A multi-detector array for high energy nuclear e+e- pair spectrosocopy

A multi-detector array has been constructed for the simultaneous measurement of energy- and angular correlation of electron-positron pairs produced in internal pair conversion (IPC) of nuclear transitions up to 18 MeV. The response functions of the individual detectors have been measured with mono-energetic beams of electrons. Experimental results obtained with 1.6 MeV protons on targets containing $^{11}$B and $^{19}$F show clear IPC over a wide angular range. A comparison with GEANT simulations demonstrates that angular correlations of $e^+e^-$ pairs of transitions in the energy range between 6 and 18 MeV can be determined with sufficient resolution and efficiency to search for deviations from IPC due to the creation and subsequent decay into $e^+e^-$ of a hypothetical short-lived neutral boson.Comment: 20 pages, 8 figure

An AMPKa2-specific phospho-switch controls lysosomal targeting for activation

AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy

Efficacy and Tolerability of Lapatinib in the Management of Breast Cancer

Approximately 20%–25% of all breast cancers over express a key cell surface growth factor receptor known as HER2. HER2 plays a key role in cell growth and proliferation and is linked to worse clinical outcomes, making it a logical therapeutic target. The first HER2 targeted drug to be approved by the FDA, was the humanized monoclonal antibody trastuzumab, after it showed improvements in survival in the adjuvant setting, and delayed time to progression in the metastatic setting. Although highly effective, for reasons that are not clear, some patients display resistance to trastuzumab. Lapatinib is an oral, small molecule tyrosine kinase inhibitor, that inhibits both the HER1 ahd HER2 receptors and may be able to overcome trastuzumab resistance. Lapatinib is approved in the second line setting for use in combination with capecitabine or with letrozole. In this review, we will discuss the indications, concerns or any issues with regards to the drug

Theoretical methods for the calculation of Bragg curves and 3D distributions of proton beams

The well-known Bragg-Kleeman rule RCSDA = A dot E0p has become a pioneer work in radiation physics of charged particles and is still a useful tool to estimate the range RCSDA of approximately monoenergetic protons with initial energy E0 in a homogeneous medium. The rule is based on the continuous-slowing-down-approximation (CSDA). It results from a generalized (nonrelativistic) Langevin equation and a modification of the phenomenological friction term. The complete integration of this equation provides information about the residual energy E(z) and dE(z)/dz at each position z (0 <= z <= RCSDA). A relativistic extension of the generalized Langevin equation yields the formula RCSDA = A dot (E0 +E02/2M dot c2)p. The initial energy of therapeutic protons satisfies E0 << 2M dot c2 (M dot c2 = 938.276 MeV), which enables us to consider the relativistic contributions as correction terms. Besides this phenomenological starting-point, a complete integration of the Bethe-Bloch equation (BBE) is developed, which also provides the determination of RCSDA, E(z) and dE(z)/dz and uses only those parameters given by the BBE itself (i.e., without further empirical parameters like modification of friction). The results obtained in the context of the aforementioned methods are compared with Monte-Carlo calculations (GEANT4); this Monte-Carlo code is also used with regard to further topics such as lateral scatter, nuclear interactions, and buildup effects. In the framework of the CSDA, the energy transfer from protons to environmental atomic electrons does not account for local fluctuations.Comment: 97 pages review pape

Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer

Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts

The HER2 phenotype of circulating tumor cells in HER2-positive early breast cancer: A translational research project of a prospective randomized phase III trial

Background: HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy. Methods: The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining. Results 258 (40.2%) of the 642 patients were positive for CTCs (median 2;range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC. Conclusion: This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance

Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: clinical relevance

INTRODUCTION: Improving technologies for the detection and purification of bone marrow (BM) micrometastatic cells in breast cancer patients should lead to earlier prognosis of the risk of relapse and should make it possible to design more appropriate therapies. The technique used has to overcome the challenges resulting from the small number of target cells (one per million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In the present study, we have assessed the clinical relevance of current methods aimed at detecting rare disseminated carcinoma cells. METHODS: BM aspirates from 32 carcinoma patients were screened for the presence of micrometastatic cells positive for epithelial cell adhesion molecule and positive for cytokeratins, using optimized immunodetection methods. A comparison with data obtained for 46 control BM aspirates and a correlation with the clinical status of patients were performed. RESULTS: We developed a sensitive and efficient immunomagnetic protocol for the enrichment of BM micrometastases. This method was used to divide 32 breast carcinoma patients into three categories according to their epithelial cell adhesion molecule status. These categories were highly correlated with the recently revised American Joint Committee on Cancer staging system for breast cancer, demonstrating the clinical relevance of this simple and reliable immunomagnetic technique. We also evaluated immunocytochemical detection of cytokeratin-positive cells and cytomorphological parameters. Immunocytochemistry-based methods for the detection of BM micrometastases did not provide any information about the clinical status of patients, but helped to refine the immunomagnetic data by confirming the presence of micrometastases in some cases. We also tested a new density gradient centrifugation system, able to enrich the tumor fraction of BM specimens by twofold to threefold as compared with standard Ficoll methods. CONCLUSION: These improved methods for the detection of micrometastatic cells in patient BM should help clinicians to predict the clinical status of breast cancer patients at the time of surgery or treatment