Search

In the absence of surface indications of burial sites, law enforcement or humanitarian organizations are faced with the difficult task of focusing large-scale ground searches to a manageable excavation area. A geoforensic-based survey may exclude parts of the landscape for reasons such as diggability or viewshed analysis but leave areas still too large for invasive exploration. This work examines how drone-based remote sensing, geophysics, and search dogs may be combined to narrow such searches. Here, we ask the reader to consider two examples where forensic geomorphology and land use provided a range of possible burial locations. Following this is a multi-proxy approach to similar dilemma, with a search-to-scene case study using remote sensing (drone photography), geophysics, ground probes, and search dogs. This approach is not presented as a definitive guide, but serves as an example of the conjunctive use of well-studied methods to approach a common problem in geoforensics.

The Permian–Triassic time interval is associated with major perturbations in the biogeochemical cycling of several redox-sensitive elements. In particular, sulphur isotope ratios (δ34S) reveal substantial perturbations in sedimentary sulphates. Despite this, few studies utilise this δ34S variability for long-term high-resolution correlation. Through the sulphur isotope analysis of sedimentary evaporites of the Staithes S-20 borehole (northeast England), we have generated the most stratigraphically complete evaporite sulphur isotope (δ34Sevap) curve from a single stratigraphic section for the late Permian to Late Triassic. The Staithes S-20 record and its comparison with the global δ34Sevap curve demonstrate the utility of sulphur isotope data for stratigraphic correlation and dating, especially evaporite bearing sequences. The δ34Sevap data for the late Permian to Late Triassic were incorporated into a biogeochemical box model to yield estimates for the pyrite burial flux with time. We propose three significant pyrite burial events (i.e. PBEs) throughout the Triassic. Our model outputs predict a major increase in pyrite burial over the Permian/Triassic boundary, possibly driven by Siberian Traps volcanism. After ~10 million years, the pyrite burial flux achieves relative stability until the latest Triassic.

Seafloor sediment flows (turbidity currents) form some of the largest sediment accumulations on Earth, carry globally significant volumes of organic carbon, and can damage critical seafloor infrastructure. These fast and destructive events are notoriously challenging to measure in action, as they often damage any instruments anchored within the flow. We present the first direct evidence that turbidity currents generate seismic signals which can be remotely sensed (~1-3 km away), revealing the internal structure and remarkably prolonged duration of the longest runout sediment flows on Earth. Passive Ocean Bottom Seismograph (OBS) sensors, located on terraces of the Congo Canyon, offshore West Africa, recorded thirteen turbidity currents over an 8-month period. The occurrence and timing of these turbidity currents was confirmed by nearby moorings with acoustic Doppler current profilers.Results show that turbidity currents travelling over ~1.5 m/s produce a seismic signal concentrated below 10 Hz with a sudden onset and more gentle decay. Comparison of the seismic signals with information on flow velocities from the acoustic Doppler current profilers demonstrates that the seismic signal is generated by the fast-moving front of the flow (frontal cell), which contains higher sediment concentrations compared to the slower-moving body. Long runout flows travelling >1000 km have a fast (3.7-7.6 m s-1) frontal cell, which can be 14 hours, and ~350 km long, with individual flows lasting >3 weeks. Flows travelling >1000 km eroded >1300 Mt of sediment in one year, yet had near-constant front speeds, contrary to past theory. The seismic dataset allows us to propose a fundamental new model for how turbidity currents self-sustain, where sediment fluxes into and from a dense frontal layer are near-balanced.Seismic monitoring of turbidity currents provides a new method to record these hazardous submarine flows, safely, over large areas, continuously for years yet at sub-second temporal resolution. Monitoring these processes from land would considerably ease deployment efforts and costs. Thus, work is underway investigating if terrestrial seismic stations can record submarine seafloor processes in Bute Inlet, a fjord in western Canada where independent measurement of delta-lip failures and turbidity currents can be compared to a passive seismic dataset.

The increasing plastic pollution of the world’s oceans represents a serious threat to marine ecosystems and has become a well-known topic garnering growing public attention. The global input of plastic waste into the oceans is estimated to be approximately 10 million tons per year and predicted to rise by one order of magnitude by 2025. More than 90% of the plastic that enters the oceans is thought to end up on the seafloor, and seafloor sediment samples show that plastics are concentrated in confined morphologies and sedimentary environments such as submarine canyons. These canyons are occasionally flushed by powerful gravity-driven sediment flows called turbidity currents, which transport vast volumes of sediment to the deep sea and deposit sediment in deep-sea fans. As such, turbidity currents may also transport plastics present in the canyon and bury plastics in deep-sea fans. These fans may therefore act as sinks for seafloor plastics. Here we present a comprehensive dataset showing the spatial distribution of microplastics in seafloor sediments from the Congo Canyon, offshore West Africa. Multicores taken from 16 locations along the canyon, sampled different sedimentary sub-environments including the canyon thalweg, canyon terraces, and distal lobe. Microplastics were extracted from the sediments by density separation and the polymer type, size, and shape of all individual microplastic particles were analysed using laser-direct infrared-spectroscopy (LDIR). Microplastic number concentrations in the sediments of the distal lobe are significantly higher than in the canyon, indicating that the Congo Canyon system is a highly efficient conduit for microplastic transport to the deep sea. Moreover, microplastic concentrations of >20,000 particles per kg of dry sediment were recorded in the lobe, which represent some of the highest ever recorded microplastic number concentrations in seafloor sediments. This shows that deep-sea fans can serve as hotspots and potential terminal sinks for seafloor microplastics.

Supplementary Figures 1-14

Supplementary Table 1

Supplementary Table Legends

Supplementary Table 3

Supplementary Table 2

Supplementary Methods and Figure Legends

Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor–bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small-molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells and reduced presence of CD4+ T cells, the main source of the TH2 cytokine IL4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8+ T-cell–dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes. Cancer Immunol Res; 3(5); 518–25. ©2015 AACR.

Supplemental Figure 1: Radiation dose response and immune profile. Supplemental Figure 2: Immune profile with RT in combination with αCSF-­1 mAb or PLX3397.

Supplementary Figure S1. B cells in human PDAC. Supplementary Figure S2. B cells and FcRgamma-positive cells regulate murine PDAC. Supplementary Figure S3. Leukocytes and BTK in human and murine PDAC. Supplementary Figure S4. Macrophage PI3Kgamma activates BTK to promote PDAC progression. Supplementary Figure S5. BTK and PI3Kgamma-inhibition decrease PDAC growth. Supplementary Figure S6. BTK inhibition improves gemcitabine response in late-stage PDAC.

Supplementary Methods, Figures 1-10, Tables 1-8 from Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy

Oncolytic virus therapies induce the direct killing of tumor cells and activation of conventional dendritic cells (cDC); however, cDC activation has not been optimized with current therapies. We evaluated the adenoviral delivery of engineered membrane-stable CD40L (MEM40) and IFNβ to locally activate cDCs in mouse tumor models. Combined tumor MEM40 and IFNβ expression induced the highest cDC activation coupled with increased lymph node migration, increased systemic antitumor CD8+ T-cell responses, and regression of established tumors in a cDC1-dependent manner. MEM40 + IFNβ combined with checkpoint inhibitors led to effective control of distant tumors and lung metastases. An oncolytic adenovirus (MEM-288) expressing MEM40 + IFNβ in phase I clinical testing induced cancer cell loss concomitant with enhanced T-cell infiltration and increased systemic presence of tumor T-cell clonotypes in non–small cell lung cancer (NSCLC) patients. This approach to simultaneously target two major DC-activating pathways has the potential to significantly affect the solid tumor immunotherapy landscape.

Supplementary Table 1. LD50 concentrations of different agents (determined at 48h) are indicated. Also shown are agents used at 10muM.

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC.Significance:These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens.See related commentary by Al-Janabi and Lewis, p. 5399

Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, Prkaa1, in tumor-MDSC was induced by cancer cell–derived granulocyte–monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5–dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8+ T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer.Significance:AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.

Key resources

Abundance of lipids in macrophages and importance of mevalonate pathway in prostate cancer cells

This file contains the Supplementary Figures 1-5. Supplementary Figure 1. Phospho-AMPKα1 levels increase in tumor-MDSC. Supplementary Figure 2. Tumor cell-derived GM-CSF triggers Ampkα expression in MDSC through Stat-5 activation. Supplementary Figure 3. MDSC in human myeloid progenitors treated with GM-CSF plus IL-6 for 7 days. Supplementary Figure 4. Extended survival of Prkaa1-null mice bearing ovarian tumors. Supplementary Figure 5. Effects of Prkaa1KO PMN-MDSC in tumor growth.