Distinguishing choroidal nevi from melanomas using the MOLES algorithm: Evaluation in an ocular nevus clinic

OBJECTIVE: The aim of this study was to determine the sensitivity and specificity of the MOLES scoring system in differentiating choroidal melanomas from nevi according to Mushroom shape, Orange pigment, Large tumor size, Enlarging tumor, and Subretinal fluid (SRF). METHODS: Color photographs, fundus-autofluorescence images, and optical coherence tomography of 222 melanocytic choroidal tumors were reviewed. Each MOLES feature was retrospectively scored between 0 and 2 and tumors categorized as "common nevus,""low-risk nevus,""high-risk nevus,"and "probable melanoma"according to the total score. MOLES scores were compared with the experts' diagnosis of melanoma. RESULTS: The MOLES scoring system indicated melanoma in all 81 tumors diagnosed as such by ocular oncologists (100% sensitivity) and nevus in 135 of 141 tumors given this diagnosis by these experts (95.7% specificity). Of the 6 tumors with discordant diagnoses, 4 had basal diameters exceeding 6 mm, all with SRF and/or orange pigment, and 2 small tumors showed either significant SRF with traces of orange pigment, or vice versa. CONCLUSIONS: The MOLES system for diagnosing melanocytic choroidal tumors compares well with expert diagnosis but needs to be evaluated when deployed by ophthalmologists and community optometrists in a wide variety of working environments

Adjuvant External Beam Radiotherapy Following Enucleation of Eyes With Extraocular Extension From Uveal Melanoma

PURPOSE: To report local disease control and all-cause mortality in patients with extraocular extension (EOE) of uveal melanoma undergoing enucleation followed by observation or external beam radiotherapy (EBRT). METHODS: Charts of patients enucleated between January 1, 1997 and December 31, 2019, with histopathological evidence of EOE of uveal melanoma were reviewed. RESULTS: The cohort comprised 51 patients with a mean age of 67 ± 15 years, 22 (43%) of whom underwent adjuvant postenucleation EBRT. Risk factors for metastasis included presence of epithelioid cells (29/45; 88%), closed loops (20/43; 47%), monosomy 3 (16/25; 64%), and gain of 8q (20/22; 91%). Patients undergoing EBRT had more extensive EOE (median: 5.1 mm vs. 2.6 mm, p = 0.008) and surgical excision was less likely to be histologically complete (2/20; 10% vs. 14/25; 56%, p = 0.002). Local side effects following EBRT were seen in 64% (14/22). At latest follow up, 59% of patients (30/51) were alive, with a median follow up of 1.8 years (interquartile range: 2.9; range: 0.1-6.5]. By Kaplan-Meier survival analysis, the 5- and 10-year overall survival rates were 56% and 12%, respectively. There was no difference in all-cause mortality between those receiving adjuvant EBRT and those who were observed (log rank, p = 0.273). No cases of orbital recurrence were documented. CONCLUSIONS: Orbital EBRT causes significant morbidity. Cases with relatively small EOE undergoing enucleation can be safely observed, without adjuvant EBRT. Multicenter studies are required to better assess the role of EBRT when EOE is more extensive

Caustic Waste-Soil Weathering Reactions and Their Impacts on Trace Contaminant Migration and Sequestration

The principal goal of this project was to assess the molecular nature and stability of radionuclide immobilization during weathering reactions in bulk Hanford sediments and their high surface area clay mineral constitutents

Speciation and fate of trace metals in estuarine sediments under reduced and oxidized conditions, Seaplane Lagoon, Alameda Naval Air Station (USA)

We have identified important chemical reactions that control the fate of metal-contaminated estuarine sediments if they are left undisturbed (in situ) or if they are dredged. We combined information on the molecular bonding of metals in solids from X-ray absorption spectroscopy (XAS) with thermodynamic and kinetic driving forces obtained from dissolved metal concentrations to deduce the dominant reactions under reduced and oxidized conditions. We evaluated the in situ geochemistry of metals (cadmium, chromium, iron, lead, manganese and zinc) as a function of sediment depth (to 100 cm) from a 60 year record of contamination at the Alameda Naval Air Station, California. Results from XAS and thermodynamic modeling of porewaters show that cadmium and most of the zinc form stable sulfide phases, and that lead and chromium are associated with stable carbonate, phosphate, phyllosilicate, or oxide minerals. Therefore, there is minimal risk associated with the release of these trace metals from the deeper sediments contaminated prior to the Clean Water Act (1975) as long as reducing conditions are maintained. Increased concentrations of dissolved metals with depth were indicative of the formation of metal HS(- )complexes. The sediments also contain zinc, chromium, and manganese associated with detrital iron-rich phyllosilicates and/or oxides. These phases are recalcitrant at near-neutral pH and do not undergo reductive dissolution within the 60 year depositional history of sediments at this site. The fate of these metals during dredging was evaluated by comparing in situ geochemistry with that of sediments oxidized by seawater in laboratory experiments. Cadmium and zinc pose the greatest hazard from dredging because their sulfides were highly reactive in seawater. However, their dissolved concentrations under oxic conditions were limited eventually by sorption to or co-precipitation with an iron (oxy)hydroxide. About 50% of the reacted CdS and 80% of the reacted ZnS were bonded to an oxide-substrate at the end of the 90-day oxidation experiment. Lead and chromium pose a minimal hazard from dredging because they are bonded to relatively insoluble carbonate, phosphate, phyllosilicate, or oxide minerals that are stable in seawater. These results point out the specific chemical behavior of individual metals in estuarine sediments, and the need for direct confirmation of metal speciation in order to constrain predictive models that realistically assess the fate of metals in urban harbors and coastal sediments

Shadowing in Inelastic Scattering of Muons on Carbon, Calcium and Lead at Low XBj

Nuclear shadowing is observed in the per-nucleon cross-sections of positive muons on carbon, calcium and lead as compared to deuterium. The data were taken by Fermilab experiment E665 using inelastically scattered muons of mean incident momentum 470 GeV/c. Cross-section ratios are presented in the kinematic region 0.0001 < XBj <0.56 and 0.1 < Q**2 < 80 GeVc. The data are consistent with no significant nu or Q**2 dependence at fixed XBj. As XBj decreases, the size of the shadowing effect, as well as its A dependence, are found to approach the corresponding measurements in photoproduction.Comment: 22 pages, incl. 6 figures, to be published in Z. Phys.

The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2 beta

Recognition of the proper start codon on mRNAs is essential for protein synthesis, which requires scanning and involves eukaryotic initiation factors (eIFs) eIF1, eIF1A, eIF2, and eIF5. The carboxyl terminal domain (CTD) of eIF5 stimulates 43S preinitiation complex (PIC) assembly; however, its precise role in scanning and start codon selection has remained unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we identified the binding sites of eIF1 and eIF2β on eIF5-CTD and found that they partially overlapped. Mutating select eIF5 residues in the common interface specifically disrupts interaction with both factors. Genetic and biochemical evidence indicates that these eIF5-CTD mutations impair start codon recognition and impede eIF1 release from the PIC by abrogating eIF5-CTD binding to eIF2β. This study provides mechanistic insight into the role of eIF5-CTD's dynamic interplay with eIF1 and eIF2β in switching PICs from an open to a closed state at start codons.publishedVersio

Poly(amidoamine)-BSA conjugates synthesised by Michael addition reaction retained enzymatic activity

Polymer-protein conjugates are key to overcome some of the therapeutic protein limitations, including inefficient intracellular delivery. Poly(amidoamine)s are bioresponsive polyelectrolytes, which can form complexes with proteins and promote their delivery into the cytosol of cells. To investigate if conjugation would affect the activity of the protein, two poly(amidoamine)-BSA conjugates were synthesised using a “grafted to” method and Michael addition reaction. Following purification, the conjugates were characterised by electrophoresis, size exclusion chromatography (Mn(C1) = 140.7 kDa ; Mn(C2) = 218.6 kDa) and light scattering (Dh(C1) = 37.5 nm ; Dh(C2) = 75.1 nm). As a result of the conjugation with the cationic polymer, the conjugates had a positive zeta potential (?(C1) = +15.4 mV; ?(C2) = +20.2 mV). TNBS assays demonstrated that 16% to 25% of the protein amine groups were modified and HPLC analysis indicated that the amount of protein in the conjugate was 0.76 mg of BSA/mg of PAA (C1) and 0.43 mg of BSA /mg of PAA (C2). Enzymatic assays indicated the conjugates displayed an esterase activity similar (C1) or reduced ~ 35% (C2) compare to BSA. Altogether the results demonstrated that the conjugation of poly(amidoamine)s to a model protein can lead to the formation of bioconjugates that retain the enzymatic activity of the native protein. Such conjugates could have some application in protein delivery and enzyme engineering for biocatalysis and biosensors

Anti-CTLA4 monoclonal antibodies: the past and the future in clinical application

Recently, two studies using ipilimumab, an anti-CTLA-4 monoclonal antibody (mab) demonstrated improvements in overall survival in the treatment of advanced melanoma. These studies utilized two different schedules of treatment in different patient categories (first and second line of treatment). However, the results were quite similar despite of different dosage used and the combination with dacarbazine in the first line treatment. We reviewed the result of randomized phase II-III clinical studies testing anti-CTLA-4 antibodies (ipilimumab and tremelimumab) for the treatment of melanoma to focus on practical or scientific questions related to the broad utilization of these products in the clinics. These analyses raised some considerations about the future of these compounds, their potential application, dosage, the importance of the schedule (induction/manteinance compared to induction alone) and their role as adjuvants. Anti-CTLA-4 antibody therapy represents the start of a new era in the treatment of advanced melanoma but we are on the steep slope of the learning curve toward the optimization of their utilization either a single agents or in combination