Proteases in cancer drug delivery

Whereas protease inhibitors have been developed successfully against hypertension and viral infections, they have failed thus far as cancer drugs. With advances in cancer profiling we now better understand that the tumor "degradome" (i.e. the repertoire of proteases and their natural inhibitors and interaction partners) forms a complex network in which specific nodes determine the global outcome of manipulation of the protease web. However, knowing which proteases are active in the tumor micro-environment, we may tackle cancers with the use of Protease-Activated Prodrugs (PAPs). Here we exemplify this concept for metallo-, cysteine and serine proteases. PAPs not only exist as small molecular adducts, containing a cleavable substrate sequence and a latent prodrug, they are presently also manufactured as various types of nanoparticles. Although the emphasis of this review is on PAPs for treatment, it is clear that protease activatable probes and nanoparticles are also powerful tools for imaging purposes, including tumor diagnosis and staging, as well as visualization of tumor imaging during microsurgical resections

Good Functional Outcome after Prolonged Postanoxic Comatose Myoclonic Status Epilepticus in a Patient Who Had Undergone Bone Marrow Transplantation

In anoxic coma, myoclonic status epilepticus and other nonreactive epileptiform patterns are considered as signs of poor prognosis. We report the case of a good recovery in a prolonged comatose myoclonic status epilepticus (MSE) after a cardiac arrest (CA) treated with mild therapeutic hypothermia (TH) in a patient who had undergone a bone marrow transplantation for Hodgkin's lymphoma. This case emphasizes the opportunity of performing an electroencephalogram (EEG) in the acute period after an hypoxic-ischemic insult and underlines the diagnostic difficulties between MSE and Lance-Adams syndrome, which classically occurs after the patient has regained consciousness, but can also begin while the patient is still comatose or sedated. Major problems in prognostication for postarrest comatose patients will also be pointed out

Last interglacial sea-level proxies in East Africa and the WesternIndian Ocean

National audienc

Pulses of South Atlantic water into the tropical North Atlantic since 1825 from coral isotopes.

Decadal and multidecadal changes in the meridional overturning circulation may originate from either the subpolar North Atlantic or the Southern Hemisphere. New records of carbon and oxygen isotopes from an eastern Martinique Island (Lesser Antilles) coral reveal irregular, decadal, double-step events of low ∆14C and enhanced vertical mixing, high δ18O and high δ13C values starting in 1885. Comparison of the new and published ∆14C records indicates that the last event (1956-1969) coincides with a widespread, double-step ∆14C low of South Atlantic origin from 32°N to 18°S, associated with a major slowdown of the Caribbean Current transport between 1963 and 1969. This event and the past Martinique ∆14C lows are attributed to pulses of northward advection of low ∆14C Sub-Antarctic Mode Waters into the tropical Atlantic. They are coeval with changes of the tropical freshwater budget and likely driven by meridional overturning circulation changes since ~1880

Pulses of South Atlantic water into the tropical North Atlantic since 1825 from coral isotopes

International audienceDecadal and multidecadal changes in the meridional overturning circulation may originate from either the subpolar North Atlantic or the Southern Hemisphere. New records of carbon and oxygen isotopes from an eastern Martinique Island (Lesser Antilles) coral reveal irregular, decadal, double-step events of low ∆ 14 C and enhanced vertical mixing, high δ 18 O and high δ 13 C values starting in 1885. Comparison of the new and published ∆ 14 C records indicates that the last event (1956-1969) coincides with a widespread, double-step ∆ 14 C low of South Atlantic origin from 32°N to 18°S, associated with a major slowdown of the Caribbean Current transport between 1963 and 1969. This event and the past Martinique ∆ 14 C lows are attributed to pulses of northward advection of low ∆ 14 C Sub-Antarctic Mode Waters into the tropical Atlantic. They are coeval with changes of the tropical freshwater budget and likely driven by meridional overturning circulation changes since ~1880

Two hundred thirty years of relative sea level changes due to climate and megathrust tectonics recorded in coral microatolls of Martinique (French West Indies)

International audienceWe sampled six coral microatolls that recorded the relative sea level changes over the last 230 years east of Martinique, on fringing reefs in protected bays. The microatolls are cup-shaped, which is characteristic of corals that have been experiencing submergence. X-ray analysis of coral slices and reconstructions of the highest level of survival (HLS) curves show that they have submerged at rates of a few millimeters per year. Their morphology reveals changes in submergence rate around 1829 ± 11, 1895, and 1950. Tide gauges available in the region indicate a regional sea level rise at a constant mean rate of 1.1 ± 0.8 mm/yr, which contrasts with our coral record, implying additional tectonic subsidence. Comparing our coral morphology with that of synthetic corals generated with Matlab by using the Key West tide gauge record (Florida), we show that their growth was controlled by tectonics and that a sudden relative sea level increase drowned them around 1950. Simple elastic models show that this sudden submergence probably occurred during the 21 May 1946 earthquake, which ruptured the plate interface in front of Martinique, in the mantle wedge, in an area of sustained seismic activity. The 1839 M8+ earthquake probably occurred in the same area. Long-term subsidence of microatolls indicates that this deep portion of the megathrust is probably locked down to 60 km depth during the interseismic period. Our oldest coral recorded a long-lasting period (50 years) of stable relative sea level after the 1839 earthquake, indicating that transient interseismic strain rate variations may occur in the Lesser Antilles

Interaction Between Climate and Tectonics in the Northern Lesser Antilles Inferred From the Last Interglacial Shoreline on Barbuda Island

International audienceIn the context of increasing evidence of plate interface coupling variability in subduction zones, there is a need to extend the short time window given by instrumental data and to gather data over multiple time and spatial scales. We hence investigated the long-term topography on Barbuda island, located in the northern part of the Lesser Antilles, west of the Caribbean subduction zone. Following pioneering work using a set of marine terraces on the eastern side of the island, we performed the first U-Th dating on 10 corals in growth position from the lowest terrace, for which the highest relative sea-level (RSL) indicator is found at 9 ± 1 m above the mean sea level. We find that this terrace corresponds to the Last Interglacial (LIG) (ages between 122.8 ± 0.3 ka and 128.1 ± 0.3 ka) and we estimate a paleo RSL of 7 ± 2 m above the current mean sea level. The present elevation of the LIG shoreline on Barbuda might imply tectonics as an additional mechanism to eustatic sea level, mantle dynamic topography and glacial isostatic adjustment. East-west morphological asymmetry of Barbuda and difference in LIG shoreline elevation between Barbuda and Antigua suggest a regional tectonic process. As with the proposed westward tilting from the forearc to the volcanic arc of the Guadeloupe archipelago, vertical deformation on Barbuda could be related to plate-scale subduction processes. Long-term uplift of Barbuda might be related to the accumulation of residual coseismic deformation not fully recovered by interseismic subsidence and the corresponding seismogenic segment would extend below the Moho