#8 - Analysis of Temporal Gene Expression of Mycobacteriophage XianYue

Analysis of Temporal Gene Expression of Mycobacteriophage XianYue Samantha Kates Abstract Antibiotic resistance has become a prevalent issue in the 21stcentury. The over-prescription and frequent use of antibiotics have allowed host bacteria to escape the effects of antibiotic therapy. An alternative treatment for bacterial infection is bacteriophage (phage) therapy. Phage are viruses that infect and hijack the genetic machinery of its bacterial host which results in host cell death. Mycobacteriophage XianYue was isolated from a soil sample on the campus of the University of North Georgia. Using its bacterial host Mycobacterium smegmatis, a non-infectious mycobacterium, XianYue’s gene expression was analyzed using quantitative polymerase chain reaction (qPCR) at different time points in its infection cycle. This data provides evidence for which genes are activated or repressed at different moments in its interaction with Mycobacterium smegmatis. Such genetic analysis allows for greater insight into the gene expression of similar mycobacteriophage within cluster A that are infectious to Mycobacterium tuberculosis (tuberculosis) or Mycobacterium leprae (leprosy). Understanding these activations and repressions will allow for genetic customization of phage treatment according to the case of the bacterially infected patient. Such customization of treatment will ultimately increase the survival outcomes of patients who are immune to antibiotic therapy

Creating a Faith-Friendly School Culture in Religiously Plural Communities: A Neglected Facet of Diversity

School leaders serve religiously diverse communities, engaging with staff and parents from many backgrounds to address the academic and development needs of all children. While educator preparation often includes some instruction in cultural competence, religious diversity gets little attention. The purpose of this conceptual article is to provide guidance for school leaders to create a workplace and school culture hospitable to employees from all religious, spiritual, and non-religious backgrounds. Using Miller and Ewest’s (2015) Faith and Work Organizational framework, this article reviews findings from the management literature on workplace spirituality including the sparse empirical literature on religious expression in the school (as a workplace) and from case law on employment-related religious expression in schools. We synthesize the concepts and findings into actionable recommendations for school leaders to guide them towards creating inclusive, religiously plural, faith-safe or faith-friendly workplaces where educators can flourish and thrive. Recommendations include a policy review, adoption of norms of respectful pluralism, and religious literacy training

Integrating HIV Prevention Services into the Clinical Care Setting in Medicaid and Ryan White CARE Act Programs: Legal, Financial, and Organizational Issues

This policy brief examines the structural-level opportunities and challenges associated with the delivery of HIV prevention services in or closely linked to the clinical care setting. It focuses on two of the major public programs for HIV care in the U.S: Medicaid, the nation\u27s major public health program for low-income Americans, and the largest source of public financing for HIV/AIDS care in the U.S.; and the Ryan White CARE Act, the nation\u27s only HIV-specific care and support services grant program which operates as the payer of last resort at the state and local level. Together, these programs provide care and support services to a significant proportion of those at risk for and living with HIV and therefore provide an important focus for assessing current prevention integration practice, identifying strategies to enhance integration, and targeting such efforts

International Health Regulations

On Tuesday, April 6, 2010, the George Washington University School of Public Health and Health Services (GW SPHHS) hosted the annual Southby Distinguished Lectureship in Comparative Health Policy on the International Health Regulations. This lectureship gave an overview of the U.S. Government\u27s approach to addressing the challenges, policies, and opportunities related to both domestic and international implementation of the IHR (2005). Introductory remarks were given by GW School of Public Health faculty, including Josef Reum, Interim Dean; Professor Sara Rosenbaum, Chair of the Department of Health Policy & Hirsh Professor of Health Law and Policy; Richard Southby, Executive Dean Emeritus; and Rebecca Katz, Assistant Professor, Department of Health Policy. The plenary speakers were Mr. Andrew Weber, Assistant to the Secretary of Defense for Nuclear, Chemical and Biological Defense Programs at the Department of Defense; Dr. Nicole Lurie, Assistant Secretary for Preparedness and Response at the Department of Health and Human Services; and Dr. Scott Dowell, Director of the Global Disease Detection Program at the Centers for Disease Control and Prevention. The discussants were: Dr. Julie Fischer, Stimson Center; Ms. Jennifer Kates, Kaiser Family Foundation; and Dr. Stephen Morrison, Center for Strategic and International Studies

Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106-115

The ability of the cellular prion protein (PrPC) to bind copper in vivo points to a physiological role for PrPC in copper transport. Six copper binding sites have been identified in the nonstructured N-terminal region of human PrPC. Among these sites, the His111 site is unique in that it contains a MKHM motif that would confer interesting CuI and CuII binding properties. We have evaluated CuI coordination to the PrP(106-115) fragment of the human PrP protein, using NMR and X-ray absorption spectroscopies and electronic structure calculations. We find that Met109 and Met112 play an important role in anchoring this metal ion. CuI coordination to His111 is pH-dependent: at pH >8, 2N1O1S species are formed with one Met ligand; in the range of pH 5-8, both methionine (Met) residues bind to CuI, forming a 1N1O2S species, where N is from His111 and O is from a backbone carbonyl or a water molecule; at pH <5, only the two Met residues remain coordinated. Thus, even upon drastic changes in the chemical environment, such as those occurring during endocytosis of PrPC (decreased pH and a reducing potential), the two Met residues in the MKHM motif enable PrPC to maintain the bound CuI ions, consistent with a copper transport function for this protein. We also find that the physiologically relevant CuI-1N1O2S species activates dioxygen via an inner-sphere mechanism, likely involving the formation of a copper(II) superoxide complex. In this process, the Met residues are partially oxidized to sulfoxide; this ability to scavenge superoxide may play a role in the proposed antioxidant properties of PrPC. This study provides further insight into the CuI coordination properties of His111 in human PrPC and the molecular mechanism of oxygen activation by this site.Fil: Arcos López, Trinidad. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Qayyum, Munzarin. University of Stanford; Estados UnidosFil: Rivillas Acevedo, Lina. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Miotto, Marco César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; ArgentinaFil: Grande Aztatzi, Rafael. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Fernandez, Claudio Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario. Universidad Nacional de Rosario. Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario; Argentina. Max Planck Laboratory for Structural Biology; ArgentinaFil: Hedman, Britt. University of Stanford; Estados UnidosFil: Hodgson, Keith O.. University of Stanford; Estados UnidosFil: Vela, Alberto. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; MéxicoFil: Solomon, Edward I.. University of Stanford; Estados UnidosFil: Quintanar, Liliana. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzado; Méxic

WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial

Background: Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure. ADAPT is one of the first new generation (neo) adjuvant trials dealing with individualization of (neo) adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e. g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment. Methods/design: The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative ``umbrella{''} protocol design. The ``umbrella{''} is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2-sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status. Discussion: Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment. Trial registration: ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN: NCT01815242

PTK7 as a potential prognostic and predictive marker of response to adjuvant chemotherapy in breast cancer patients, and resistance to anthracycline drugs

Biomarkers predicting resistance to particular chemotherapy regimens could play a key role in optimally individualized treatment concepts. PTK7 (protein tyrosine kinase 7) belongs to the receptor tyrosine kinase family involved in several physiological, but also malignant, cell behaviors. Recent studies in acute myeloid leukemia have associated PTK7 expression with resistance to anthracycline therapy. PTK7 mRNA expression in primary tumor tissue (PTT) and corresponding lymph node tissue (LNT) were retrospectively measured in 117 patients with early breast cancer;PTK7 expression was available in 103 PTT and 108 LNT samples. Median age was 60 years (range, 27-87 years). At a median follow-up of 28.5 months, 6 deaths and 16 recurrences had occurred. PTK7 expression correlations with clinicopathological features were computed and PTK7 expression effects on patient outcome were analyzed in three cohorts defined by adjuvant treatment: anthracycline-based treatment, other chemotherapy regimens (including taxane or other substances),or no chemotherapy. Association of PTK7 expression with clinicopathological features was seen only for age in PTT and nodal stage in LNT. High LN PTK7 was associated with poorer disease-free survival (DFS) in the total population (3-year DFS: low [81.7%] versus high [70.4%];P=0.016) and in patients without adjuvant chemotherapy (3-year DFS: low [91.7%] versus high [22.3%];P<0.001),but not in patients receiving adjuvant chemotherapy (P=0.552). DFS stratified by PTK7 expression was compared in treatment cohorts: In patients with low LN PTK7 expression, neither chemotherapy cohort showed significantly better survival than the no-chemotherapy cohort. In patients with high LN PTK7 expression, those receiving chemotherapy, including substances other than anthracyclines, but not those receiving only anthracycline-based chemotherapy, showed significantly better DFS than those receiving no chemotherapy (P=0.001). Our results support earlier findings that PTK7 may be a prognostic and predictive marker associated with resistance to anthracycline-based chemotherapy. Further investigations are needed to validate these findings in breast cancer

Derivation of an optimal directivity pattern for sweet spot widening in stereo sound reproduction

In this paper the correction of the degradation of the stereophonic illusion during sound reproduction due to off-center listening is investigated. The main idea is that the directivity pattern of a loudspeaker array should have a well-defined shape such that a good stereo reproduction is achieved in a large listening area. Therefore, a mathematical description to derive an optimal directivity pattern lopt that achieves sweet spot widening in a large listening area for stereophonic sound applications is described. This optimal directivity pattern is based on parametrized time/intensity trading data coming from psycho-acoustic experiments within a wide listening area. After the study, the required digital FIR filters are determined by means of a least-squares optimization method for a given stereo base setup (two pair of drivers for the loudspeaker arrays and 2.5-m distance between loudspeakers), which radiate sound in a broad range of listening positions in accordance with the derived lopt. Informal listening tests have shown that the lopt worked as predicted by the theoretical simulations. They also demonstrated the correct central sound localization for speech and music for a number of listening positions. This application is referred to as "Position-Independent (PI) stereo.