Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors.

The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors.

Comparing Seamounts and Coral Reefs with eDNA and BRUVS Reveals Oases and Refuges on Shallow Seamounts.

Seamounts are the least known ocean biome. Considered biodiversity hotspots, biomass oases, and refuges for megafauna, large gaps exist in their real diversity relative to other ecosystems like coral reefs. Using environmental DNA metabarcoding (eDNA) and baited video (BRUVS), we compared fish assemblages across five environments of different depths: coral reefs (15 m), shallow seamounts (50 m), continental slopes (150 m), intermediate seamounts (250 m), and deep seamounts (500 m). We modeled assemblages using 12 environmental variables and found depth to be the main driver of fish diversity and biomass, although other variables like human accessibility were important. Boosted Regression Trees (BRT) revealed a strong negative effect of depth on species richness, segregating coral reefs from deep-sea environments. Surprisingly, BRT showed a hump-shaped effect of depth on fish biomass, with significantly lower biomass on coral reefs than in shallowest deep-sea environments. Biomass of large predators like sharks was three times higher on shallow seamounts (50 m) than on coral reefs. The five studied environments showed quite distinct assemblages. However, species shared between coral reefs and deeper-sea environments were dominated by highly mobile large predators. Our results suggest that seamounts are no diversity hotspots for fish. However, we show that shallower seamounts form biomass oases and refuges for threatened megafauna, suggesting that priority should be given to their protection.

In vitro hyperspectral biomarkers of human chondrosarcoma cells in nanoparticle-mediated radiosensitization using carbon ions.

New therapeutic approaches are needed for the management of the highly chemo- and radioresistant chondrosarcoma (CHS). In this work, we used polyethylene glycol-encapsulated iron oxide nanoparticles for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to augment the cytotoxic effects of carbon ions in comparison to photon radiation therapy. The in vitro biological effects were investigated in SW1353 chondrosarcoma cells focusing on the following parameters: cell survival using clonogenic test, detection of micronuclei (MN) by cytokinesis blocked micronucleus assay and morphology together with spectral fingerprints of nuclei using enhanced dark-field microscopy (EDFM) assembled with a hyperspectral imaging (HI) module. The combination of IONPDOX with ion carbon or photon irradiation increased the lethal effects of irradiation alone in correlation with the induction of MN. Alterations in the hyperspectral images and spectral profiles of nuclei reflected the CHS cell biological modifications following the treatments, highlighting possible new spectroscopic markers of cancer therapy effects. These outcomes showed that the proposed combined treatment is promising in improving CHS radiotherapy.

Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions.

Chondrosarcoma is a malignant cartilaginous tumor that is particularly chemoresistant and radioresistant to X-rays. The first line of treatment is surgery, though this is almost impossible in some specific locations. Such resistances can be explained by the particular composition of the tumor, which develops within a dense cartilaginous matrix, producing a resistant area where the oxygen tension is very low. This microenvironment forces the cells to adapt and dedifferentiate into cancer stem cells, which are described to be more resistant to conventional treatments. One of the main avenues considered to treat this type of tumor is hadrontherapy, in particular for its ballistic properties but also its greater biological effectiveness against tumor cells. In this review, we describe the different forms of chondrosarcoma resistance and how hadrontherapy, combined with other treatments involving targeted inhibitors, could help to better treat high-grade chondrosarcoma.

Label-Free Direct Mass Spectrometry Analysis of the Bystander Effects Induced in Chondrocytes by Chondrosarcoma Cells Irradiated with X-rays and Carbon Ions.

BACKGROUND: Radiation-induced bystander effects are induced changes in cells that were not themselves directly irradiated but were in the vicinity of a radiation path. Such effects, which occur in the microenvironment of an irradiated tumor, remain poorly understood and depend on the cell type and irradiation quality. This study aimed to evaluate bystander effects in non-irradiated chondrocytes that received conditioned medium from irradiated chondrosarcoma cells. METHODS: SW1353 chondrosarcoma cells were irradiated with X-rays and carbon ions, each at 0.1 Gy and 2 Gy, and the conditioned media of the irradiated cells were transferred to T/C-28A2 chondrocytes and Human Umbilical Venous Endothelial Cells (HUVECs). The whole proteome of bystander chondrocytes was analyzed by label-free mass spectrometry, and a comparative study was performed by dose and irradiation quality. HUVECs were evaluated for inflammatory cytokine secretion. RESULTS: The bystander response of chondrocytes to X-ray irradiation primarily affected the protein translation pathway (DHX36, EIF3B, EIF3D, EIF3M, EIF5, RPL6, RPLP0, RPS24, SYNCRIP), IL-12 (AIP, BOLA2, MIF, GAS6, MIF, PDGFRB) and the oxidative stress pathway (MGST3, PRDX2, PXDN, SOD2, TXN, TXNL1). Following carbon-ion irradiation, the G1/S pathway (PCBP4, PSMD12, PSME, XIAP) and mitotic G2 DNA damage checkpoint pathway (MRE11, TAOK1, UIMC1) were engaged. Changes in the regulation of chromosome separation (BCL7C, BUB3, CENPF, DYNC1LI1, SMARCA4, SMC4) were associated with only low-dose X-ray and carbon-ion irradiation. Modification of the protein translation pathway represented at least 30% of bystander effects and could play a role, possibly along with stress granules, in reduction in cellular metabolism to protect proteins. Stress granules were significantly enriched according to an interaction map. CONCLUSIONS: All these accessions corresponded to a window of the proteins modulated in response to the bystander effect. Our chondrosarcoma model clarified the nature of the bystander response of chondrocytes and may suggest several interesting new mechanisms that are specific to particular irradiation doses and qualities.

A Proteomic Study Suggests Stress Granules as New Potential Actors in Radiation-Induced Bystander Effects.

Besides the direct effects of radiations, indirect effects are observed within the surrounding non-irradiated area; irradiated cells relay stress signals in this close proximity, inducing the so-called radiation-induced bystander effect. These signals received by neighboring unirradiated cells induce specific responses similar with those of direct irradiated cells. To understand the cellular response of bystander cells, we performed a 2D gel-based proteomic study of the chondrocytes receiving the conditioned medium of low-dose irradiated chondrosarcoma cells. The conditioned medium was directly analyzed by mass spectrometry in order to identify candidate bystander factors involved in the signal transmission. The proteomic analysis of the bystander chondrocytes highlighted 20 proteins spots that were significantly modified at low dose, implicating several cellular mechanisms, such as oxidative stress responses, cellular motility, and exosomes pathways. In addition, the secretomic analysis revealed that the abundance of 40 proteins in the conditioned medium of 0.1 Gy irradiated chondrosarcoma cells was significantly modified, as compared with the conditioned medium of non-irradiated cells. A large cluster of proteins involved in stress granules and several proteins involved in the cellular response to DNA damage stimuli were increased in the 0.1 Gy condition. Several of these candidates and cellular mechanisms were confirmed by functional analysis, such as 8-oxodG quantification, western blot, and wound-healing migration tests. Taken together, these results shed new lights on the complexity of the radiation-induced bystander effects and the large variety of the cellular and molecular mechanisms involved, including the identification of a new potential actor, namely the stress granules.

Evidence for mitigation of coral bleaching by manganese.

Unprecedented mass coral bleaching events due to global warming and overall seawater pollution have been observed worldwide over the last decades. Although metals are often considered as toxic substances for corals, some are essential at nanomolar concentrations for physiological processes such as photosynthesis and antioxidant defenses. This study was designed to elucidate, the individual and combined effects of nanomolar seawater enrichment in manganese (Mn) and iron (Fe), on the main physiological traits of Stylophora pistillata, maintained under normal growth and thermal stress conditions. We provide, for the first time, evidence that Mn is a key trace element for coral symbionts, enhancing cellular chlorophyll concentrations, photosynthetic efficiency and gross photosynthetic rates at ambient temperature. Our experiment also highlights the key role of Mn in increasing coral resistance to heat stress-induced bleaching. While Mn-enriched corals did not bleach and did not reduce their rates of photosynthesis and calcification, control corals experienced significant bleaching. On the contrary to Mn, Fe enrichment not only impaired calcification but induced significant bleaching. Such information is an important step towards a better understanding of the response of corals to seawater enrichment in metals. It can also explain, to some extent, species susceptibility to environmental stress.

Power analysis as a tool to identify statistically informative indicators for monitoring coral reef disturbances.

Extensive biological field surveys are costly and time consuming. To optimize sampling and ensure regular monitoring on the long term, identifying informative indicators of anthropogenic disturbances is a priority. In this study, we used 1800 candidate indicators by combining metrics measured from coral, fish, and macro-invertebrate assemblages surveyed from 2006 to 2012 in the vicinity of an ongoing mining project in the Voh-Koné-Pouembout lagoon, New Caledonia. We performed a power analysis to identify a subset of indicators which would best discriminate temporal changes due to a simulated chronic anthropogenic impact. Only 4% of tested indicators were likely to detect a 10% annual decrease of values with sufficient power (>0.80). Corals generally exerted higher statistical power than macro-invertebrates and fishes because of lower natural variability and higher occurrence. For the same reasons, higher taxonomic ranks provided higher power than lower taxonomic ranks. Nevertheless, a number of families of common sedentary or sessile macro-invertebrates and fishes also performed well in detecting changes: Echinometridae, Isognomidae, Muricidae, Tridacninae, Arcidae, and Turbinidae for macro-invertebrates and Pomacentridae, Labridae, and Chaetodontidae for fishes. Interestingly, these families did not provide high power in all geomorphological strata, suggesting that the ability of indicators in detecting anthropogenic impacts was closely linked to reef geomorphology. This study provides a first operational step toward identifying statistically relevant indicators of anthropogenic disturbances in New Caledonia's coral reefs, which can be useful in similar tropical reef ecosystems where little information is available regarding the responses of ecological indicators to anthropogenic disturbances.

Growth, Survival and Reproduction of the Giant Clam Tridacna maxima (Röding 1798, Bivalvia) in Two Contrasting Lagoons in French Polynesia.

Shell growth, reproduction, and natural mortality of the giant clam Tridacna maxima were characterized over a two-year-period in the lagoon of the high island of Tubuai (Austral Archipelago) and in the semi-closed lagoon of Tatakoto (Tuamotu Archipelago) in French Polynesia. We also recorded temperature, water level, tidal slope, tidal range, and mean wave height in both lagoons. Lower lagoon aperture and exposure to oceanic swells at Tatakoto than at Tubuai was responsible for lower lagoon water renewal, as well as higher variability in temperature and water level at Tatakoto across the studied period. These different environmental conditions had an impact on giant clams. Firstly, spawning events in the lagoon of Tatakoto, detected by gonad maturity indices in June and July 2014, were timed with high oceanic water inflow and a decrease in lagoon water temperature. Secondly, temperature explained differences in shell growth rates between seasons and lagoons, generating different growth curves for the two sites. Thirdly, local mortality rates were also found to likely be related to water renewal patterns. In conclusion, our study suggests that reef aperture and lagoon water renewal rates play an integral role in giant clam life history, with significant differences in rates of shell growth, mortality and fertility found between open versus semi-closed atoll lagoons in coral reef ecosystems.

Localised and limited impact of a dredging operation on coral cover in the northwestern lagoon of New Caledonia.

We report here an interannual survey (2006-2012) of coral cover in the northwestern lagoon of New Caledonia, to assess the impact of an important dredging operation (August 2008-February 2010) associated with the construction of the largest nickel mining site in the Pacific. A BACI (Before-After Control-Impact) analysis failed to detect any significant interaction between period (before, during, and after dredging) and the category of the stations (impact vs. control). Among the 31 stations surveyed, only seven showed decreasing coral cover during the study period, mainly due to a decline in Acroporidae. However, the relationship between the dredging and this decrease was highly plausible only for one station, situated 0.9km from the dredging site. High hydrodynamism in the study area, the abundance of resistant corals and efficient protective measures during the dredging operation might explain these localised and limited impacts.

Endangered New Caledonian endemic mushroom coral Cantharellus noumeae in turbid, metal-rich, natural and artificial environments.

Since its description in 1984, little attention has been paid to the New Caledonian endemic mushroom coral Cantharellus noumeae (Fungiidae), an IUCN Red-listed, endangered coral species. Our study presents the first ever quantitative assessment conducted on C. noumeae populations for two contrasting sites in the same turbid bay. Sites differed by their substrates of artificial or natural origins. Metal concentrations of superficial sediment were measured. C. noumeae was found in high densities in metal-rich and turbid environments at both locations, reaching up to 288 individuals per 50m(2). It was 3.5 times more abundant on natural rock than on artificial substrates. Recruitment was also higher proportionally on rock (47% vs 7-14%). The composition of the associated coral communities included 30-37 species occurring in low densities. Our findings clarify the environmental niche of this species and its colonization potential, in order to eventually better characterize its conservation status.

Alert thresholds for monitoring environmental variables: a new approach applied to seagrass beds diversity in New Caledonia.

Monitoring ecological variables is mandatory to detect abnormal changes in ecosystems. When the studied variables exceed predefined alert thresholds, management actions may be required. In the past, alert thresholds have been typically defined by expert judgments and descriptive statistics. Recently, approaches based on statistical power were also used. In New Caledonia, seagrass monitoring is a priority given their vulnerability to natural and anthropic disturbances. To define a suitable monitoring strategy and alert thresholds, we compared a Percentile Based Approach (PBA) and a sensitivity analysis of power (SAP). Both methods defined statistically relevant alert thresholds, but the SAP approach was more robust to spatial and temporal variability of seagrass cover. Moreover, this method characterized the sensitivity of threshold values to sampling efforts, a useful knowledge for managers.

Best management strategies for sustainable giant clam fishery in French Polynesia islands: answers from a spatial modeling approach.

The giant clam Tridacna maxima has been largely overexploited in many tropical regions over the past decades, and was therefore listed in appendix II of the Convention of International Trade in Endangered Species (CITES) in 1985. In French Polynesia, several atolls and islands harbor the world's highest stocks of giant clams in very shallow and accessible areas, which are therefore highly vulnerable to fishing pressure. The local fishery authority (i.e., Direction des Resources Marines or "DRM") implemented several management schemes in 2002 to control and regulate fishing pressure. However, for further decisions DRM was missing a sensitivity analysis on the effectiveness of the possible management actions. Here, we report on the use of a deterministic Viable Population Analysis (VPA) and spatially-explicit age-based population model that simulated the 30-year trajectory of a Tridacna maxima stock under different management approaches. Specifically, given various scenarios of intra-island larval dispersal, we tested which of No-take-Areas (NTAs), rotational closures, size limits, quotas, and restocking schemes would lead to the highest future stocks in Tubuai and Raivavae, two exploited islands of the Austral archipelago. For both islands, stock abundances were estimated in 2004/2010 and 2005/2010 respectively, and natural mortalities were assessed previously only in Tubuai. When compared to field data, the model successfully predicted the 2010 stocks for Tubuai, but proved to be less reliable for Raivavae, where natural mortality rates may well be different from those on Tubuai. For Tubuai, the spatial model suggested that reducing fishing effort (through fixed quotas) and banning fishing below the 12 cm size limit (as currently implemented) were the most effective management actions to sustain T. maxima populations into the future. Implementing NTAs was of poor effectiveness. NTAs increased giant clam stock inside the protected area, but also increased overfishing in the neighboring areas, and were ineffective overall.