Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention

The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.Fil: Nocera, Nadia F.. University of Pennsylvania; Estados UnidosFil: Lee, M. Catherine. H. Lee Moffitt Cancer Center; Estados UnidosFil: De La Cruz, Lucy M.. University of Pennsylvania; Estados UnidosFil: Rosemblit, Cinthia. University of Pennsylvania; Estados UnidosFil: Czerniecki, Brian J.. H. Lee Moffitt Cancer Center; Estados Unido

The Incorporation of Moral-Development Language for Machine-Learning Companion Robots

Among the ongoing debates over ethical implications of artificial-intelligence development and applications, AI morality, and the nature of autonomous agency for robots, how to think about the moral assumptions implicit in machine-learning capacities for so-called companion robots is arguably an urgent one. This project links the development of machine-learning algorithmic design with moral-development theory language. It argues that robotic algorithmic responses should incorporate language linked to higher-order moral reasoning, reflecting notions of universal respect, community obligation and justice to encourage similar deliberation among human subjects

Short-Term H-alpha Variability in M Dwarfs

We spectroscopically study the variability of H-alpha emission in mid- to late-M dwarfs on timescales of ~0.1-1 hr as a proxy for magnetic variability. About 80% of our sample exhibits statistically significant variability on the full range of timescales probed by the observations, and with amplitude ratios in the range of ~1.2-4. No events with an order of magnitude increase in H-alpha luminosity were detected, indicating that their rate is < 0.05 /hr (95% confidence level). We find a clear increase in variability with later spectral type, despite an overall decrease in H-alpha "activity" (i.e., L_{H-alpha}/L_{bol}). For the ensemble of H-alpha variability events, we find a nearly order of magnitude increase in the number of events from timescales of about 10 to 30 min, followed by a roughly uniform distribution at longer durations. The event amplitudes follow an exponential distribution with a characteristic scale of Max(EW)/Min(EW)}-1 ~ 0.7. This distribution predicts a low rate of ~ 10^{-6} /hr for events with (Max(EW)/Min(EW) > 10, but serendipitous detections of such events in the past suggests that they represent a different distribution. Finally, we find a possible decline in the amplitude of events with durations of > 0.5 hr, which may point to a typical energy release in H-alpha events for each spectral type (E_{H-alpha} ~ L_{H-alpha} x t ~ const). Longer observations of individual active objects are required to further investigate this possibility. Similarly, a larger sample may shed light on whether H-alpha variability correlates with properties such as age or rotation velocity.Comment: Accepted for publication in Ap

A method for computing the overall statistical significance of a treatment effect among a group of genes

BACKGROUND: In studies that use DNA arrays to assess changes in gene expression, our goal is to evaluate the statistical significance of treatments on sets of genes. Genes can be grouped by a molecular function, a biological process, or a cellular component, e.g., gene ontology (GO) terms. The meaning of an affected GO group is often clearer than interpretations arising from a list of the statistically significant genes. RESULTS: Computer simulations demonstrated that correlations among genes invalidate many statistical methods that are commonly used to assign significance to GO terms. Ignoring these correlations overstates the statistical significance. Meta-analysis methods for combining p-values were modified to adjust for correlation. One of these methods is elaborated in the context of a comparison between two treatments. The form of the correlation adjustment depends upon the alternative hypothesis. CONCLUSION: Reliable corrections for the effect of correlations among genes on the significance level of a GO term can be constructed for an alternative hypothesis where all transcripts in the GO term increase (decrease) in response to treatment. For general alternatives, which allow some transcripts to increase and others to decrease, the bias of naïve significance calculations can be greatly decreased although not eliminated

Spin-Phonon Coupling in Iron Pnictide Superconductors

The magnetic moment in the parent phase of the iron-pnictide superconductors varies with composition even when the nominal charge of iron is unchanged. We propose the spin-lattice coupling due to the magneto-volume effect as the primary origin of this effect, and formulate a Landau theory to describe the dependence of the moment to the Fe-As layer separation. We then compare the superconductive critical temperature of doped iron pnictides to the local moment predicted by the theory, and suggest that the spin-phonon coupling may play a role in the superconductivity of this compound

New Higgs signals induced by mirror fermion mixing effects

We study the conditions under which flavor violation arises in scalar-fermion interactions, as a result of the mixing phenomena between the standard model and exotic fermions. Phenomenological consequences are discussed within the specific context of a left-right model where these additional fermions have mirror properties under the new SU(2)_R gauge group. Bounds on the parameters of the model are obtained from LFV processes; these results are then used to study the LFV Higgs decays (H --> tau l_j, l_j = e, mu), which reach branching ratios that could be detected at future colliders.Comment: 12 pages, 2 figures, ReVTex4, graphicx, to be published in Phys. Rev.

Chitosan microparticles gel for In vitro 3D culture of human chondrocytes

[EN] Chondrocytes are frequently cultured embedded in gels that provide them with a three-dimensional environment. Nevertheless cells in these constructs cannot remodel their neighbourhood when producing their own extracellular matrix. In this work we explore 3D environments that the cells can easily remodel. For this, human mature chondrocytes were cultured in the three-dimensional environment created by chitosan microparticles whose diameter is in the order of magnitude of the cell size. Chondrocytes and microparticles suspensions were mixed and the agglomerates were cultured in static tubes in chondrogenic medium. The poor adhesion between cells and chitosan surface maintained the mobility of the ensemble. In these conditions chondrocytes are viable during the 28 days of culture. The cells produce glycosaminoglycans, S100 and collagen type II up to 14 days of culture although production of type I collagen is also noticeable.J.L. Gomez Ribelles acknowledges the support of the Spanish Ministerio de Ciencia e Innovacion through MAT2010-21611-C03-00 project (including the FEDER financial support). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. N Garcia-Giralt acknowledges the support by grants from the Generalitat de Catalunya (DIUE 2009 SGR 818, 2009 SGR 971) and the Red Tematica de Investigacion Cooperativa en Envejecimiento y Fragilidad (RETICEF) and FEDER funds. Grand MAT2007-66759-C03-02 of Plan Nacional del MINISTERIO DE EDUCACION Y CIENCIA are also acknowledged.Garcia-Giralt, N.; García Cruz, DM.; Nogues, X.; Escobar Ivirico, JL.; Gómez Ribelles, JL. (2013). Chitosan microparticles gel for In vitro 3D culture of human chondrocytes. RSC Advances. 3(18):6362-6368. doi:10.1039/c3ra23173aS6362636831

Under-utilization of antenatal care services in Timor-Leste: Results from Demographic and Health Survey 2009-2010

Background: Timor-Leste is a young country in the Asia-Pacific region with a high maternal mortality rate of 557 per 100,000 live births. As most maternal deaths can be prevented by providing quality antenatal care (ANC) and skilled assistance during childbirth, understanding the barriers to the utilization of ANC services can enhance program implementation. This study aimed to investigate the prevalence and factors associated with the under-utilization of ANC services in Timor-Leste. Methods: Timor-Leste Demographic and Health Survey (TDHS) 2009-2010 was a nationally representative multi-stage cross-sectional study involving 11,463 households and 9,828 childbirths. Information on last born child was recorded for 5,895 mother-child pairs. Factors influencing under-utilization of ANC were assessed using hierarchical logistic regression analysis. Results: Only 3311 (55.2, 95 % confidence interval (CI) 53.1 to 57.3 %) made the recommended four ANC visits, while 2584 (44.8; 95 % CI 42.7 to 46.9 %) of them reported attending three or less ANC services. Significant factors positively associated with the under-utilization of ANC were low wealth status (odds ratio (OR) 2.09; 95 % CI 1.68 to 2.60), no maternal education (OR 1.54; 95 % CI 1.30 to 1.82) or primary maternal education (OR 1.21; 95 % CI 1.04 to 1.41), no paternal education (OR 1.34; 95 % CI 1.13 to 1.60), and having a big problem in permission to visit health facility (OR 1.65; 95 % CI 1.39 to 1.96). Conclusions: Despite the apparently good progress made in re-establishing the healthcare infrastructure, 45 % of mothers remained in need of a focused intervention to increase their use of ANC services. Further prenatal care program should pay attention to women with low wealth status and those and their partners who are uneducated. Moreover, women should be encouraged to make decision on their own health