Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells

SummarySelf-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial. Here, we construct a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells, and human cancers. This map reveals two predominant gene modules that distinguish ESCs and adult tissue stem cells. The ESC-like transcriptional program is activated in diverse human epithelial cancers and strongly predicts metastasis and death. c-Myc, but not other oncogenes, is sufficient to reactivate the ESC-like program in normal and cancer cells. In primary human keratinocytes transformed by Ras and IκBα, c-Myc increases the fraction of tumor-initiating cells by 150-fold, enabling tumor formation and serial propagation with as few as 500 cells. c-Myc-enhanced tumor initiation is cell-autonomous and independent of genomic instability. Thus, activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristic of cancer stem cells

Human immunodeficiency virus, type 1 protease substrate specificity is limited by interactions between substrate amino acids bound in adjacent enzyme subsites

The specificity of the retroviral protease is determined by the ability of substrate amino acid side chains to bind into eight individual subsites within the enzyme. Although the subsites are able to act somewhat independently in selection of amino acid side chains that fit into each pocket, significant interactions exist between individual subsites that substantially limit the number of clearable amino acid sequences. The substrate peptide binds within the enzyme in an extended anti-parallel β sheet conformation with substrate amino acid side chains adjacent in the linear sequence extending in opposite directions in the enzyme-substrate complex. From this geometry, we have defined both cis and trans steric interactions, which have been characterized by a steady state kinetic analysis of human immunodeficiency virus, type-1 protease using a series of peptide substrates that are derivatives of the avian leukosis/sarcoma virus nucleocapsid-protease cleavage site. These peptides contain both single and double amino acid substitutions in seven positions of the minimum length substrate required by the retroviral protease for specific and efficient cleavage. Steady state kinetic data from the single amino acid substituted peptides were used to predict effects on protease-catalyzed cleavage of corresponding double substituted peptide substrates. The calculated Gibbs' free energy changes were compared with actual experimental values in order to determine how the fit of a substrate amino acid in one subsite influences the fit of amino acids in adjacent subsites. Analysis of these data shows that substrate specificity is limited by steric interactions between pairs of enzyme subsites. Moreover, certain enzyme subsites are relatively tolerant of substitutions in the substrate and exert little effect on adjacent subsites, whereas others are more restrictive and have marked influence on adjacent cis and trans subsites

Temperature and Humidity Dependence of Air Fluorescence Yield measured by AIRFLY

The fluorescence detection of ultra high energy cosmic rays requires a detailed knowledge of the fluorescence light emission from nitrogen molecules over a wide range of atmospheric parameters, corresponding to altitudes typical of the cosmic ray shower development in the atmosphere. We have studied the temperature and humidity dependence of the fluorescence light spectrum excited by MeV electrons in air. Results for the 313.6 nm, 337.1 nm, 353.7 nm and 391.4 nm bands are reported in this paper. We found that the temperature and humidity dependence of the quenching process changes the fluorescence yield by a sizeable amount (up to 20%) and its effect must be included for a precise estimation of the energy of ultra high energy cosmic rays.Comment: presented at the 5th Fluorescence Workshop, El Escorial - Madrid, Spain, 16 - 20 September 2007, to appear in Nuclear Instruments and Methods

Histological Review of Skin cancers in African Albinos: A 10-year Retrospective Review.

Skin cancer is rare among Africans and albinism is an established risk for skin cancer in this population. Ultraviolet radiation is highest at the equator and African albinos living close to the equator have the highest risk of developing skin cancers. This was a retrospective study that involved histological review of all specimens with skin cancers from African albinos submitted to The Regional Dermatology Training Center in Moshi, Tanzania from 2002 to 2011. A total of 134 biopsies from 86 patients with a male to female ratio of 1:1 were reviewed. Head and neck was the commonest (n = 75, 56.0%) site affected by skin cancers. Squamous cell carcinoma (SCC) was more common than basal cell carcinoma (BCC) with a ratio of 1.2:1. Only one Acral lentiginous melanoma was reported. Majority (55.6%) of SCC were well differentiated while nodular BCC (75%) was the most common type of BCC. Squamous cell carcinoma is more common than basal cell carcinoma in African albinos

A novel method for the absolute fluorescence yield measurement by AIRFLY

One of the goals of the AIRFLY (AIR FLuorescence Yield) experiment is to measure the absolute fluorescence yield induced by electrons in air to better than 10% precision. We introduce a new technique for measurement of the absolute fluorescence yield of the 337 nm line that has the advantage of reducing the systematic uncertainty due to the detector calibration. The principle is to compare the measured fluorescence yield to a well known process - the Cerenkov emission. Preliminary measurements taken in the BFT (Beam Test Facility) in Frascati, Italy with 350 MeV electrons are presented. Beam tests in the Argonne Wakefield Accelerator at the Argonne National Laboratory, USA with 14 MeV electrons have also shown that this technique can be applied at lower energies.Comment: presented at the 5th Fluorescence Workshop, El Escorial - Madrid, Spain, 16 - 20 September 200

An analytical program for fermion pair production in e+e- annihilation

We describe how to use {\tt ZFITTER}, a program based on a semi-analytical approach to fermion pair production in e^+ e^- annihilation and Bhabha scattering. A flexible treatment of complete {\cal O}(\alpha) QED corrections, also including higher orders, allows for three calculational {\bf chains} with different realistic sets of restrictions in the photon phase space. {\tt ZFITTER} consists of several {\bf branches} with varying assumptions on the underlying hard scattering process. One includes complete {\cal O}(\alpha) weak loop corrections with a resummation of leading higher-order terms. Alternatively, an ansatz inspired from S-matrix theory, or several model-independent effective Born cross sections may be convoluted. The program calculates cross sections, forward-backward asymmetries, and for \tau~pair production also the final-state polarization. Various {\bf interfaces} allow fits to be performed with different sets of free parameters

Programming the Rous sarcoma virus protease to cleave new substrate sequences

The Rous sarcoma virus protease displays a high degree of specificity and catalyzes the cleavage of only a limited number of amino acid sequences. This specificity is governed by interactions between side chains of eight substrate amino acids and eight corresponding subsite pockets within the homodimeric enzyme. We have examined these complex interactions in order to learn how to introduce changes into the retroviral protease (PR) that direct it to cleave new substrates. Mutant enzymes with altered substrate specificity and wild-type or greater catalytic rates have been constructed previously by substituting single key amino acids in each of the eight enzyme subsites with those residues found in structurally related positions of human immunodeficiency virus (HIV)-1 PR. These individual amino acid substitutions have now been combined into one enzyme, resulting in a highly active mutant Rous sarcoma virus (RSV) protease that displays many characteristics associated with the HIV-1 enzyme. The hybrid protease is capable of catalyzing the cleavage of a set of HIV-1 viral polyprotein substrates that are not recognized by the wild-type RSV enzyme. Additionally, the modified PR is inhibited completely by the HIV-1 PR-specific inhibitor KNI-272 at concentrations where wild-type RSV PR is unaffected. These results indicate that the major determinants that dictate RSV and HIV-1 PR substrate specificity have been identified. Since the viral protease is a homodimer, the rational design of enzymes with altered specificity also requires a thorough understanding of the importance of enzyme symmetry in substrate selection. We demonstrate here that the enzyme homodimer acts symmetrically in substrate selection with each enzyme subunit being capable of recognizing both halves of a peptide substrate equally

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201