A Next-Generation Liquid Xenon Observatory for Dark Matter and Neutrino Physics

The nature of dark matter and properties of neutrinos are among the mostpressing issues in contemporary particle physics. The dual-phase xenontime-projection chamber is the leading technology to cover the availableparameter space for Weakly Interacting Massive Particles (WIMPs), whilefeaturing extensive sensitivity to many alternative dark matter candidates.These detectors can also study neutrinos through neutrinoless double-beta decayand through a variety of astrophysical sources. A next-generation xenon-baseddetector will therefore be a true multi-purpose observatory to significantlyadvance particle physics, nuclear physics, astrophysics, solar physics, andcosmology. This review article presents the science cases for such a detector.<br

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector

Loss of the Retinoblastoma Tumor Suppressor: Differential Action on Transcriptional Programs Related to Cell Cycle Control and Immune Function

Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function

Loss of the Retinoblastoma Tumor Suppressor: Differential Action on Transcriptional Programs Related to Cell Cycle Control and Immune Function

Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function

Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase

Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G2/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by γ-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTμ, but not the π, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options

A Next-Generation Liquid Xenon Observatory for Dark Matter and Neutrino Physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for Weakly Interacting Massive Particles (WIMPs), while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector