Pregnancy-associated breast cancer - Special features in diagnosis and treatment

For obvious psychological reasons it is difficult to associate pregnancy - a life-giving period of our existence with life-threatening malignancies. Symptoms pointing to malignancy are often ignored by both patients and physicians, and this, together with the greater difficulty of diagnostic imaging, probably results in the proven delay in the detection of breast cancers during pregnancy. The diagnosis and treatment of breast cancer are becoming more and more important, as the fulfillment of the desire to have children is increasingly postponed until a later age associated with a higher risk of carcinoma, and improved cure rates of solid tumors no longer exclude subsequent pregnancies. The following article summarizes the special features of the diagnosis and primary therapy of pregnancy-associated breast cancer with particular consideration of cytostatic therapy

Prognostic relevance of disseminated tumor cells in the bone marrow and biological factors of 265 primary breast carcinomas

Introduction The prognostic significance of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has been demonstrated in many studies. Yet, it is not clear which of the primary tumors' biological factors predict hematogenous dissemination. We therefore examined `tissue micro arrays' (TMAs) of 265 primary breast carcinomas from patients with known bone marrow ( BM) status for HER2, Topoisomerase IIa ( Top IIa), Ki 67, and p53. Methods BM analysis was performed by cytospin preparation and immunocytochemical staining for cytokeratin (CK). TMAs were examined by immunohistochemistry (IHC) for HER2, Top IIa, Ki 67 and p53, and fluorescence in situ hybridization ( FISH) for HER2. Results HER2 ( 2+/ 3+) was positive in 35/167 (21%) cases ( FISH 24.3%), Top IIa (> 10%) in 87/187 (46%), Ki 67 in 52/ 184 (28%) and p53 (> 5%) in 61/174 cases (34%). Of 265 patients, 68 (25.7%) showed DTC-BM with a median of 2/2 x 106 cells ( 1 to 1,500). None of the examined factors significantly predicted BM positivity. Significant correlation was seen between HER2 IHC and Top IIa ( p = 0.06), Ki 67 ( p = 0.031), and p53 ( p <.001). Top IIa correlated with Ki 67 and p53, and Ki 67 also with p53 ( p = 0.004). After a median follow-up of 60.5 months ( 7 to 255), the presence of DTC-BM showed prognostic relevance for overall survival ( p = 0.03), whereas HER2 ( IHC, p = 0.04; FISH, p = 0.03) and Ki 67 ( p = 0.04) correlated with disease free survival, and HER2 with distant disease free survival ( IHC, p = 0.06; FISH, p = 0.05). Discussion The congruence of the examined factors' expression rates indicates a causal line of suppressor, proliferation, and mitosis markers, and growth factor receptors. Hematogenous tumor cell spread seems to be an independent process. The examination of these factors on DTC-BM is the aim of ongoing research

Increasing the amylose content of durum wheat through silencing of the SBEIIa genes

<p>Abstract</p> <p>Background</p> <p>High amylose starch has attracted particular interest because of its correlation with the amount of Resistant Starch (RS) in food. RS plays a role similar to fibre with beneficial effects for human health, providing protection from several diseases such as colon cancer, diabetes, obesity, osteoporosis and cardiovascular diseases. Amylose content can be modified by a targeted manipulation of the starch biosynthetic pathway. In particular, the inactivation of the enzymes involved in amylopectin synthesis can lead to the increase of amylose content. In this work, genes encoding starch branching enzymes of class II (SBEIIa) were silenced using the RNA interference (RNAi) technique in two cultivars of durum wheat, using two different methods of transformation (biolistic and Agrobacterium). Expression of RNAi transcripts was targeted to the seed endosperm using a tissue-specific promoter.</p> <p>Results</p> <p>Amylose content was markedly increased in the durum wheat transgenic lines exhibiting <it>SBEIIa </it>gene silencing. Moreover the starch granules in these lines were deformed, possessing an irregular and deflated shape and being smaller than those present in the untransformed controls. Two novel granule bound proteins, identified by SDS-PAGE in SBEIIa RNAi lines, were investigated by mass spectrometry and shown to have strong homologies to the waxy proteins. RVA analysis showed new pasting properties associated with high amylose lines in comparison with untransformed controls. Finally, pleiotropic effects on other starch genes were found by semi-quantitative and Real-Time reverse transcription-polymerase chain reaction (RT-PCR).</p> <p>Conclusion</p> <p>We have found that the silencing of <it>SBEIIa </it>genes in durum wheat causes obvious alterations in granule morphology and starch composition, leading to high amylose wheat. Results obtained with two different methods of transformation and in two durum wheat cultivars were comparable.</p

Observation of the Charge Symmetry Breaking d + d -> 4He + pi0 Reaction Near Threshold

We report the first observation of the charge symmetry breaking d + d -> 4He + pi0 reaction near threshold at the Indiana University Cyclotron Facility. Kinematic reconstruction permitted the separation of 4He + pi0 events from double radiative capture 4He + gamma + gamma events. We measured total cross sections for neutron pion production of 12.7 +- 2.2 pb at 228.5 MeV and 15.1 +- 3.1 pb at 231.8 MeV. The uncertainty is dominated by statistical errors.Comment: 7 pages, 2 figures, plain Te

A multi-detector array for high energy nuclear e+e- pair spectrosocopy

A multi-detector array has been constructed for the simultaneous measurement of energy- and angular correlation of electron-positron pairs produced in internal pair conversion (IPC) of nuclear transitions up to 18 MeV. The response functions of the individual detectors have been measured with mono-energetic beams of electrons. Experimental results obtained with 1.6 MeV protons on targets containing $^{11}$B and $^{19}$F show clear IPC over a wide angular range. A comparison with GEANT simulations demonstrates that angular correlations of $e^+e^-$ pairs of transitions in the energy range between 6 and 18 MeV can be determined with sufficient resolution and efficiency to search for deviations from IPC due to the creation and subsequent decay into $e^+e^-$ of a hypothetical short-lived neutral boson.Comment: 20 pages, 8 figure

Methylation patterns in serum DNA for early identification of disseminated breast cancer

BACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC. CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent

Human Herpesvirus 6B

Abstract Infection with human herpesvirus (HHV)-6B alters cell cycle progression and stabilizes tumor suppressor protein p53. In this study, we have analyzed the activity of p53 after stimulation with p53-dependent and -independent DNA damaging agents during HHV-6B infection. Microarray analysis, Western blotting and confocal microscopy demonstrated that HHV-6B-infected cells were resistant to p53-dependent arrest and cell death after c irradiation in both permissive and nonpermissive cell lines. In contrast, HHV-6B-infected cells died normally through p53-independet DNA damage induced by UV radiation. Moreover, we identified a viral protein involved in inhibition of p53 during HHV-6B-infection. The protein product from the U19 ORF was able to inhibit p53-dependent signaling following c irradiation in a manner similar to that observed during infection. Similar to HHV-6B infection, overexpression of U19 failed to rescue the cells from p53-independent death induced by UV radiation. Hence, infection with HHV-6B specifically blocks DNA damage-induced cell death associated with p53 without inhibiting the p53-independent cell death response. This block in p53 function can in part be ascribed to the activities of the viral U19 protein

Inhibition of p53-Dependent, but Not p53-Independent, Cell Death by U19 Protein from Human Herpesvirus 6B

Infection with human herpesvirus (HHV)-6B alters cell cycle progression and stabilizes tumor suppressor protein p53. In this study, we have analyzed the activity of p53 after stimulation with p53-dependent and -independent DNA damaging agents during HHV-6B infection. Microarray analysis, Western blotting and confocal microscopy demonstrated that HHV-6B-infected cells were resistant to p53-dependent arrest and cell death after γ irradiation in both permissive and non-permissive cell lines. In contrast, HHV-6B-infected cells died normally through p53-independet DNA damage induced by UV radiation. Moreover, we identified a viral protein involved in inhibition of p53 during HHV-6B-infection. The protein product from the U19 ORF was able to inhibit p53-dependent signaling following γ irradiation in a manner similar to that observed during infection. Similar to HHV-6B infection, overexpression of U19 failed to rescue the cells from p53-independent death induced by UV radiation. Hence, infection with HHV-6B specifically blocks DNA damage-induced cell death associated with p53 without inhibiting the p53-independent cell death response. This block in p53 function can in part be ascribed to the activities of the viral U19 protein