Report on the Alternative Platform Observer Program in North Carolina: March 2006 to March 2007

In February 2006, an Alternative Platform Observer Program (APP) was implemented in North Carolina (NC) to observe commercial gillnet trips by small vessels [<24 ft (7.2 m)] in nearshore waters out to three nm (5.6 km). Efforts began with outreach to the fishing industry while simultaneously gathering information to be incorporated in a Database of Fishermen. From 30 March 2006 through 31 March 2007, 36 trips were observed. Observed trips of the NC nearshore gillnet fishery targeted seven species: kingfish (Menticirrhus spp.), Spanish mackerel (Scomberomorus maculatus), spiny dogfish (Squalus acanthias), spot (Leiostomus xanthurus), spotted seatrout (Cynoscion nebulosus), striped bass (Morone saxatilis), and weakfish (Cynoscion regalis). Of the 36 trips, 20 (55.6%) were with vessels that were new to the Northeast Fisheries Observer Program (NEFOP), having never carried an observer. Based on the landings data for small vessels from North Carolina Division of Marine Fisheries (NCDMF), the APP has achieved 10.1% coverage by number of trips and 4.0% by pounds landed. No incidental takes of bottlenose dolphins were observed by the APP, although bottlenose dolphins were sighted during 19 (52.8%) observed trips. The APP has drastically increased the number of observed trips of small vessels in the nearshore waters of NC. When combined with trips observed by NEFOP (n=205), the APP resulted in a 15.6% increase in the number of observed gillnet trips. (PDF contains 34 pages

Meta-analysis & Review of Learner Performance & Preference: Virtual vs. Optical Microscopy

Background & Purpose: For nearly two decades, a wealth of literature has been published describing the various capabilities, uses, and adaptations of virtual microscopy (VM). Many studies have investigated the effects and benefits of VM on student learning compared to optical microscopy (OM). As such, this study statistically aggregated the findings of multiple comparative studies through a meta-analysis to summarize and substantiate the pedagogical efficacy of teaching with VM. Methods Using predefined eligibility criteria, teams of paired researchers screened the titles and abstracts of VM studies retrieved from seven different databases. After two rounds of screening, numerical and thematic data were extracted from the eligible studies for analysis. A summary effect size and estimate of heterogeneity were calculated to determine the effects of VM on learner performance and the amount of variance between studies, respectively. Trends in student perceptions were also analyzed and reported. Results: Of the 725 records screened, 72 studies underwent full-text review. In total, 12 studies were viable for meta-analysis and additional studies were reviewed to extract themes relating to learners’ perceptions of VM. The meta-analysis detected a small yet significant positive effect on learner performance (SMD=0.28, [CI=0.09, 0.47], p=0.003), indicating that learners experience marked knowledge gains when exposed to VM over OM. Variation among studies was evident as high heterogeneity was reported. An analysis of trends in learner perceptions noted that respondents favored VM over OM by a large margin. Conclusions: Despite many individual studies reporting non-significant findings when comparing VM to OM, the enhanced power afforded by meta-analysis revealed that the pedagogical approach of VM is modestly superior to OM and is preferred by learners

Tumor-vascular interactions promote STING-driven inflammation in the tumor microenvironment

The recruitment of T cells following intratumoral administration of Stimulation of Interferon Genes (STING) agonists in the tumor microenvironment (TME) is a critical event in the STING-driven antitumor immune response, a pathway with great relevance in the context of cancer immunotherapy. We have previously demonstrated that LKB1 mutation is associated with suppression of tumor cell STING levels and reduced production of T-cell chemoattractants such as CXCL10 in KRAS-driven non-small cell lung cancer (NSCLC). Consistent with this, immunohistochemical staining of patient samples showed poor infiltration of CD3, CD4, and CD8 T cells into LKB1 negative versus LKB1 intact cancer epithelium, and instead, retention of T-cells in stroma. To examine how LKB1 alters immune cell recruitment in a STING-dependent manner, we used a 3-D microfluidic co-culture system to study interactions between vasculature and tumor spheroids derived from a KRAS/LKB1 mutated (KL) cell line with LKB1 reconstitution +/- STING deletion. To form the vasculature, we co-cultured tumor spheroids with fibroblasts and endothelial cells for 7 days, and identified changes in morphology, cytokine production, and gene expression that occur in co-culture. We first observed that co-culture induced synergistic production of multiple immune cell chemo-attractants such as CXCL10, CCL2, CCL5, and G-CSF. Interestingly, this more physiologic ex vivo tumor model of LKB1 reconstitution revealed particularly strong cooperative production of STING-dependent cytokines such as CXCL10 in the vasculature. Moreover, STING depletion in LKB1 reconstituted tumor cells did not significantly attenuate production of CXCL10 and other cytokines in co-culture, suggesting that tumor/vessel interaction may promote STING activation in the vasculature regardless of cancer cell-intrinsic STING function. Furthermore, although there was no appreciable response after treatment of KL cancer cells with cGAMP based STING agonists, treatment of isolated 3-D vascular networks with cGAMP enhanced vascular permeability and increased production of CXCL10 and CCL5, possibly contributing to defective chemokine gradients that retain T cells near the vasculature. Thus, developing these more complex models that incorporate the vasculature may elucidate important aspects of STING biology and may ultimately aid further development of effective immunotherapies targeting this signaling axi

Plasma inflammatory cytokines and survival of pancreatic cancer patients.

OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome. METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for death were estimated using multivariate Cox proportional hazards models. RESULTS: Overall mortality was significantly increased in patients in the top quartile of CRP (HR = 2.52, 95% CI: 1.82-3.49), IL-6 (HR = 2.78, 95% CI: 2.03-3.81), sTNF-RII (HR = 2.00, 95% CI: 1.46-2.72), and MIC-1 (HR = 2.53, 95% CI: 1.83-3.50), compared to those in the bottom quartile (P-trend CONCLUSION: Individual elevated plasma inflammatory cytokines are associated with significant and dramatic reductions in pancreatic cancer patient survival. Furthermore, we observed an independent combined effect of those cytokines on patient survival, suggesting that multiple inflammatory pathways are likely involved in PDAC progression. Future research efforts to target the inflammatory state using combination strategies in pancreatic cancer patients are warranted

Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Epithermal Mineralization of the Bonanza-Sandy Vein System, Masara Gold District, Mindanao, Philippines

The Masara Gold District in southeastern Mindanao island is an area of prolific hydrothermal copper and gold mineralization. This study documents the mineralization characteristics of the NW-trending Bonanza-Sandy epithermal veins to constrain possible hydrothermal fluid sources and ore-forming mechanisms. Epithermal mineralization in the NW veins is divided into three main stages: Stage 1 - massive quartz-sulfide; Stage 2 - massive to amorphous quartz-carbonate (calcite); and Stage 3 - colloform-cockade quartz-carbonate (bladed rhodochrosite). Stage 1 is the main gold mineralization phase, with chalcopyrite, pyrite, sphalerite and galena occurring with native gold and tellurides. Stages 2 and 3 contain invisible gold in the sphalerite, galena, pyrite and chalcopyrite. The deposit exhibits mineralization characteristics typical of intermediate sulfidation epithermal deposits based on the dominant chalcopyrite-pyrite mineral assemblage; illite-muscovite-chlorite alteration mineralogy that point to neutral pH conditions; and sphalerite composition of 2.26 to 8.72 mol% FeS in Stage 1 and 0.55 to 1.13 mol% FeS in Stage 2. The K-Ar age date of illite separates from highly altered diorite porphyry of the Lamingag Intrusive Complex yielded an Early Pliocene age (5.12 ± 0.16 Ma). Hydrothermal fluid exsolved from the magma that formed the Lamingag Intrusive Complex probably formed the ore-forming Stage 1 veins. Stages 2 and 3 involved the deposition of quartz and carbonate veins possibly by boiling hydrothermal fluids. Precious and base metal deposition was controlled by the Masara Fault Zone. Exploration markers for gold mineralization in the Masara Gold District and vicinity include the presence of Lamingag Intrusive Complex and massive sulfide veins

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies