The protective role of pregnancy in breast cancer

Epidemiological, clinical, and experimental data indicate that the risk of developing breast cancer is strongly dependent on the ovary and on endocrine conditions modulated by ovarian function, such as early menarche, late menopause, and parity. Women who gave birth to a child when they were younger than 24 years of age exhibit a decrease in their lifetime risk of developing breast cancer, and additional pregnancies increase the protection. The breast tissue of normally cycling women contains three identifiable types of lobules, the undifferentiated Lobules type 1 (Lob 1) and the more developed Lobules type 2 and Lobules type 3. The breast attains its maximum development during pregnancy and lactation (Lobules type 4). After menopause the breast regresses in both nulliparous and parous women containing only Lob 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women indicates that Lob 1 in these two groups of women might be biologically different, or might exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that Lob 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and are therefore susceptible to undergo neoplastic transformation. These epithelial cells are called Stem cells 1, whereas Lob 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the contrary, are composed of an epithelial cell population that is refractory to transformation, called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the 'genomic signature' that differentiates Lob 1 of the early parous women from that of the nulliparous women by shifting the Stem cells 1 to Stem cells 2 that are refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full-term pregnancy. The identification of a putative breast stem cell (Stem cells 1) has, in the past decade, reached a significant impulse, and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although further work needs to be carried out in order to better understand the role of the Stem cells 2 and their interaction with the genes that confer them a specific signature, collectively the data presently available provide evidence that pregnancy, through the process of cell differentiation, shifts Stem cells 1 to Stem cells 2 – cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis

M2-M5 blackfold funnels

We analyze the basic M2-M5 intersection in the supergravity regime using the blackfold approach. This approach allows us to recover the 1/4-BPS self-dual string soliton solution of Howe, Lambert and West as a three-funnel solution of an effective fivebrane worldvolume theory in a new regime, the regime of a large number of M2 and M5 branes. In addition, it allows us to discuss finite temperature effects for non-extremal self-dual string soliton solutions and wormhole solutions interpolating between stacks of M5 and anti-M5 branes. The purpose of this paper is to exhibit these solutions and their basic properties.Comment: 19 pages, 5 figures, harvmac; typo corrected in equation (3.19

The Omega Deformation From String and M-Theory

We present a string theory construction of Omega-deformed four-dimensional gauge theories with generic values of \epsilon_1 and \epsilon_2. Our solution gives an explicit description of the geometry in the core of Nekrasov and Witten's realization of the instanton partition function, far from the asymptotic region of their background. This construction lifts naturally to M-theory and corresponds to an M5-brane wrapped on a Riemann surface with a selfdual flux. Via a 9-11 flip, we finally reinterpret the Omega deformation in terms of non-commutative geometry. Our solution generates all modified couplings of the \Omega-deformed gauge theory, and also yields a geometric origin for the quantum spectral curve of the associated quantum integrable system.Comment: LaTeX, 35 pages, 1 figure. Appendix on couplings of hypermultiplets in N=4 SYM adde

Classification of IIB backgrounds with 28 supersymmetries

We show that all IIB backgrounds with strictly 28 supersymmetries are locally isometric to the plane wave solution of arXiv:hep-th/0206195. Moreover, we demonstrate that all solutions with more than 26 supersymmetries and only 5-form flux are maximally supersymmetric. The N=28 plane wave solution is a superposition of the maximally supersymmetric IIB plane wave with a heterotic string solution. We investigate the propagation of strings in this background, find the spectrum and give the string light-cone Hamiltonian.Comment: 30 pages, typos correcte

Quantification of Epithelial Cell Differentiation in Mammary Glands and Carcinomas from DMBA- and MNU-Exposed Rats

Rat mammary carcinogenesis models have been used extensively to study breast cancer initiation, progression, prevention, and intervention. Nevertheless, quantitative molecular data on epithelial cell differentiation in mammary glands of untreated and carcinogen-exposed rats is limited. Here, we describe the characterization of rat mammary epithelial cells (RMECs) by multicolor flow cytometry using antibodies against cell surface proteins CD24, CD29, CD31, CD45, CD49f, CD61, Peanut Lectin, and Thy-1, intracellular proteins CK14, CK19, and FAK, along with phalloidin and Hoechst staining. We identified the luminal and basal/myoepithelial populations and actively dividing RMECs. In inbred rats susceptible to mammary carcinoma development, we quantified the changes in differentiation of the RMEC populations at 1, 2, and 4 weeks after exposure to mammary carcinogens DMBA and MNU. DMBA exposure did not alter the percentage of basal or luminal cells, but upregulated CD49f (Integrin α6) expression and increased cell cycle activity. MNU exposure resulted in a temporary disruption of the luminal/basal ratio and no CD49f upregulation. When comparing DMBA- or MNU-induced mammary carcinomas, the RMEC differentiation profiles are indistinguishable. The carcinomas compared with mammary glands from untreated rats, showed upregulation of CD29 (Integrin β1) and CD49f expression, increased FAK (focal adhesion kinase) activation especially in the CD29hi population, and decreased CD61 (Integrin β3) expression. This study provides quantitative insight into the protein expression phenotypes underlying RMEC differentiation. The results highlight distinct RMEC differentiation etiologies of DMBA and MNU exposure, while the resulting carcinomas have similar RMEC differentiation profiles. The methodology and data will enhance rat mammary carcinogenesis models in the study of the role of epithelial cell differentiation in breast cancer

Prelamin A mediates inflammation in dilated and HIV associated cardiomyopathies

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues yet its impact upon the heart is unknown. Here we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy and show that a novel mouse model of cardiac specific prelamin A accumulation exhibited a phenotype consistent with ‘inflammatory cardiomyopathy’ which we observed to be similar to HIV associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings: (1) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (2) have implications for the management of HIV patients with cardiac disease suggesting protease inhibitors should be replaced with alternative therapies i.e. non-nucleoside reverse transcriptase inhibitors; and (3) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

Higher derivative type II string effective actions, automorphic forms and E11

By dimensionally reducing the ten-dimensional higher derivative type IIA string theory effective action we place constraints on the automorphic forms that appear in the effective action in lower dimensions. We propose a number of properties of such automorphic forms and consider the prospects that E11 can play a role in the formulation of the higher derivative string theory effective action.Comment: 34 page

D-brane Charges in Gravitational Duals of 2+1 Dimensional Gauge Theories and Duality Cascades

We perform a systematic analysis of the D-brane charges associated with string theory realizations of d=3 gauge theories, focusing on the examples of the N=4 supersymmetric U(N)xU(N+M) Yang-Mills theory and the N=3 supersymmetric U(N)xU(N+M) Yang-Mills-Chern-Simons theory. We use both the brane construction of these theories and their dual string theory backgrounds in the supergravity approximation. In the N=4 case we generalize the previously known gravitational duals to arbitrary values of the gauge couplings, and present a precise mapping between the gravity and field theory parameters. In the N=3 case, which (for some values of N and M) flows to an N=6 supersymmetric Chern-Simons-matter theory in the IR, we argue that the careful analysis of the charges leads to a shift in the value of the B-field in the IR solution by 1/2, in units where its periodicity is one, compared to previous claims. We also suggest that the N=3 theories may exhibit, for some values of N and M, duality cascades similar to those of the Klebanov-Strassler theory.Comment: 47 pages, 9 figures; minor changes, references adde

Ecological implications of a flower size/number trade-off in tropical forest trees

Peer reviewedPublisher PD

The Breast Cancer and the Environment Research Centers: Transdisciplinary Research on the Role of the Environment in Breast Cancer Etiology

ObjectivesWe introduce and describe the Breast Cancer and the Environment Research Centers (BCERC), a research network with a transdisciplinary approach to elucidating the role of environmental factors in pubertal development as a window on breast cancer etiology. We describe the organization of four national centers integrated into the BCERC network.Data sourcesInvestigators use a common conceptual framework based on multiple levels of biologic, behavioral, and social organization across the life span. The approach connects basic biologic studies with rodent models and tissue culture systems, a coordinated multicenter epidemiologic cohort study of prepubertal girls, and the integration of community members of breast cancer advocates as key members of the research team to comprise the network.Data extractionRelevant literature is reviewed that describes current knowledge across levels of organization. Individual research questions and hypotheses in BCERC are driven by gaps in our knowledge that are presented at genetic, metabolic, cellular, individual, and environmental (physical and social) levels.Data synthesisAs data collection on the cohort, animal experiments, and analyses proceed, results will be synthesized through a transdisciplinary approach.ConclusionCenter investigators are addressing a large number of specific research questions related to early pubertal onset, which is an established risk factor for breast cancer. BCERC research findings aimed at the primary prevention of breast cancer will be disseminated to the scientific community and to the public by breast cancer advocates, who have been integral members of the research process from its inception