The data indicate that PDT utilizing a conventional light source is at least as effective as laser-induced treatment in vitro. Furthermore, PDT achieves significant bactericidal activity in the presence of serum and blood when used with the set parameters of 10 J/cm2, 100 mW/cm2 and 12.5 micro g/ml TBO.
Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 highgrade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n ¼ 42), mutation (n ¼ 75), methylation (n ¼ 31), and SNP array analyses (n ¼ 75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1 þ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P ¼ 0.016) compared with the p16 heterogeneous/RB1 þ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1 À subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1 À subgroup showed a significant increase in overall survival (460 months; P ¼ 0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1 À subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1 þ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1 þ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical outcomes. Furthermore, deregulations identified in precursor lesions suggest a key role of this pathway in serous tumor development. Recognition of these categories may identify patients with increased sensitivity to chemotherapy and new opportunities for novel therapeutics.
Two invasion-related loci, apiA and the two-gene operon apiBC, were isolated from the oral pathogen Actinobacillus actinomycetemcomitans UT32. apiA encodes a 32.5 kDa protein that migrates on SDS-PAGE as a 101 kDa protein as detected by Western blot analysis or silver staining of an outer membrane-enriched fraction of Escherichia coli transformants. E. coli expressing ApiA have a different phenotype than the host vector, in broth and on solid media, and a colony morphology that resembles that of fresh A. actinomycetemcomitans isolates. These E. coli transformants bound to chicken collagen type II, human collagen type II, III, V and fibronectin. apiB and apiC encode proteins of 130.1 and 70.6 kDa, respectively. ApiBC conferred on E. coli a slightly enhanced ability to bind to collagen type III. ApiA- and ApiB-deficient mutants were constructed in A. actinomycetemcomitans. The ApiB-mutant had 4-fold diminished invasion of KB cells; the ApiA-mutant had increased invasion. Both loci were found in all A. actinomycetemcomitans strains, although polymorphism was detected only for apiBC. The deduced sequences of these invasion-related proteins are homologous to members of the YadA adhesin/invasin family.
The results show the importance of investigating patients without prior family history for the presence of mutational mosaicism, as detecting this would enable appropriate genetic screening and targeted medical care for at-risk children of mosaic patients.
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