Adjuvant low-dose interferon α2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis

Background: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) α2a with or without dacarbazine (DTIC) compared with observation alone. Patients and methods: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNα2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNα2a plus DTIC 850 mg/m2 every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. Results: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNα2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). Conclusions: 3 MU interferon α2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon α2a therap

Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF

Composition and distribution of the peracarid crustacean fauna along a latitudinal transect off Victoria Land (Ross Sea, Antarctica) with special emphasis on the Cumacea

The following study was the first to describe composition and structure of the peracarid fauna systematically along a latitudinal transect off Victoria Land (Ross Sea, Antarctica). During the 19th Antarctic expedition of the Italian research vessel “Italica” in February 2004, macrobenthic samples were collected by means of a Rauschert dredge with a mesh size of 500 m at depths between 85 and 515 m. The composition of peracarid crustaceans, especially Cumacea was investigated. Peracarida contributed 63% to the total abundance of the fauna. The peracarid samples were dominated by amphipods (66%), whereas cumaceans were represented with 7%. Previously, only 13 cumacean species were known, now the number of species recorded from the Ross Sea increased to 34. Thus, the cumacean fauna of the Ross Sea, which was regarded as the poorest in terms of species richness, has to be considered as equivalent to that of other high Antarctic areas. Most important cumacean families concerning abundance and species richness were Leuconidae, Nannastacidae, and Diastylidae. Cumacean diversity was lowest at the northernmost area (Cape Adare). At the area off Coulman Island, which is characterized by muddy sediment, diversity was highest. Diversity and species number were higher at the deeper stations and abundance increased with latitude. A review of the bathymetric distribution of the Cumacea from the Ross Sea reveals that most species distribute across the Antarctic continental shelf and slope. So far, only few deep-sea records justify the assumption of a shallow-water–deep-sea relationship in some species of Ross Sea Cumacea, which is discussed from an evolutionary point of view

Dacarbazine and interferon α with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG)

In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2. This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon α (IFN-α) only to that of therapy with DTIC and IFN-α with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy. 290 patients were randomized to receive either DTIC (850 mg/m2every 28 days) plus IFN-α2a/b (3 MIU/m2, twice on day 1, once daily from days 2 to 5; 5 MIU/m23 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m2for 3 hours i.v. on day 3; 9.0 MIU/m2i.v. day 3/4; 4.5 MIU/m2s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms (P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-α as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-α and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-α only (5.6%). In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-α. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.co

Quantitative analysis of soft-bottom molluscs in the Bellingshausen Sea and around Peter I Island

Macrobenthic soft-bottom molluscs were sampled in 30 stations located in the Bellingshausen Sea at depths ranging from 90 to 3304 m. The samples were collected using a quantitative grab box-corer during the cruises BENTART 03, from 24 January to 3 March 2003, and BENTART 06, from 2 January to 16 February 2006. Molluscs represent 1074 specimens belonging to 62 species of Polyplacophora, Gastropoda, Bivalvia and Scaphopoda. The bivalve Cyamiocardium denticulatum was the most abundant species (448 specimens). The abundance per station varied between 1 and 446 specimens. The Shannon–Wiener diversity index ranged between one specimen and 2.36, the Pielou evenness index ranged between 0.00 and 1 and species richness ranged from 1 to 14 species. Diversity showed great variations at different stations. After multivariate analysis (cluster analysis and nonmetrical multidimensional scaling) based on Bray–Curtis similarities, we were able to separate two principal clusters. The first cluster groups together species from shallower bottoms near Peter I Island and the Antarctic Peninsula, and the second cluster groups together species from deeper bottoms in the Bellingshausen Sea. The combination of environmental variables with the highest correlations with faunistic data was that of depth and coarse sand at the surface.Publicado

Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide

Understanding the influence of macromolecular crowding and nanoparticles on the formation of in-register $\beta$-sheets, the primary structural component of amyloid fibrils, is a first step towards describing \emph{in vivo} protein aggregation and interactions between synthetic materials and proteins. Using all atom molecular simulations in implicit solvent we illustrate the effects of nanoparticle size, shape, and volume fraction on oligomer formation of an amyloidogenic peptide from the transthyretin protein. Surprisingly, we find that inert spherical crowding particles destabilize in-register $\beta$-sheets formed by dimers while stabilizing $\beta$-sheets comprised of trimers and tetramers. As the radius of the nanoparticle increases crowding effects decrease, implying smaller crowding particles have the largest influence on the earliest amyloid species. We explain these results using a theory based on the depletion effect. Finally, we show that spherocylindrical crowders destabilize the ordered $\beta$-sheet dimer to a greater extent than spherical crowders, which underscores the influence of nanoparticle shape on protein aggregation

Composition of abyssal macrofauna along the Vema Fracture Zone and the hadal Puerto Rico Trench, northern tropical Atlantic

We analyzed composition and variations in benthic macrofaunal communities along a transect of the entire length of the Vema-Fracture Zone on board of RV Sonne (SO-237) between December 2014 and January 2015 in order to test whether the Mid-Atlantic Ridge serves as a barrier limiting benthic taxon distribution in the abyssal basins on both sides of the ridge or whether the fracture zone permits the migration of species between the western and eastern abyssal Atlantic basins. The Puerto Rico Trench, much deeper than the surrounding abyssal West Atlantic, was sampled to determine whether the biodiversity of its hadal macrofauna differs from that of the abyssal Atlantic. The composition of the macrofauna from the epibenthic sledge catches yielded a total of 21,332 invertebrates. Crustacea occurred most frequently (59%) with 12,538 individuals followed by Annelida (mostly Polychaeta) (26%) with 5,491 individuals, Mollusca (7%) with 1,458 individuals, Echinodermata (4%) with 778 individuals, Nematoda (2%) with 502 individuals and Chaetognatha (1%) with 152 and Porifera (1%) with 131 individuals. All other taxa occurred with overall less than ten individuals (Hemichordata, Phoronida, Priapulida, Brachiopoda, invertebrate Chordata, Echiurida, Foraminifera (here refereed to macrofaunal Komokiacea only), Chelicerata, Platyhelminthes). Within the Crustacea, Peracarida (62.6%) with 7,848 individuals and Copepoda (36.1%) with 44,526 individuals were the most abundant taxa. Along the abyssal Vema-Fracture Zone macrofaunal abundances (ind./1,000 m2) were generally higher on the eastern side, while the highest normalized abundance value was reported in the Puerto Rico Trench at abyssal station 14-1 2,313 individuals/1,000 m2. The lowest abundance was reported at station 11-4 with 120 ind./1,000 m2 located at the western side of the Vema-Fracture Zone. The number of major macrofaunal taxa (phylum, class) ranged between five (stations 12-5, 13-4 and 13-5 at hadal depths in the Puerto Rico Trench) and 14 (station 9-8) in the western abyssal basin of the Vema-Fracture Zone. Differences are seen in the distribution of Porifera at macrofaunal level between eastern and western sides of the Vema-Fracture Zone. Macrofaunal composition of the study area is compared with data from other expeditions in the Atlantic and the northwest Pacific Ocean

The Dynamics of Ca2+ Ions within the Solvation Shell of Calbindin D9k

The encounter of a Ca2+ ion with a protein and its subsequent binding to specific binding sites is an intricate process that cannot be fully elucidated from experimental observations. We have applied Molecular Dynamics to study this process with atomistic details, using Calbindin D9k (CaB) as a model protein. The simulations show that in most of the time the Ca2+ ion spends within the Debye radius of CaB, it is being detained at the 1st and 2nd solvation shells. While being detained near the protein, the diffusion coefficient of the ion is significantly reduced. However, due to the relatively long period of detainment, the ion can scan an appreciable surface of the protein. The enhanced propagation of the ion on the surface has a functional role: significantly increasing the ability of the ion to scan the protein's surface before being dispersed to the bulk. The contribution of this mechanism to Ca2+ binding becomes significant at low ion concentrations, where the intervals between successive encounters with the protein are getting longer. The efficiency of the surface diffusion is affected by the distribution of charges on the protein's surface. Comparison of the Ca2+ binding dynamics in CaB and its E60D mutant reveals that in the wild type (WT) protein the carboxylate of E60 function as a preferred landing-site for the Ca2+ arriving from the bulk, followed by delivering it to the final binding site. Replacement of the glutamate by aspartate significantly reduced the ability to transfer Ca2+ ions from D60 to the final binding site, explaining the observed decrement in the affinity of the mutated protein to Ca2+

Structural Anisotropy in Polar Fluids Subjected to Periodic Boundary Conditions

A heuristic model based on dielectric continuum theory for the long-range solvation free energy of a dipolar system possessing periodic boundary conditions (PBCs) is presented. The predictions of the model are compared to simulation results for Stockmayer fluids simulated using three different cell geometries. The boundary effects induced by the PBCs are shown to lead to anisotropies in the apparent dielectric constant and the long-range solvation free energy of as much as 50%. However, the sum of all of the anisotropic energy contributions yields a value that is very close to the isotropic one derived from dielectric continuum theory, leading to a total system energy close to the dielectric value. It is finally shown that the leading-order contribution to the energetic and structural anisotropy is significantly smaller in the noncubic simulation cell geometries compared to when using a cubic simulation cell

A critical assessment of methods for the intrinsic analysis of liquid interfaces. 1. surface site distributions

Substantial progress in our understanding of interfacial structure and dynamics has stemmed from the recent development of algorithms that allow for an intrinsic analysis of fluid interfaces. These work by identifying the instantaneous location of the interface, at the atomic level, for each molecular configuration and then computing properties relative to this location. Such a procedure eliminates the broadening of the interface caused by capillary waves and reveals the underlying features of the system. However, a precise definition of which molecules actually belong to the interfacial layer is difficult to achieve in practice. Furthermore, it is not known if the different intrinsic analysis methods are consistent with each other and yield similar results for the interfacial properties. In this paper, we carry out a systematic and detailed comparison of the available methods for intrinsic analysis of fluid interfaces, based on a molecular dynamics simulation of the interface between liquid water and carbon tetrachloride. We critically assess the advantages and shortcomings of each method, based on reliability, robustness, and speed of computation, and establish consistent criteria for determining which molecules belong to the surface layer. We believe this will significantly contribute to make intrinsic analysis methods widely and routinely applicable to interfacial systems