Art History

The paper deals with the oddities and peculiarities of critical history of a bronze bust representing Francesco del Nero (1487-1563). Formerly in the Kaiser-Friedrich-Museum, Berlin, and long considered lost in the fire of Friedrichshain bunker in May 1945, it has recently resurfaced in the Pushkin Museum, Moscow, in custody there since 1946. The dramatic history of the bust, acquired in 1895 for Berlin Museums by Wilhelm von Bode himself, is examined in detail, along with that of a plaster cast of the aforementioned work also in Moscow, acquired around 1899 in Berlin by the founder of the Moscow museum Ivan Tsvetaev. New material available at hand and a critical analysis of the sources allows the author to effectively challenge the attribution to Giulio Mazzoni from Piacenza (1525 – 1618), together with the long-held assumption of the bust being the original after which a marble effigy in the roman church of Santa Maria Minerva was made, thus raising important concerns about the work’s provenance and authenticity.

The Italian Courtyard of the Moscow State Pushkin Museum of Fine Arts has for many years conserved the same outlook, familiar to visitors over the world and to generations of art history students and pupils. Under the staircase leading up, itself a free copy of its more famous counterpart in the Florentine Bargello, a dark plaster cast of a bronze bust representing a man in his sixties, draped in an imposing cloak, is placed casually between the life-size plaster copies of Michelangelo's David and Verrochio's Equestrian statue of Bartolomeo Colleoni (Fig. 2). While it would perhaps be unfair to pretend that the nondescript figure of the sitter attracts any kind of extraordinary attention to itself, the story behind it, upon closer scrutiny, is linked to several dramatic events that bear retelling in the following article. 1 The present-day interiors of this and other halls of the museum continue to reflect the deep reverence that Ivan Tsvetajev, the driving force and masterm...

Persistent DNA double strand breaks (DSBs) may determine the anti-tumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe or permanent growth arrest. Ionizing radiation (IR) induces rapid modification of megabase chromatin domains surrounding double strand breaks (DSBs) via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these ionizing radiation-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked relocalization of GFP fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy.

Much like replicative senescence, the irreversible cell-cycle arrest induced by eroded telomeres, accelerated senescence occurs when replicative cells suffer irreparable DNA double-strand breaks (DSBs). Along with apoptosis and necrosis, senescence is a desirable outcome in cancer treatment with ionizing radiation (IR) or chemotherapy. In both normal and cancer cells, DSBs promote the assembly of IR-induced foci (IRIF), domains of modified chromatin that serve a key role in DNA damage signaling. IRIF persistence is a critical determinant of accelerated senescence, making drugs that promote persistent IRIF an attractive strategy to sensitize cancer to genotoxic therapy. As an IRIF reporter, we have expressed an inducible green fluorescent protein (GFP) fusion to the IRIF-binding domain (IBD) of 53BP1 (GFP-IBD) in the breast cancer cell line MCF7. Within minutes of exposure to IR, the GFP-IBD relocalizes to form fluorescent nuclear foci, which disperse within several hours. A pair of high-content screening assays for IRIF formation and persistence were established in multiwell plates based on imaging and quantifying GFP-IBD foci per Hoechst-stained MCF7 nucleus at 2 hours and 24 hours. Using the ataxia telangiectasia-mutated inhibitor CGK733 to block IRIF formation and the topoisomerase II inhibitor etoposide to prevent IRIF resolution, we obtained a Z 0.8 both for IRIF formation at 2 hours and IRIF persistence at 24 hours. Screening the diverse drugs and natural products in the National Cancer Institute Developmental Therapeutics Program Approved Oncology Drugs Set, the National Institutes of Health Clinical Collection, and the MicroSource Spectrum Collection yielded multiple hits that significantly delayed IRIF resolution. Secondary screening suggested some of these otherwise nontoxic drugs also enhance accelerated senescence, indicating strong potential for their repurposing as radiation sensitizers to improve the efficacy of cancer therapy.

Purpose: To determine the mechanisms of Signal Transducer and Activator of Transcription 1 (Stat1)-associated radioresistance developed by nu61 tumour selected in vivo by fractionated irradiation of the parental radiosensitive tumour SCC61. Materials and methods: Radioresistence of nu61 and SCC61 in vitro was measured by clonogenic assay. Apoptotic response of nu61 and SCC61 cells to genotoxic stress was examined using caspase-based apoptotic assays. Co-cultivation of carboxyfluorescein diacetate, succinimidyl ester (CFDE-SE)-labeled nu61 with un-labeled SCC61 was performed at 1:1 ratio. Production of interleukin-6, interleukin-8 and soluble receptor of interleukin 6 (IL6, IL8 and sIL6R) was measured using Enzyme-Linked Immunosorbent Assay (ELISA). Results: Radioresistant nu61 was also resistant to interferon-gamma (IFNg) and the death ligands of tumour necrosis factor alpha receptor (TNFR) family when compared to SCC61. This combined resistance is due to an impaired apoptotic response in nu61. Relative to SCC61, nu61 produced more IL6, IL8 and sIL6R. Using Stat1 knock-downs we demonstrated that IL6 and IL8 production is Stat1-dependent. Treatment with neutralising antibodies to IL6 and IL8, but not to either cytokine alone sensitised nu61 to genotoxic stress induced apoptosis. Conclusion: Nu61, which over-expresses Stat1 pathway, is deficient in apoptotic response to ionising radiation and cytotoxic ligands. This resistance to apoptosis is associated with Stat1-dependent production of IL6 and IL8 and suppression of 8, 9 and 3.

We have previously demonstrated that the ultraviolet (UV) light is effective against a variety of cancer cells in vivo as well as in vitro. In the present report, we imaged the DNA damage repair response of minimal cancer after UVC irradiation. DNA-damage repair response to UV irradiation was imaged on tumors growing in 3D culture and in superficial tumors grown in vivo. UV-induced DNA damage repair was imaged with GFP fused to the DNA damage response (DDR)-related chromatin-binding protein 53BP1 in MiaPaCa-2 human pancreatic cancer cells. Three-dimensional Gelfoam® histocultures and confocal imaging enabled 53BP1-GFP nuclear foci to be observed within 1 h after UVC irradiation, indicating the onset of DNA damage repair response. A clonogenic assay showed that UVC inhibited MiaPaCa-2 cell proliferation in a dose-dependent manner, while UVA and UVB showed little effect on cell proliferation. Induction of UV-induced 53BP1-GFP focus formation was limited up to a depth of 40 mm in 3D-culture of MiaPaCa-2 cells. The MiaPaCa-2 cells irradiated by UVC light in a skin-flap mouse model had a significant decrease of tumor growth compared to untreated controls. Our results also demonstrate that 53BP1-GFP is an imageable marker of UV-induced DNA damage repair response of minimal cancer and that UVC is a useful tool for the treatment of residual cancer since UVC can kill superficial cancer cells without damage to deep tissue.

Caffeine enhances the effect of certain anticancer drugs, but the mechanism of modulation is poorly understood. In this study, modulation of cisplatinum efficacy induced by caffeine was visualized at the subcellular level by real-time fluorescent-protein imaging. Mitotic and apoptotic changes were observed by imaging 143B human osteosarcoma dual-color cells, in which GFP is expressed in the nucleus and RFP is expressed in the cytoplasm. Modulation of the cell cycle was imaged using time-lapse imaging of HeLa cells expressing a fluorescent ubiquitination-based cell cycle indicator (FUCCI) in the nucleus. Clonogenic assays showed that caffeine increased the inhibition by cisplatinum on cell proliferation. Subcellular imaging demonstrated that cisplatinum decreased mitosis and induced apoptosis in 143B cells. The combination of cisplatinum and caffeine enhanced mitosis and subsequently increased apoptosis. Time-lapse imaging showed that cisplatinum strongly induced cell-cycle arrest in the S/G 2 phase in HeLa-FUCCI cells. Caffeine overcame the cell-cycle arrest induced by cisplatinum, thereby increasing its efficacy, since cisplatinum is ineffective against quiescent cells. The data in this report indicate that caffeine modulates the cell cycle in cancer cells, thereby enhancing efficacy of cell-cycle-dependent anticancer drugs such as cisplatinum.

Radiation therapy remains a promising modality for curative treatment of localized prostate cancer, but dose-limiting toxicities significantly limit its effectiveness. Agents that enhance efficacy at lower radiation doses might have considerable value in increasing tumor control without compromising organ function. Here, we tested the hypothesis that the PARP inhibitor can enhance the response of prostate cancer cells and tumors to ionizing radiation (IR). Following exposure of DU-145 and PC-3 prostate cancer cell lines to the combination of 10μM ABT-888 and 6 Gy, we observed similar persistence between both cell lines of DNA damage foci and in vitro radiosensitization. We have previously observed that persistent DNA damage foci formed after ABT-888 plus IR efficiently promote accelerated cell senescence, but only PC-3 cells displayed the expected senescent response of G2/M arrest, induction of p21 and β-galactosidase expression, and accumulation as large, flat cells. In turn, combining ABT-888 with 6 Gy resulted in delayed tumor regrowth compared with either agent alone only in PC-3 xenograft tumors while DU-145 tumors continued to grow. By 7 days after treatment with ABT-888 plus IR, PC-3 tumors contained abundant senescent cells displaying persistent DNA damage foci, but no evidence of senescence was noted in the DU-145 tumors. That equivalent radiosensitization by ABT-888 plus IR in vitro failed to predict comparable results with tumors in vivo suggests that the efficacy of PARP inhibitors may partially depend on a competent senescence response to accumulated DNA damage.

We have previously demonstrated that the ultraviolet (UV) light is effective against a variety of cancer cells expressing fluorescent proteins in vivo as well as in vitro. In the present report, we compared the DNA damage repair (DDR) response of pancreatic cancer cells after UVB or UVC irradiation. UV-induced DNA damage repair was imaged with green fluorescent protein (GFP) fused to the DDR-related chromatin-binding protein 53BP1 in MiaPaCa-2 human pancreatic cancer cells growing in 3D Gelfoam® histoculture and in superficial tumors grown in mice. 53BP1-GFP forms foci during DNA damage repair. A clonogenic assay in 2D monolayer culture initially showed that UVC and UVB inhibited MiaPaCa-2 cell proliferation in a dose-dependent manner, with UVC having more efficacy. Three-dimensional Gelfoam® histocultures and confocal imaging enabled 53BP1-GFP nuclear foci to be observed within 1 h after UV irradiation, indicating the onset of DDR response. UVB-induced 53BP1-GFP focus formation was...

We have previously demonstrated that ultraviolet (UV) light treatment is effective against various types of cancer cells expressing fluorescent proteins. In order to further understand the efficacy of UV treatment of cancer cells, we determined the kinetics of focus formation by imaging of a DNA damage-response (DDR) protein after UVC irradiation of human pancreatic cancer cells. A fusion protein consisting of the DDR protein 53BP1 and green fluorescent protein (GFP) (GFP-53BP1) was used as a live-cell imaging marker for cellular response after UVC irradiation. GFP-53BP1 foci were observed after UVC irradiation of MiaPaCa-2 human pancreatic cancer cells. During live-cell imaging, GFP-53BP1 foci were observed in the cells within 15 min after UVC irradiation, and some of the foci remained stable for at least three hours. GFP-53BP1 focus formation was observed in the pancreatic-cancer cells irradiated by 25-200 J/m(2) UVC. Our results indicate that an early response to DNA damage cause...

and density of the adhesive ligand, surface topography, texture, rigidity and more. I will also describe specific siRNA screens, which were conducted to functionally map genes that are playing key roles in the formation of focal adhesion and driving cell migration. Specific attention will be focused on the molecular diversity of cancer cells, and difference in the tumorigenic behavior of cancer cell sub-populations differing in their adhesive behavior.

The IG20 gene encodes at least four splice variants, including DENN-SV and IG20. DENN-SV is constitutively expressed at higher levels in tumor tissues. Cells transfected with the DENN-SV cDNA show in- creased resistance to tumor necrosis factor (TNF), TNF-related apo- ptosis-inducing ligand (TRAIL), etoposide, and vinblastine treatment, whereas overexpression of IG20 enhanced susceptibility to both intrinsic (drugs) and extrinsic (e.g.,

The IG20 gene encodes at least four splice variants, including DENN-SV and IG20. DENN-SV is constitutively expressed at higher levels in tumor tissues. Cells transfected with the DENN-SV cDNA show increased resistance to tumor necrosis factor alpha (TNFalpha), TNF-related apoptosis-inducing ligand (TRAIL), etoposide, and vinblastine treatment, whereas overexpression of IG20 enhanced susceptibility to both intrinsic (drugs) and extrinsic (e.g., TNFalpha and TRAIL) death signals. In this study, we investigated whether expression of the IG20 can render cells susceptible to gamma-irradiation. Consistent with previous results, overexpression of DENN-SV and IG20 in HeLa cells conferred resistance and susceptibility, respectively, to the effects of gamma-irradiation. HeLa IG20 cell susceptibility was attributable to enhanced apoptosis and reduced cell growth. This growth suppression was mediated by secreted soluble factors. Although HeLa DENN-SV cells grew more rapidly than control cells, ...

Elsewhere, we reported that multiple serial in vivo passage of a squamous cell carcinoma cells (SCC61) concurrent with ionizing radiation (IR) treatment resulted in the selection of radioresistant tumor (nu61) that overexpresses the signal transducer and activator of transcription 1 (Stat1)/IFN-dependent pathway. Here, we report that (a) the Stat1 pathway is induced by IR, (b) constitutive overexpression of Stat1 is linked with failure to transmit a cytotoxic signal by radiation or IFNs, (c) selection of parental cell line SCC61 against IFN-alpha and IFN-gamma leads to the same IR- and IFN-resistant phenotype as was obtained by IR selection, and (d) suppression of Stat1 by short hairpin RNA renders the IR-resistant nu61 cells radiosensitive to IR. We propose a model that transient induction of Stat1 by IFN, IR, or other stress signals activates cytotoxic genes and cytotoxic response. Constitutive overexpression of Stat1 on the other hand leads to the suppression of the cytotoxic res...