Intrauterine environment, mammary gland mass and breast cancer risk

Two intimately linked hypotheses on breast cancer etiology are described. The main postulate of the first hypothesis is that higher levels of pregnancy estrogens and other hormones favor the generation of a higher number of susceptible stem cells with compromised genomic stability. The second hypothesis postulates that the mammary gland mass, as a correlate of the number of cells susceptible to transformation, is an important determinant of breast cancer risk. A simple integrated etiological model for breast cancer is presented and it is indicated that the model accommodates most epidemiological aspects of breast cancer occurrence and natural history

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

Peer reviewedPublisher PD

Long-term all-sites cancer mortality time trends in Ohio, USA, 1970–2001: differences by race, gender and age

BACKGROUND: There were significant changes in cancer mortality in the USA over the last several decades, in the whole country and in particular states. However, no in depth analysis has been published so far, dealing with changes in mortality time trends in the state of Ohio. Since the state of Ohio belongs to the states of relatively high level of all-sites mortality in both males and females, it is of interest to analyze recent changes in mortality rates, as well as to compare them with the situation in the rest of the USA. The main aim of this study was to analyze, describe and interpret all-sites cancer mortality time trends in the population of the State of Ohio. METHODS: Cancer mortality data by age, sex, race and year for the period 1970–2001 were obtained from the Surveillance Research Program of the National Cancer Institute SEER*Stat software. A joinpoint regression methodology was used to provide estimated annual percentage changes (EAPCs) and to detect points in time where significant changes in the trends occurred. RESULTS: In both, males and females mortality rates were higher in blacks compared with whites. The difference was bigger in males (39.9%) than in women (23.3%). Mortality rates in Ohio are generally higher than average USA rates – an overall difference was 7.5% in men in 1997–2001, and 6.1% in women. All-sites mortality trends in Ohio and in the whole USA are similar. However, in general, mortality rates in Ohio remained elevated compared with the USA rates throughout the entire analyzed period. The exceptions are the rates in young and middle-aged African Americans. CONCLUSION: Although direction of time trends in Ohio are similar in Ohio and the whole US, Ohio still have cancer mortality rates higher than the US average. In addition, there is a significant discrepancy between white and black population of Ohio in all-sites mortality level, with disadvantage for Blacks. To diminish disparities in cancer mortality between African Americans and white inhabitants of Ohio efforts should be focused on increasing knowledge of black people regarding healthy lifestyle and behavioral risk factors, but also on diminishing socioeconomic differences, and last but not least, on better access to medical care

Cattle Mammary Bioreactor Generated by a Novel Procedure of Transgenic Cloning for Large-Scale Production of Functional Human Lactoferrin

Large-scale production of biopharmaceuticals by current bioreactor techniques is limited by low transgenic efficiency and low expression of foreign proteins. In general, a bacterial artificial chromosome (BAC) harboring most regulatory elements is capable of overcoming the limitations, but transferring BAC into donor cells is difficult. We describe here the use of cattle mammary bioreactor to produce functional recombinant human lactoferrin (rhLF) by a novel procedure of transgenic cloning, which employs microinjection to generate transgenic somatic cells as donor cells. Bovine fibroblast cells were co-microinjected for the first time with a 150-kb BAC carrying the human lactoferrin gene and a marker gene. The resulting transfection efficiency of up to 15.79×10−2 percent was notably higher than that of electroporation and lipofection. Following somatic cell nuclear transfer, we obtained two transgenic cows that secreted rhLF at high levels, 2.5 g/l and 3.4 g/l, respectively. The rhLF had a similar pattern of glycosylation and proteolytic susceptibility as the natural human counterpart. Biochemical analysis revealed that the iron-binding and releasing properties of rhLF were identical to that of native hLF. Importantly, an antibacterial experiment further demonstrated that rhLF was functional. Our results indicate that co-microinjection with a BAC and a marker gene into donor cells for somatic cell cloning indeed improves transgenic efficiency. Moreover, the cattle mammary bioreactors generated with this novel procedure produce functional rhLF on an industrial scale

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs