receptor], daf-7 [encoding a transforming growth factor-beta (TGF-beta) ligand], and nhr-49 (encoding a nuclear hormone receptor). Besides, mutation of daf-16 did not obviously affect the phenotype of increased fat storage in unc-64 or ric-4 mutant. Furthermore, unc-64 and ric-4 regulated fat storage probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways. In addition, fat storage in unc-64; ric-4 was higher than that in either unc-64 or ric-4 single mutant nematodes, suggesting that unc-64 functions in parallel with ric-4 in regulating fat storage.The plasma membrane-associated SNAREs syntaxin/unc-64 and SNAP-25/ric-4 function in parallel in regulating fat storage in C. elegans, probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways.

Lymphatic vessel invasion (LVI) is promising in determining prognosis and treatment strategies, but the application of LVI as a histopathological criterion in breast cancer patients especially those of different subgroups is controversial. This research aims to evaluate the prognostic value of LVI assessed by D2-40 not only in patients with early invasive breast cancer but also in lymph node-negative, lymph node-positive, luminal A-like, luminal B-like, HER2-enriched, and triple-negative subgroups. The study cohort included 255 patients with a median follow-up of 101 months. Immunohistochemical staining for D2-40 was performed to identify LVI. LVI was present in 64 (25.1%), 15 (12.1%), 49 (37.4%), 19 (20.9%), 23 (27.7%), 13 (31.7%), and 9 (22.5%), respectively, in the whole cohort, lymph node-negative, lymph node-positive, luminal A-like, luminal B-like, HER2-enriched, and triple-negative patients. LVI was associated with large tumor size (P = .04), high histological grade (P = .004), involved lymph node (P

Here we selected HgCl(2) to investigate the mechanism of Hg toxicity on reproduction in hermaphrodite nematodes. Accompanied with decrease of brood size, Hg exposure caused severe deficits in egg number in uterus, egg laying and reproductive structures, including gonad arms and vulva, and formation of protruding phenotype for vulva. Meanwhile, Hg exposure induced severe stress response and oxidative damage in gonad and vulva. Pre-treatment with vitamin E, a potent antioxidant, at the L2-larval stage prevented the oxidative damage and formation of reproductive deficits in Hg exposed nematodes; however, pre-treatment with paraquat, a regent generating superoxide anions, induced more severe reproductive deficits in Hg exposed nematodes. Moreover, Hg exposure increased expression of clk-2 and isp-1 genes, whose mutations decrease ROS production, and decreased expression of mev-1 and gas-1 genes, whose mutations increase ROS production. Thus, oxidative stress may be essential for the induction of reproductive deficits in Hg exposed hermaphrodite nematodes.

Metal exposure causes reproductive damage in hermaphrodite nematodes, but effects of metals on male development are unclear. We here investigated the effects of mercury chloride exposure on development of males. Hg exposure severely increased the percentage of abnormal males, disrupted the development of male-specific structures, and caused high reactive oxygen species (ROS) production in male tails. Pre-treatment with antioxidant (vitamin E) protected the nematodes against toxicity from Hg exposure on development of male-specific structures. The ROS production in tails was closely correlated with formation of abnormal male-specific structures in males induced by Hg exposure. Moreover, mutations of clk-1, encoding ortholog of COQ7/CAT5, and daf-2, encoding an insulin/IGF receptor, functioned in two different pathways to suppress the formation of deficits in development of male-specific structures. Thus, three different lines of evidence support our conclusion that HgCl2 causes male structure-specific teratogenesis via production of oxidative stress.

Environmental studies of the creosote sites on the Bow River, Calgary, Alberta, can greatly benefit from someappropriate evolutionary spatial modeling of those sites to enable correlations with different surface imagery and borehole information. This evolutionary digital terrain modeling consists in integrating terrain models corresponding to different epochs into a sequence of models with the corresponding aerial photography draped over the reconstructedsurface. Correlations with other available photography and discrete measurements are also planned to be done tofacilitate the surface environmental studies. The presentation will describe the results from the first phase of thisresearch project which has concentrated on the terrain modeling with appropriate visualization of the surface for the environmental scientists and engineers. 1. INTRODUCTION In order to help environmental scientists and engineers to visualize the surface changes over the years, some appropriate evolutionary spatial modeling has been developed for the creosote sites on the Bow River, Calgary, Alberta.Evolutionary spatial terrain modeling of creosote sites first requires the terrain reconstruction at different epochs for