NOXA as critical mediator for drug combinations in polychemotherapy

During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug–drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA-independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens

Expedition 376 summary

Volcanic arcs are the surface expression of magmatic systems that result from subduction of mostly oceanic lithosphere at convergent plate boundaries. Arcs with a submarine component include intraoceanic arcs and island arcs that span almost 22,000 km on Earth’s surface, and the vast majority of them are located in the Pacific region. Hydrothermal systems hosted by submarine arc volcanoes commonly contain a large component of magmatic fluid. This magmatic-hydrothermal signature, coupled with the shallow water depths of arc volcanoes and their high volatile contents, strongly influences the chemistry of the fluids and resulting mineralization and likely has important consequences for the biota associated with these systems. The high metal content and very acidic fluids in these hydrothermal systems are thought to be important analogs to numerous porphyry copper and epithermal gold deposits mined today on land. During International Ocean Discovery Program (IODP) Expedition 376 (5 May–5 July 2018), a series of five sites was drilled on Brothers volcano in the Kermadec arc. The expedition was designed to provide the missing link (i.e., the third dimension) in our understanding of hydrothermal activity and mineral deposit formation at submarine arc volcanoes and the relationship between the discharge of magmatic fluids and the deep biosphere. Brothers volcano hosts two active and distinct hydrothermal systems: one is seawater influenced and the other is affected by magmatic fluids (largely gases). In total, 222.4 m of volcaniclastics and lavas were recovered from the five sites drilled, which include Sites U1527 and U1530 in the Northwest (NW) Caldera seawater-influenced hydrothermal field; Sites U1528 and U1531 in the magmatic fluid-influenced hydrothermal fields of the Upper and Lower Cones, respectively; and Site U1529, located within an area of low crustal magnetization that marks the West (W) Caldera upflow zone on the caldera floor. Downhole logging and borehole fluid sampling were completed at two sites, and two tests of a prototype turbine-driven coring system (designed by the Center for Deep Earth Exploration [CDEX] at Japan Agency for Marine-Earth Science and Technology [JAMSTEC]) for drilling and coring hard rocks were conducted. Core recovered from all five sites consists of dacitic volcaniclastics and lava flows with only limited chemical variability relative to the overall range in composition of dacites in the Kermadec arc. Pervasive alteration with complex and variable mineral assemblages attest to a highly dynamic hydrothermal system. The upper parts of several drill holes at the NW Caldera hydrothermal field are characterized by secondary mineral assemblages of goethite + opal + zeolites that result from low-temperature (<150°C) reaction of rock with seawater. At depth, NW Caldera Site U1527 exhibits a higher temperature (~250°C) secondary mineral assemblage dominated by chlorite + quartz + illite + pyrite. An older mineral assemblage dominated by diaspore + quartz + pyrophyllite + rutile at the bottom of Hole U1530A is indicative of acidic fluids with temperatures of ~230°–320°C. In contrast, the alteration assemblage at Site U1528 on the Upper Cone is dominated by illite + natroalunite + pyrophyllite + quartz + opal + pyrite, which attests to high-temperature reaction of rocks with acid-sulfate fluids derived from degassed magmatic volatiles and the disproportionation of magmatic SO2. These intensely altered rocks exhibit extreme depletion of major cation oxides, such as MgO, K2O, CaO, MnO, and Na2O. Furthermore, very acidic (as low as pH 1.8), relatively hot (≤236°C) fluids collected at 160, 279, and 313 meters below seafloor in Hole U1528D have chemical compositions indicative of magmatic gas input. In addition, preliminary fluid inclusion data provide evidence for involvement of two distinct fluids: phase-separated (modified) seawater and a ~360°C hypersaline brine, which alters the volcanic rock and potentially transports metals in the system. The material and data recovered during Expedition 376 provide new stratigraphic, lithologic, and geochemical constraints on the development and evolution of Brothers volcano and its hydrothermal systems. Insights into the consequences of the different types of fluid–rock reactions for the microbiological ecosystem elucidated by drilling at Brothers volcano await shore-based studies

Semi-groupe de Lie associé à un cône symétrique

Volcanic arcs are the surface expression of magmatic systems that result from the subduction of mostly oceanic lithosphere at convergent plate boundaries. Arcs with a submarine component include intraoceanic arcs and island arcs that span almost 22,000 km on Earth\u27s surface, the vast majority of which are located in the Pacific region. Hydrothermal systems hosted by submarine arc volcanoes commonly contain a large component of magmatic fluid. This magmatic-hydrothermal signature, coupled with the shallow water depths of arc volcanoes and their high volatile contents, strongly influences the chemistry of the fluids and resulting mineralization and likely has important consequences for the biota associated with these systems. The high metal contents and very acidic fluids in these hydrothermal systems are thought to be important analogs to numerous porphyry copper and epithermal gold deposits mined today on land

Critical role of caldera collapse in the formation of seafloor mineralization: The case of Brothers volcano

Hydrothermal systems hosted by submarine arc volcanoes commonly include a large component of magmatic fluid. The high Cu-Au contents and strongly acidic fluids in these systems are similar to those that formed in the shallow parts of some porphyry copper and epithermal gold deposits mined today on land. Two main types of hydrothermal systems occur along the submarine portion of the Kermadec arc (offshore New Zealand): magmatically influenced and seawater-dominated systems. Brothers volcano hosts both types. Here, we report results from a series of drill holes cored by the International Ocean Discovery Program into these two types of hydrothermal systems. We show that the extent of hydrothermal alteration of the host dacitic volcaniclastics and lavas reflects primary lithological porosity and contrasting spatial and temporal contributions of magmatic fluid, hydrothermal fluid, and seawater. We present a two-step model that links the changes in hydrothermal fluid regime to the evolution of the volcano caldera. Initial hydrothermal activity, prior to caldera formation, was dominated by magmatic gases and hypersaline brines. The former mixed with seawater as they ascended toward the seafloor, and the latter remained sequestered in the subsurface. Following caldera collapse, seawater infiltrated the volcano through fault-controlled permeability, interacted with wall rock and the segregated brines, and transported associated metals toward the seafloor and formed Cu-Zn-Au-rich chimneys on the caldera walls and rim, a process continuing to the present day. This two-step process may be common in submarine arc caldera volcanoes that host volcanogenic massive sulfide deposits, and it is particularly efficient at focusing mineralization at, or near, the seafloor

Preliminary Characterization of Submarine Basalt Magnetic Mineralogy Using Amplitude‐Dependence of Magnetic Susceptibility

Abstract The past ∼200 million years of Earth's geomagnetic field behavior have been recorded within oceanic basalts, many of which are only accessible via scientific ocean drilling. Obtaining the best possible paleomagnetic measurements from such valuable samples requires an a priori understanding of their magnetic mineralogies when choosing the most appropriate protocol for stepwise demagnetization experiments (either alternating field or thermal). Here, we present a quick, and non‐destructive method that utilizes the amplitude‐dependence of magnetic susceptibility to screen submarine basalts prior to choosing a demagnetization protocol, whenever conducting a pilot study or other detailed rock‐magnetic characterization is not possible. We demonstrate this method using samples acquired during International Ocean Discovery Program Expedition 391. Our approach is rooted in the observation that amplitude‐dependent magnetic susceptibility is observed in basalt samples whose dominant magnetic carrier is multidomain titanomagnetite (∼TM60–65, (Ti0.60–0.65Fe0.35–0.40)Fe2O4). Samples with low Ti contents within titanomagnetite or samples that have experienced a high degree of oxidative weathering do not display appreciable amplitude dependence. Due to their low Curie temperatures, basalts that possess amplitude‐dependence should ideally be demagnetized either using alternating fields or via finely‐spaced thermal demagnetization heating steps below 300°C. Our screening method can enhance the success rate of paleomagnetic studies of oceanic basalt samples