Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin.

Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), NAD(+)-dependent enzymes, link cellular energy status with responses to environmental stresses. Skin is frequently exposed to the DNA damaging effects of UV irradiation, a known etiology in skin cancer. Thus, understanding the defense mechanisms in response to UV, including the role of SIRTs and PARPs, may be important in developing skin cancer prevention strategies. Here, we report expression of the seven SIRT family members in human skin. SIRTs gene expressions are progressively upregulated in A431 epidermoid carcinoma cells (SIRTs1 and 3), actinic keratoses (SIRTs 2, 3, 5, 6, and 7) and squamous cell carcinoma (SIRTs 1-7). Photodamage induces dynamic changes in SIRT expression with upregulation of both SIRT1 and SIRT4 mRNAs. Specific losses of SIRT proteins occur early after photodamage followed by accumulation later, especially for SIRT4. Niacin restriction, which decreases NAD(+), the sirtuin substrate, results in an increase in acetylated proteins, upregulation of SIRTs 2 and 4, increased inherent DNA damage, alterations in SIRT responses to photodamage, abrogation of PARP activation following photodamage, and increased sensitivity to photodamage that is completely reversed by repleting niacin. These data support the hypothesis that SIRTs and PARPs play important roles in resistance to photodamage and identify specific SIRTs that respond to photodamage and may be targets for skin cancer prevention

IFNγ-induced PD-L1 expression is JAK2 but not JAK1 dependent and its inhibition enhances NK-cetuximab mediated ADCC of HNSCC cells

Programmed death ligand 1 (PD-L1) is an immunosuppressive molecule expressed by many cancer types, including a large proportion of head and neck cancers (HNC), and ligation of its receptor, programmed death 1 (PD-1), induces exhaustion of effector T cells. It has been shown that interferon gamma (IFNγ) induces PD-L1 expression in many cancer types including glioblastoma, melanoma, lung and kidney cancer. Importantly, the stimuli and mechanism for PD-L1 upregulation in HNC cells are not well characterized. IFNγ signals through Janus Kinase 1/2 (JAK1/2) heterodimer complex and mediates signal transducer and activator of transcription 1 (STAT1) phosphorylation, leading to type I cytokine expression, upregulation of antigen presentation, and tumor cell recognition by cytolytic T lymphocytes (CTL). We investigated basal PD-L1 expression and the mechanism by which IFNγ signaling upregulates PD-L1 in HNC cells including dependence on JAK/STAT pathway. We observed that IFNγ signaling increased PD-L1 expression in a JAK2 but not JAK1 dependent fashion. In addition, interferon alpha (IFNα), which signals via JAK1/TYK2 did not upregulate PD-L1 expression while still upregulated HLA class I. Specific JAK2 inhibition downregulated NK cell-derived IFNγ induced PD-L1 expression and enhanced cetuximab mediated ADCC. Our data suggest a crucial role for JAK2/STAT1 in IFNγ mediated PD-L1 upregulation. JAK2 inhibition provides a promising strategy to increase tumor cell lysis through maintaining HLA class I while suppressing tumor cell expressed PD-L1 in combination with anti-EGFR cetuximab therapy

A longitudinal retrospective study on intracranial arterial pulsatility index: its evolution in ten years' time and how it relates to the occurrence of cerebral and systemic ischemic disease

BACKGROUND AND AIMS: Intracranial arterial pulsatility index (PI) has been related to old age, hypertension, diabetes and small vessel disease. However, the cross- sectional design of most studies prevents a proper assessment of causality and evolution. We sought to explore how this index changes through time, which conditions affect this evolution and whether or not it can predict the occurrence of future ischemic events. METHODS: Between the years 2001-2006, 1288 patients underwent a transcranial Doppler evaluation in the Department of Neurology of the Hospital Universitario Central de Asturias. PI values for the middle cerebral and basilar arteries were systematically annotated. After exclusion of deceased patients and significant large artery stenoses, 89 patients were recruited for a re-evaluation in 2012. Afterwards, the sample was expanded up to 150 patients, with 61 randomly selected patients –either alive or deceased- who did not undergo a second exploration. Both groups had their clinical files reviewed, with special attention to vascular risk factors and brain or coronary ischemic events. RESULTS AND DISCUSSION: Our results pointed to the following conclusions: • Intracranial arterial PI works as a dynamic measure of both cerebral and systemic vascular disease. • Age is the main factor influencing PI value and variation, but, within a certain age group, PI is able to point subjects at higher long-term risk of future ischemic events. • Basilar artery PI seems to be a better predictor of future cerebral and coronary ischemic disease than middle cerebral artery PI

EGFR-mediated tumor immunoescape: The imbalance between phosphorylated STAT1 and phosphorylated STAT3

The epidermal growth factor receptor (EGFR) supports the escape of malignant cells from immunosurveillance by inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) while promoting that of STAT3. We have recently demonstrated that protein tyrosine phosphatase, non-receptor type 11 (PTNP11, best known as SHP2), a phosphatase that operates downstream of EGFR, is responsible for the dephosphorylation of active STAT1 and for the inhibition of the antigen-processing machinery (APM), hence favoring tumor immunoescape. Thus, EGFR signaling may skew the tumor microenvironment to suppress cellular immune responses

Efectos de los temporales sobre las playas de la Bahía de Cádiz

[Resumen] En el presente trabajo se estudian los efectos que los temporales de Diciembre e 1995 y Enero de 1996 tuvieron sobre las playas de la Bahía de Cádiz. Del análisis del oleaje incidente se observa cómo sus efectos se multiplican cuando los picos de temporal coinciden con el máximo rango de mareas. Los cambios morfológicos registrados en las playas se estudian mediante el perfilamiento pre y post-temporal de playas tanto naturales como regeneradas artificialmente. La cuantificación de dichos cambios muestra cómo la forma inicial de los perfiles es determinante en el tipo de respuesta de las playas frente a olejaes de gran energía. También se manifiestan procesos de erosión en cordones dunares, mediante incisiones, desbordamientos, etc. La estimación final de los daños sufridos por las playas revela mayores pérdidas en aquellas zonas donde la presión antrópica es mayor[Abstract] The work deals with the effects that the storm surges of December-1995 and January-1996 made upon the beaches of Cádiz Bay (SW Spain). From the incidentwave analysis it can be deduced that the effects are much stronger when the surge peak coincides with maximum tidal ranges. The morphological changes recorded in the beaches are studied through pre- and post-surge profiling of both natural and artificially nourished beaches. The quantification of such morphological transformations shows that the initial beach profile is determinant in the kind of response of the beach to high wave-energy conditions. The erosive processes upon dune ridges are represented by gullying, overwashing, etc. The final estimation of losses in the beaches reveals higher damages in zones where anthropic preassure is higher

Reversing EGFR Mediated Immunoescape by Targeted Monoclonal Antibody Therapy

Uncontrolled growth is a signature of carcinogenesis, in part mediated by overexpression or overstimulation of growth factor receptors. The epidermal growth factor receptor (EGFR) mediates activation of multiple oncogenic signaling pathways and escape from recognition by the host immune system. We discuss how EGFR signaling downregulates tumor antigen presentation, upregulates suppressive checkpoint receptor ligand programmed death ligand (PD-L1), induces secretion of inhibitory molecules such as transforming growth factor beta (TGFβ) and reprograms the metabolic pathways in cancer cells to upregulate aerobic glycolysis and lactate secretion that ultimately lead to impaired cellular immunity mediated by natural killer (NK) cell and cytotoxic T lymphocytes (CTL). Ultimately, our understanding of EGFR-mediated escape mechanisms has led us to design EGFR-specific monoclonal antibody therapies that not only inhibit tumor cell metabolic changes and intrinsic oncogenic signaling but also activates immune cells that mediate tumor clearance. Importantly, targeted immunotherapy may also benefit from combination with antibodies that target other immunosuppressive pathways such PD-L1 or TGFβ and ultimately enhance clinical efficacy

Outcomes of a Multi-Component Family Enrichment Project: 12-Month Follow-up

Previous research has established that family enrichment programs work with a variety of populations (e.g., Hawkins, Stanley, Blanchard, & Albright, 2012). It is unclear if a multi-component program focusing on a variety of family outcomes can lead to lasting change. This study used growth modeling to examine effects of relationship (i.e., Within My Reach), parenting (i.e., Making Parenting a Pleasure), and financial enrichment (i.e., Spend Some, Save Some, Share Some) classes over 12 months. Results revealed improvement in family functioning at one year post for all three programs. Program specific improvements included relationship functioning and parenting alliance. Program participants reported overall satisfaction and gaining of valuable skills. Findings suggest these family enrichment programs can have long-lasting effects; potential reasons for sample success and implications are discussed

Observations and dynamical implications of active normal faulting in South Peru

SUMMARY Orogenic plateaus can exist in a delicate balance in which the buoyancy forces due to gravity acting on the high topography and thick crust of the plateau interior are balanced by the compressional forces acting across their forelands. Any shortening or extension within a plateau can indicate a perturbation to this force balance. In this study, we present new observations of the kinematics, morphology and slip rates of active normal faults in the South Peruvian Altiplano obtained from field studies, high-resolution DEMs, Quaternary dating and remote sensing. We then investigate the implications of this faulting for the forces acting on the Andes. We find that the mountains are extending ∼NNE–SSW to ∼NE–SW along a normal fault system that cuts obliquely across the Altiplano plateau, which in many places reactivates Miocene-age reverse faults. Radiocarbon dating of offset late Quaternary moraines and alluvial fan surfaces indicates horizontal extension rates across the fault system of between 1 and 4 mm yr–1—equivalent to an extensional strain rate in the range of 0.5–2 × 10−8 1 yr–1 averaged across the plateau. We suggest the rate and pattern of extension implies there has been a change in the forces exerted between the foreland and the Andes mountains. A reduction in the average shear stresses on the sub-Andean foreland detachment of ≲4 MPa (20–25 per cent of the total force) can account for the rate of extension. These results show that, within a mountain belt, the pattern of faulting is sensitive to small spatial and temporal variations in the strength of faults along their margins.Denman Baynes Senior Studentship, Clare College Cambridge Arup Santander Mobility Grant (University of Cambridge

Thermographic imaging: assessment of drought and heat tolerance in Spanish germplasm of Brachypodium distachyon.

The annual grass Brachypodium distachyon has been recently recognized as the model plant for functional genomics of temperate grasses, including cereals of economic relevance like wheat and barley. Sixty-two lines of B. distachyon were assessed for response to drought stress and heat tolerance. All these lines, except the reference genotype BD21, derive from specimens collected in 32 distinct locations of the Iberian Peninsula, covering a wide range of geo- climatic conditions. Sixteen lines of Brachypodium hybridum, an allotetraploid closely related to B. distachyon were used as reference of abiotic-stress well-adapted genotypes. Drought tolerance was assessed in a green-house trial. At the rosette-stage, no irrigation was applied to treated plants whereas their replicates at the control were maintained well watered during all the experiment. Thermographic images of treated and control plants were taken after 2 and 3 weeks of drought treatment, when stressed plants showed medium and extreme wilting symptoms. The mean leaf temperature of stressed (LTs) and control (LTc) plants was estimated based upon thermographic records from selected pixels (183 per image) that strictly correspond to leaf tissue. The response to drought was based on the analysis of two parameters: LTs and the thermal difference (TD) between stressed and control plants (LTs – LTc). The response to heat stress was based on LTc. Comparison of the mean values of these parameters showed that: 1) Genotypes better adapted to drought (B. hybridum lines) presented a higher LTs and TD than B. distachyon lines. 2) Under high temperature conditions, watered plants of B. hybridum lines maintained lower LTc than those of B. distachyon. Those results suggest that in these species adaptation to drought is linked to a more efficient stomata regulation: under water stress stomata are closed, increasing foliar temperature but also water use efficiency by reducing transpiration. With high temperature and water availability the results are less definite, but still seems that opening stomata allow plants to increase transpiration and therefore to diminish foliar temperature

Estudio de la cinética de adsorción de Cu y Hg a partir de soluciones binarias usando quitosano

pEn este trabajo se estudió la cinética de adsorción de Cu(II) y Hg(II) en quitosano a partir de una solución binaria, a diferentes concentraciones iniciales de los iones metálicos, tamaño de partículas del adsorbente y velocidad de agitación. El quitosano fue extraído por métodos químicos de caparazón de camarón. Soluciones de 1 L de Cu(II) y Hg(II) fueron puestas en contacto con 2 g de quitosano y se agitaron por un período de 8 h. Al final del proceso, las muestras fueron analizadas en un espectrómetro de absorción atómica. Los datos experimentales fueron evaluados aplicando los modelos cinéticos de pseudo-primer orden y pseudo-segundo orden. Los resultados del proceso de adsorción de los iones metálicos Cu(II) y Hg(II) con quitosano, mostraron que en la mayoría de los casos, ambos iones fueron eficazmente adsorbidos por la quitosano, obteniéndose un porcentaje de adsorción entre 44-100 % para Cu(II) y entre 95-100 % para el Hg(II). Para ambos iones, los resultados mostraron que a bajas concentraciones el proceso de adsorción se ajusta mejor al modelo de pseudo-primer orden y a concentraciones altas el modelo que mejor se ajusta a los datos experimentales es el modelo de pseudo-segundo orden; es decir, el paso limitante en la velocidad es la reacción de adsorción y no la transferencia de masa./pp /pp /ppstrongPalabras claves:/strong Caparazón de camarón; Cinética de adsorción; Modelos cinéticos; Solución binaria; Quitosano/p pDOI: a href="http://dx.doi.org/10.5377/nexo.v24i1.591"http://dx.doi.org/10.5377/nexo.v24i1.591/a/p pNexo, Vol. 24, No. 1, pp. 20-32, 2011/