Tombstones of Joseph Benjamin and Marianne Benjamin nee Sussmann; Strangriede Cemetery (R 83.8 and R 83.9); Hannover Cemeteries Tombs

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Tombstones of Lea Benjamin nee Levy and Herz Benjamin; Strangriede Cemetery (R 83.11 and R 83.12); Hannover Cemeteries Tombs

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Adolpf Molling, Janet Krakauer nee McColl, Hymie Joachim and Thomas Krakauer (l-r); Weggis, Switzerland Portraits Groups

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Tombstone of Joseph Benjamin; Strangriede Cemetery (R 83.8); Hannover Cemeteries Tombs

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p53 and DNA damage checkpoint responses in the human prostate

Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer mortality in men. In 2004, 5237 new cases were diagnosed and altogether 25 664 men suffered from prostate cancer in Finland (Suomen Syöpärekisteri). Although extensively investigated, we still have a very rudimentary understanding of the molecular mechanisms leading to the frequent transformation of the prostate epithelium. Prostate cancer is characterized by several unique features including the multifocal origin of tumors and extreme resistance to chemotherapy, and new treatment options are therefore urgently needed. The integrity of genomic DNA is constantly challenged by genotoxic insults. Cellular responses to DNA damage involve elegant checkpoint cascades enforcing cell cycle arrest, thus facilitating damage repair, apoptosis or cellular senescence. Cellular DNA damage triggers the activation of tumor suppressor protein p53 and Wee1 kinase which act as executors of the cellular checkpoint responses. These are essential for genomic integrity, and are activated in early stages of tumorigenesis in order to function as barriers against tumor formation. Our work establishes that the primary human prostatic epithelial cells and prostatic epithelium have unexpectedly indulgent checkpoint surveillance. This is evidenced by the absence of inhibitory Tyr15 phosphorylation on Cdk2, lack of p53 response, radioresistant DNA synthesis, lack of G1/S and G2/M phase arrest, and presence of persistent gammaH2AX damage foci. We ascribe the absence of inhibitory Tyr15 phosphorylation to low levels of Wee1A, a tyrosine kinase and negative regulator of cell cycle progression. Ectopic Wee1A kinase restored Cdk2-Tyr15 phosphorylation and efficiently rescued the ionizing radiation-induced checkpoints in the human prostatic epithelial cells. As variability in the DNA damage responses has been shown to underlie susceptibility to cancer, our results imply that a suboptimal checkpoint arrest may greatly increase the accumulation of genetic lesions in the prostate epithelia. We also show that small molecules can restore p53 function in prostatic epithelial cells and may serve as a paradigm for the development of future therapeutic agents for the treatment of prostate cancer We hypothesize that the prostate has evolved to activate the damage surveillance pathways and molecules involved in these pathways only to certain stresses in extreme circumstances. In doing so, this organ inadvertently made itself vulnerable to genotoxic stress, which may have implications in malignant transformation. Recognition of the limited activity of p53 and Wee1 in the prostate could drive mechanism-based discovery of preventative and therapeutic agents.

Portrait of (l-r) unidentified man, Thomas Mann, Singer (painter), Lion Feuchtwanger and unidentified man Portraits Groups Men

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Tombstone of Sophie Molling nee Benjamin; Strangriede Cemetery (R 20.09); Hannover Cemeteries Tombs

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Tombstone of Lea Benjamin nee Levy; Strangriede Cemetery (R 83.11); Hannover Cemeteries Tombs

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Reiss family portrait; (l-r) Olga, Herbert, Flora Lotte, Walter, Moritz and Kurt; Saaz, Czechoslovakia Portraits Family

Olga Reiss nee Kohn died 1950s; Herbert Reiss, 1905-circa 1980; Flora Lotte "Lola" Reiss, 1910-1995; Walter Reiss, 1908-1937; Moritz Reiss, 1876-1965; Kurt Reiss, 1906-1996

Studio portrait of the six daughters of Solomon and Emilie Kohnberger: (l-r) Laura, Irene, Johanna, Melanie, Hermine and Martha.

Laura (1878-1917) died during a flu epidemic. She married Sigmund Stiassny and had two children, Lisbeth (Gersuny) (1900-1986) and Walter (1902-1912) who died of a ruptured appendix.

Lilly Baum, her mother Lina Baum, and Grete Baum nee Dublon (l-r) standing in a forest Portraits Women

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Kisch family portrait; Alexander, Mizzi, Charlotte, Guido and Bruno (l-r); Prague.

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ITC Hardwoods Nutrition R&D

Hardwoods nutrition R&D to improve tree growth, wood quality and resistance to disease attack. Improved diagnotic tools. North Queensland and Burnett region soils.

Studio portrait of infant twins Beatrice and Fred Herz (l-r).

The Herz twins were born 4 February 1913

Reproduction of grammar school class portrait including Ella, Beatrice and Rose Herz (circled l-r).

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