Advances in Preventive Therapy for Estrogen-Receptor-Negative Breast Cancer.

Preventing breast cancer is an effective strategy for reducing breast cancer deaths. The purpose of chemoprevention (also termed preventive therapy) is to reduce cancer incidence by use of natural, synthetic, or biological agents. The efficacy of tamoxifen, raloxifene, and exemestane as preventive therapy against estrogen-receptor (ER)-positive breast cancer is well established for women at increased risk for breast cancer. However, because breast cancer is a heterogeneous disease, distinct preventive approaches may be required for effective prevention of each subtype. Current research is, therefore, focused on identifying alternative mechanisms by which biologically active compounds can reduce the risk of all breast cancer subtypes including ER-negative breast cancer. Promising agents are currently being developed for prevention of HER2-positive and triple-negative breast cancer (TNBC) and include inhibitors of the ErbB family receptors, COX-2 inhibitors, metformin, retinoids, statins, poly(ADP-ribose) polymerase inhibitors, and natural compounds. This review focuses on recent progress in research to develop more effective preventive agents, in particular for prevention of ER-negative breast cancer

Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs).

Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.

Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells

Mycobacterium avium complex immune reconstitution inflammatory syndrome: Long term outcomes

Abstract Background To describe long term outcomes of Mycobacterium avium complex (MAC) immune reconstitution inflammatory syndrome (IRIS). Methods Cases of MAC IRIS were retrospectively identified at four HIV clinics (Michigan, Maryland, Rhode Island, and Indiana) from 1996–2004. Patients were included if they were initially diagnosed with AIDS and found to have evidence of focal MAC infection documented by tissue culture or PCR after initiating HAART, and at least 6 months of follow up. Results Among the 20 patients included, the mean age was 40 years, mean CD4 cell count was 24/mm3 at pretreatment baseline and 100/mm3 at time of MAC IRIS diagnosis. Sites of disease included lymph nodes (15 patients [8 peripheral, 8 abdominal and 1 peripheral and abdominal]), gastrointestinal tract (7) and liver (3). Sixteen patients (80%) responded to treatment and were disease free after a mean of 17.4 months of therapy for MAC IRIS; IRIS therapy was withdrawn in 6 without relapse. Four patients (non-responder group) had persistent or relapsing disease despite 27 months of ongoing MAC IRIS treatment. At the time of resolution or last follow-up, the mean CD4 cell count and viral load was 143/mm3 and 7,000 c/mL for responders, and 65/mm3 and 17,000 c/mL for non-responders, respectively. Most patients with peripheral adenopathy were responders (7/8; 88%); many with abdominal adenopathy (4/8; 50%) were nonresponders. Conclusion The majority of patients with MAC IRIS eventually responded to treatment. Our sample size was not adequate to perform statistical analysis, but there was a tendency towards adequate CD4 response to HAART and peripheral rather than intraabdominal adenopathy among responders.http://deepblue.lib.umich.edu/bitstream/2027.42/112767/1/12967_2007_Article_210.pd

Higher order terms in the inflaton potential and the lower bound on the tensor to scalar ratio r

The MCMC analysis of the CMB+LSS data in the context of the Ginsburg-Landau approach to inflation indicated that the fourth degree double--well inflaton potential best fits the present CMB and LSS data. This provided a lower bound for the ratio r of the tensor to scalar fluctuations and as most probable value r = 0.05, within reach of the forthcoming CMB observations. We systematically analyze here the effects of arbitrary higher order terms in the inflaton potential on the CMB observables: spectral index ns and ratio r. Furthermore, we compute in close form the inflaton potential dynamically generated when the inflaton field is a fermion condensate in the inflationary universe. This inflaton potential turns to belong to the Ginsburg-Landau class too. The theoretical values in the (ns,r) plane for all double well inflaton potentials in the Ginsburg-Landau approach (including the potential generated by fermions) turn to be inside a universal banana-shaped region B. The upper border of the banana-shaped region B is given by the fourth order double--well potential and provides an upper bound for the ratio r.The lower border of B is defined by the quadratic plus an infinite barrier inflaton potential and provides a lower bound for the ratio r. For example, the current best value of the spectral index ns = 0.964, implies r is in the interval: 0.021 < r < 0.053. Interestingly enough, this range is within reach of forthcoming CMB observations.Comment: 24 pages, 10 figures. Presentation improved. To appear in Annals of Physic

Investigation of thermal and magnetic properties of defects in a spin-gap compound NaV2O5

The specific heat, magnetic susceptibility and ESR signals of a Na-deficient vanadate Na_xV_2O_5 (x=1.00 - 0.90) were studied in the temperature range 0.07 - 10 K, well below the transition point to a spin-gap state. The contribution of defects provided by sodium vacancies to the specific heat was observed. It has a low temperature part which does not tend to zero till at least 0.3 K and a high temperature power-like tail appears above 2 K. Such dependence may correspond to the existence of local modes and correlations between defects in V-O layers. The magnetic measurements and ESR data reveal S=1/2 degrees of freedom for the defects, with their effective number increasing in temperature and under magnetic field. The latter results in the nonsaturating magnetization at low temperature. No long-range magnetic ordering in the system of defects was found. A model for the defects based on electron jumps near vacancies is proposed to explain the observed effects. The concept of a frustrated two-dimensional correlated magnet induced by the defects is considered to be responsible for the absence of magnetic ordering.Comment: 6 pages, 8 figure

Risk indicators of elder mistreatment in the community

This study examined risk indicators of chronic verbal aggression, physical aggression, and financial mistreatment in a population-based sample of 1,797 independently living elderly in Amsterdam, The Netherlands. Included were socio-demographic characteristics, physical and psychological health, and functional capacity. The data were collected using standardized interviews that took place in the homes of the respondents. The results showed that chronic verbal aggression was associated with an elder living with a partner or other(s) and in poor or bad health. Physical aggression was associated with an elder living with a partner or other(s) and having depressive symptoms. Finally, financial mistreatment was associated with being male, living alone, being partially dependent in instrumental activities of daily living and having depressive symptoms. The results indicate that the risk indicators of victims of financial mistreatment differ from those of chronic verbal aggression and physical aggression, suggesting that financial mistreatment may occur more often as a single form of abuse whereas verbal and physical aggression may more frequently occur together

Multiple Front Propagation Into Unstable States

The dynamics of transient patterns formed by front propagation in extended nonequilibrium systems is considered. Under certain circumstances, the state left behind a front propagating into an unstable homogeneous state can be an unstable periodic pattern. It is found by a numerical solution of a model of the Fr\'eedericksz transition in nematic liquid crystals that the mechanism of decay of such periodic unstable states is the propagation of a second front which replaces the unstable pattern by a another unstable periodic state with larger wavelength. The speed of this second front and the periodicity of the new state are analytically calculated with a generalization of the marginal stability formalism suited to the study of front propagation into periodic unstable states. PACS: 47.20.Ky, 03.40.Kf, 47.54.+rComment: 12 page