We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma. Second, there are the immunotherapies, with anti-CTLA-4 and anti-PD-1 antibodies that are used for patients harboring a B-Raf wild-type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.

Aim: The aim of this work was to characterize rabbit ear skin in view of its use in transdermal permeation experiments. Method: The characterization included histological analysis of the tissue, qualitative and quantitative analysis of stratum corneum (SC) lipids, differential scanning calorimetry and permeation experiments (caffeine, nicotinamide, progesterone). As a reference, pig ear skin was used. Results: The results obtained show that rabbit ear skin has a similar SC thickness compared to pig skin although the viable epidermis has a different structure. The lipid composition of rabbit SC was similar to pig SC but was characterized by a lower content of ceramides and a higher content of cholesterol esters and triglycerides. In terms of permeability, rabbit ear skin was 4–7 times less permeable to hydrophilic compounds, probably because of the higher lipophilicity of its SC. The permeability to progesterone was comparable between isolated pig epidermis and rabbit ear skin. Conclusion: Overall, the results obtained in this work support the usefulness of rabbit ear skin as barrier for skin penetration studies, for both lipophilic and hydrophilic permeants.

Highlights d SIV-specific CD8 + T cells in acute infection show poor SIVsuppressive activity ex vivo d SIV-suppressive activity increases over time in SIV controllers preceding viral control d Controllers develop memory-like CD8 + T cells, which seems to favor protective immunity d Cells from non-controllers have a skewed phenotype and fail to gain antiviral potential

International audienceThe aim of this study is to identify, in a small catchment area located within a tropical forest, the pedological compartments in which the export of nutrients and chemical erosion of solutes occur during a stormflow event. The catchment area displays two types of lateral flow: (i) overland flow at the surface of the soil in the litter and root mat and (ii) groundwater flow in a macroporous subsurface horizon. We interpret the variations of stream-water chemistry during a storm-flow event using the separation of storm-flow hydrograph data between overland and groundwater flow, and (Cl as a chemical parameter characterizing the residence time of water in the soil. It appears that K+ especially was released into the throughfall, whereas Ca++, Mg++ and Na+ were clearly released from the litter. K+ disappeared rapidly from soil solution, whereas Ca++ and Mg++ were more progressively absorbed by the vegetation. The Ca++ and Mg++ contents in groundwater increased with increasing residence time owing to the transpiration of trees. The export of H4SiO4 in the overland flow was moderate, i.e. 24% of total H4SiO4 export in the stream flow, as overland flow represented 39% of total runoff. The subsurface horizon—where active groundwater flow occurs—was successively affected by chemical erosion during the storm-flow peak, and then by neoformation of kaolinite favoured by increasing water residence time

In the originally published version of this article, coauthor Andrew M. Intlekofer was listed incorrectly as Andrew M. Intlekoffer and coauthor Nicole R. LeBoeuf was listed incorrectly as Nicole LaBoeuf. These errors have now been corrected here and in the article online. The authors apologize for the errors and any inconvenience that may have resulted.

A new phase-transition mastering (PTM) process was developed for Blu-ray Disc read-only memory (BD-ROM) mastering. Results obtained with both a 266 and 405 nm laser beam recorder (LBR) are discussed in this paper. The feasibility of BD-ROM mastering was successfully demonstrated on both LBRs. With the insight that 25 Gbytes BD-ROM can be mastered with a 405 nm wavelength LBR, the availability of the 266 nm wavelength LBR opened the route to explore PTM of near-field data densities. First experiments indicate that the PTM process is also suitable for mastering data densities beyond 25 Gbytes data density.

27Highly efficient virus-specific CD8 + T-cells are associated with immune control of HIV 28 infection, but it remains unclear how these cells are generated and maintained over time. 29 We used a macaque model of spontaneous control of SIVmac251 infection to monitor the 30 development and evolution of potent antiviral CD8 + T-cell responses. SIV-specific CD8 + T-31 cells emerged during primary infection in all animals. However, the ability of CD8 + T cells to 32 suppress SIV replication was low in early stages but increased after a period of maturation, 33 temporally linked with the establishment of sustained low-level viremia in controller 34 macaques. SIV-specific CD8 + T-cells with a central memory phenotype expressed higher 35 levels of survival markers in controllers versus non-controllers. In contrast, a persistently 36 skewed differentiation phenotype was observed among central memory SIV-specific CD8 + T-37 cells in non-controllers since primary infection, typified by relatively high expression levels of 38 T-bet.