Cellular radiosensitivity of primary and metastatic human uveal melanoma cell lines

PURPOSE: To investigate the radiosensitivity of uveal melanoma cell lines by a clonogenic survival assay, to improve the efficiency of the radiation regimen. METHODS: Four primary and four metastatic human uveal melanoma cell lines were cultured in the presence of conditioned medium. After single-dose irradiation (0-12 Gy), colonies were allowed to form for 6 to 14 days. Two cutaneous melanomas cell lines were also tested for comparison. The survival curves were analyzed by the linear quadratic (LQ) model, and the surviving fraction at a dose of 2 Gy (SF(2)), the SF at 10 Gy (SF(10)), the ratio of initial irreparably damaged DNA (alpha-coefficient) to the capacity to repair sublethally damaged DNA (beta-coefficient), and the plating efficiency were calculated. RESULTS: The melanomas displayed a wide range of initial irreparable DNA damage (alpha-component), as well as a capacity for repair of sublethal DNA damage (beta-component), which ultimately resulted in a wide range of alpha/beta ratios. These findings were similar in both primary and metastatic melanomas and were comparable with data obtained from two cutaneous melanomas. CONCLUSIONS: Cell lines obtained from primary and metastatic human uveal melanomas displayed a wide range of radiosensitivity, similar to that published for cutaneous melanomas. Translating these data to the clinical setting indicates that a fractionated dose of 8 to 10 Gy administered in three to four fractions, as currently delivered in many centers, should be sufficient to eradicate tumors of approximately 1 cm(3)

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Human neurology The Human Central Nervous System: A Synopsis and Atlas. 3rd revised ed. Ed. by R. Nieuwenhuys, J. Voogd, C. H. R. van Huijzen. Pp. xii + 437. Illustrated. DM 85. Berlin: SpringerVerlag. 1988.Paediatric respiratory disorders Kendig's Disorders of the Respiratory Tract in Children. 5th ed. Ed. by Victor Chernick. Consulting ed. Edwin L. Kendig, jun. Pp. xxi + 1055. Philadelphia: WB Saunders. 1990.Maxillofacial imaging Maxillofacial Imaging. Ed. by A. M. Delbalso. pp. Vlll + 799. Illustrated. Kent: Harcourt Brace Jovanovich. 1990.Introduction to philosophy of medicine Philosophy of Medicine: An Introduction. Ed. by H. R. Wulff, S. A. Pedersen and R. Rosenberg. pp. xv + 222. £14,95. Oxford: Blackwell. 1990.Cataract management Management of Cataract in Primary Health Care Services. Pp. vi + 43. Illustrated. SFr. 15. Geneva: WHO. 1990.Family practice-management Family Practice Management. Ed. by G. J. and C. M. 1. Pistorius. Pp. 587. Illustrated. R99,50. Parow: Haurn/De Jager. J99O.Obstetrics and gynaecology Essential Obstetrics and Gynaecology. By E. Malcolm Symonds. pp. vi + 266. Illustrated. Edinburgh: Maskew Miller Longman.Surgical memoirs Surgical Roots and Branches. Ed. by R. Murley. Pp. x + 341. Illustrated. £18,50. Hamilton: Libriger Book Distribution. 1990.Survival in a hostile environment Staying Alive. Ed. by Ron Reid-Daly. Pp. ix + 259. Illustrated. R49,95. Rivonia: Ashami. 1990.Urolithiasis Urolithiasis: Medical and Surgical Reference. Ed. by M. 1. Resnick and C. Y. C. Pak. Pp. x + 375. Illustrated. R53,50. Kent: Harcoun Brace Jovanovich. 1990.Mental health in primary health care The Introduction of a Mental Health Component into Primary Health Care. pp. 1-59. SFr. 11,50. Geneva: WHO. 1990Tuberculosis in South Africa White Plague, Black Labor: Tuberculosis and the Political Economy of Health and Disease in South Africa. Ed. by Randall M. Packard. pp. xxii + 389. Illustrated. $40 (cloth) and$15,95 (paperback). California: University of California Press. 1989.Medical research Research in Medicine:"A Guide to Writing a Thesis in the Medical Sciences. Ed. by G. Murrell, C. Huang and H. Ellis. PP: xii + 105. Illustrated. £19,50 (hIb) £7,50 (Plb). Cambridge: Cambridge University Press. 1990

Detection of genetic prognostic markers in uveal melanoma biopsies using fluorescence in situ hybridization

PURPOSE: In uveal melanoma, specific chromosomal abnormalities are known to correlate with the risk of metastases; changes in chromosomes 3 and 8q correlate strongly with a decreased survival of the patient, whereas chromosome 6 abnormalities are associated with a better prognosis. Usual

Metastatic disease in polyploid uveal melanoma patients is associated with BAP1 mutations

PURPOSE. Most of the uvea melanoma (UM) display a near-diploid (normal, ~2N) karyotype with only a few chromosomal changes. In contrast to these simple aberrations 18% of the UM samples show a polyploid character (>2N) and this was associated with an unfavorable prognosis. This study attempts to gain insight in the prognostic value of polyploidy in UM. METHODS. In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ-hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing. RESULTS. Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P ¼ 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16- fold increased hazard ratio (HR 15.90, P = 0.009). CONCLUSIONS. The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM

Master Sculptor at Work: Enteropathogenic Escherichia coli Infection Uniquely Modifies Mitochondrial Proteolysis during Its Control of Human Cell Death

Enteropathogenic Escherichia coli (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject 20 effector proteins into human intestinal cells. Three effectors travel to mitochondria and modulate apoptosis; however, the mechanisms by which effectors control apoptosis from within mitochondria are unknown. To identify and quantify global changes in mitochondrial proteolysis during infection, we applied the mitochondrial terminal proteomics technique mitochondrial stable isotope labeling by amino acids in cell culture-terminal amine isotopic labeling of substrates (MS-TAILS). MS-TAILS identified 1,695 amino N-terminal peptides from 1,060 unique proteins and 390 N-terminal peptides from 215 mitochondrial proteins at a false discovery rate of 0.01. Infection modified 230 cellular and 40 mitochondrial proteins, generating 27 cleaved mitochondrial neo-N termini, demonstrating altered proteolytic processing within mitochondria. To distinguish proteolytic events specific to EPEC from those of canonical apoptosis, we compared mitochondrial changes during infection with those reported from chemically induced apoptosis. During infection, fewer than half of all mitochondrial cleavages were previously described for canonical apoptosis, and we identified nine mitochondrial proteolytic sites not previously reported, including several in proteins with an annotated role in apoptosis, although none occurred at canonical Asp-Glu-Val-Asp (DEVD) sites associated with caspase cleavage. The identification and quantification of novel neo-N termini evidences the involvement of noncaspase human or EPEC protease(s) resulting from mitochondrialtargeting effectors that modulate cell death upon infection. All proteomics data are available via ProteomeXchange with identifier PXD016994. IMPORTANCE To our knowledge, this is the first study of the mitochondrial proteome or N-terminome during bacterial infection. Identified cleavage sites that had not been previously reported in the mitochondrial N-terminome and that were not generated in canonical apoptosis revealed a pathogen-specific strategy to control human cell apoptosis. These data inform new mechanisms of virulence factors targeting mitochondria and apoptosis during infection and highlight how enteropathogenic Escherichia coli (EPEC) manipulates human cell death pathways during infection, including candidate substrates of an EPEC protease within mitochondria. This understanding informs the development of new antivirulence strategies against the many human pathogens that targe

Spliceosome mutations in uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies

Genetics of ocular melanoma: Insights into genetics, inheritance and testing

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. T

Search for charginos in e+e- interactions at sqrt(s) = 189 GeV

An update of the searches for charginos and gravitinos is presented, based on a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by combining the chargino searches with neutralino searches at the Z resonance implies a limit on the mass of the lightest neutralino which, for a heavy sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure

Hadronization properties of b quarks compared to light quarks in e+e- -> q qbar from 183 to 200 GeV

The DELPHI detector at LEP has collected 54 pb^{-1} of data at a centre-of-mass energy around 183 GeV during 1997, 158 pb^{-1} around 189 GeV during 1998, and 187 pb^{-1} between 192 and 200 GeV during 1999. These data were used to measure the average charged particle multiplicity in e+e- -> b bbar events, _{bb}, and the difference delta_{bl} between _{bb} and the multiplicity, _{ll}, in generic light quark (u,d,s) events: delta_{bl}(183 GeV) = 4.55 +/- 1.31 (stat) +/- 0.73 (syst) delta_{bl}(189 GeV) = 4.43 +/- 0.85 (stat) +/- 0.61 (syst) delta_{bl}(200 GeV) = 3.39 +/- 0.89 (stat) +/- 1.01 (syst). This result is consistent with QCD predictions, while it is inconsistent with calculations assuming that the multiplicity accompanying the decay of a heavy quark is independent of the mass of the quark itself.Comment: 13 pages, 2 figure

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results