Graduate Recital:Maria Ventura, Mezzo Soprano

Kemp Recital Hall Sunday Afternoon October 29, 2000 3:00 p.m

Study of anti-tumoral activity of HIV-Protease Inhibitor nelfinavir and identification of new nelfinavir-derivative compounds

Human Immunodeficiency Virus-Protease Inhibitors (HIV-PIs) are peptidomimetic drugs used in AIDS therapy to inhibit HIV infection by blocking viral protease. The advent of these drugs has led to a reduced incidence of HIV-associated tumors, particularly Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer. Many studies have also reported an anti-proliferative non-virological action of HIV-PIs in HIV-free models leading them to be further investigated as anti-cancer drugs. In particular HIV-PIs affect several pathways involved in tumor-cell proliferation and survival, angiogenesis, invasion, inflammation, and antitumor immunity in HIV-free models. The most effective anti-cancer HIV-PIs is nelfinavir, that is in clinical trial for several tumor types, thus encouraging the study of the intracellular pathways at the basis of their anti-tumor activity. The anti-tumoral effects of nelfinavir have been related to inhibition of Akt activation, but to date the molecular mechanism at the basis of anti-cancer activity in breast cancer is poorly understood. My results suggest an anti-proliferative activity of nelfinavir in a panel of cancer cell lines. In particular, nelfinavir induces apoptosis and necrosis in breast cancer cell lines such as MDA-MB231 and MCF-7 cells by affecting cell cycle in a cell line dependent way. The anti-tumor activity of nelfinavir is linked to the perturbation of cellular redox state; resulting in an increase of intracellular reactive oxygen species (ROS) production in breast cancer cells but not in normal breast epithelial cells. Nelfinavir treated tumor cells show also a downregulation of akt pathway due to the disruption of akt-Heat Shock Protein 90 kDa (HSP90) complex that is induced by nelfinavir and subsequent degradation of akt via proteasome. These effects result to be ROS dependent. Since treatment with anti-oxidant free radical scavenger tocopherol restores akt expression levels as well as viability of nelfinavir-untrated cells, the increase of ROS production represents the main and necessary molecular mechanism to induce cell death in breast cancer cell lines. The anti-cancer effectiveness of nelfinavir has motivated its use as lead compound in this study to design novel anti-tumoral compounds. Primary screening has led to the identification of novel nelfinavir-derivative (4n) with a high anti-cancer efficacy (IC50 50nM), that is a promising molecule to further evaluate for cancer therapy

Decision-Epoch Matters: Unveiling its Impact on the Stability of Scheduling with Randomly Varying Connectivity

A classical queuing theory result states that in a parallel-queue single-server model, the maximum stability region does not depend on the scheduling decision epochs, and in particular is the same for preemptive and non-preemptive systems. We consider here the case in which each of the queues may be connected to the server or not, depending on an exogenous process. In our main result, we show that the maximum stability region now does strongly depend on how the decision epochs are defined. We compare the setting where decisions can be made at any moment in time (the unconstrained setting), to two other settings: decisions are taken either (i) at moments of a departure (non-preemptive scheduling), or (ii) when an exponentially clock rings with rate $\gamma$. We characterise the maximum stability region for the two constrained configurations, allowing us to observe a reduction compared to the unconstrained configuration. In the non-preemptive setting, the maximum stability region is drastically reduced compared to the unconstrained setting and we conclude that a non-preemptive scheduler cannot take opportunistically advantage (in terms of stability) of the random varying connectivity. Instead, for the $\gamma$ decision epochs, we observe that the maximum stability region is monotone in the rate of the decision moments $\gamma$, and that one can be arbitrarily close to the maximum stability region in the unconstrained setting if we choose $\gamma$ large enough. We further show that Serve Longest Connected (SLC) queue is maximum stable in both constrained settings, within the set of policies that select a queue among the connected ones. From a methodological viewpoint, we introduce a novel theoretical tool termed a ``test for fluid limits'' (TFL) that might be of independent interest. TFL is a simple test that, if satisfied by the fluid limit, allows us to conclude for stability

Traditional Processing Meets Islandora

The Caltech Archives have been digitizing the papers of Paul B. MacCready, a major figure in aeronautical engineering in the second half of the 20th century. His papers include notebooks, diaries, correspondence, drawings, photographs, and audiovisual material. Islandora was chosen as the platform for access and preservation. The collection had previously been processed and a finding aid had been created. We present three innovations that have contributed to efficient digitization and ingest into Islandora, and to optimal user experience. We created a naming scheme for digitized files based on the series, box, and folder numbering of the collection. This allowed us to automatically match files with descriptive metadata and to create local identifier links as part of the ingested metadata in Islandora. We built on UCLA’s prior work to allow navigation of the collection by means of the finding aid, which is displayed in Islandora and contains links to folders. This gives intellectual context to searches. Finally, we have been working to incorporate the IIIF-compliant Universal Viewer as an additional viewer available for multipage objects

Military and elites in XXth and XXIst centuries in Argentina. Problematizing theoretical definitions and empirical uses of categories

Los militares han sido asociados con las élites sociales, económicas, políticas y estatales de la Argentina. Este artículo estudia sus relaciones desde principios del siglo XX hasta el presente. Analiza el reclutamiento de los oficiales principalmente entre las clases medias urbanas de la región pampeana; las relaciones de los oficiales con la sociabilidad de la clase alta, la construcción de su prestigio como élite moral, el aumento de sus funciones de responsabilidad social en actividades educativas, la incorporación a la élite dirigente como altos funcionarios políticos y técnicos del Estado; y su proceso de declive como élite dirigente con la pérdida de prestigio y reconocimiento social de las Fuerzas Armadas desde la crisis de la última dictadura.The military has been associated with Argentina’s social, economic, political and State elites. This article studies their relations from the beginning of the XXth century up to the present. It analyzes military recruitment carried out, mainly, in urban middle classes of the pampeana region; the officers’ relations with upper class society; the construction of military prestige as moral elite, the increase of its functions of social responsibility in educational activities, their incorporation to the ruling elite as high political and technical State officials; and its decline as ruling elite resulting from the loss of prestige and social recognition of the Armed Forces since the crisis of the last dictatorship.Fil: Soprano Manzo, Germán Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Mellado, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Ciencias Humanas, Sociales y Ambientales; Argentin

A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells

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NutriLive: An Integrated Nutritional Approach as a Sustainable Tool to Prevent Malnutrition in Older People and Promote Active and Healthy Ageing—The EIP-AHA Nutrition Action Group

The present document describes a nutritional approach that is nested in the European Innovation Partnership for Active and Healthy Aging (EIP-AHA) and aims to provide the first common European program translating an integrated approach to nutritional frailty in terms of a multidimensional and transnational methodology. The document has been developed by the A3 Nutrition Action Area of the EIP-AHA and aims at providing a stepwise approach to malnutrition in older citizens, identifying adequate interventions based on a unified assessment and ICT-supported solutions. "NutriLive" is an integrated nutritional approach, represented by a structured Screening-Assessment-Monitoring-Action-Pyramid-Model (SAM-AP). Its core concept is the stratification of the nutritional needs, considered by the working group as the key for targeted, effective, and sustainable interventions. "NutriLive" tries to close gaps in epidemiological data within an aging population, creating a unified language to deal with the topic of nutrition and malnutrition in Europe. By assembling all the validated screening, assessment, and monitoring tools on malnutrition in a first pyramid, which is interrelated to a second intervention pyramid, the A3 Nutrition WG identifies a common, integrated vision on the nutritional approach to frailty, which applies to the various health care settings

Cellular subtype expression and activation of CaMKII regulate the fate of atherosclerotic plaque

Abstract Background and aims Atherosclerosis is a degenerative process of the arterial wall implicating activation of macrophages and proliferation of vascular smooth muscle cells. Calcium-calmodulin dependent kinase type II (CaMKII) in vascular smooth muscle cells (VSMCs) regulates proliferation, while in macrophages, this kinase governs diapedesis, infiltration and release of extracellular matrix enzymes. We aimed at understanding the possible role of CaMKII in atherosclerosis plaques to regulate plaque evolution towards stability or instability. Methods Clinically defined stable and unstable plaques obtained from patients undergoing carotid end arteriectomy were processed for evaluation of CaMKs protein expression, activity and localization. Results The larger content of CaMKII was found in CD14 + myeloid cells that were more abundant in unstable rather than stable plaques. To test the biological effect of activated CD14 + myeloid cells, VSMCs were exposed to the conditioned medium (CM) of macrophages extracted from carotid plaques. CM induced attenuation of CaMKs expression and activity in VSMCs, leading to the reduction of VSMCs proliferation. This appears to be due to the CaMKII dependent release of cytokines. Conclusions These results indicate a pivotal role of CaMKs in atherosclerosis by regulating activated myeloid cells on VSMCs activity. CaMKII could represent a possible target for therapeutic strategies based on macrophages specific inhibition for the stabilization of arteriosclerotic lesions

Nutrition and osteoporosis: preliminary data of campania region of european personalised ict supported service for independent living and active ageing

Background: Bone impairment and malnutrition are associated with significant disability and mortality. PERSSILAA is an European project developing health services to detect and prevent frailty in older adults by addressing cognitive, physical and nutritional. Methods: Subjects underwent anthropometric measurements, calcaneal quantitative ultrasound (QUS) scan and PREDIMED (PREvención con DIetaMEDiterránea) questionnaire. Aim: To investigate the association between adherence to the Mediterranean Diet (MD) and bone health. Results: 87 subjects (4 males and 83 females) 70.1±4.9 aged, were examined. Mean Body Mass Index (BMI) was 28.7±4.7(kg/m2): in particular 28 subjects (32.2%) resulted obese, 42 (48.3%) overweight, and only 17 (19.5%) with normal weight. Mean T score was -1.2±1.2: in particular 13 subjects (14.9%) resulted osteoporotic; 43 (49.5%) osteopenic; and 31 (35.6%) with normal bone mineral density. Regarding adherence to MD, 9 subjects (10.3%) were poorly adherent; 41 (47.2%) average adherent; 37 (42.5%) highly adherent. T-score was associated with PREDIMED score and osteoporotic nsubjects presented the lowest PREDIMED score (5.8±2.2). Conclusions: These preliminary data show a significant correlation between the adherence to the MD and bone health parameters. The association between MD and bone health highlights the potential beneficial effects of nutritional interventions promoting a Mediterranean food pattern, as safe adjuvant treatment in ageing

Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis

Glycosylation is recognized as a key process for proper megakaryopoiesis and platelet formation. The enzyme uridine diphosphate (UDP)-galactose-4-epimerase, encoded by GALE, is involved in galactose metabolism and protein glycosylation. Here, we studied 3 patients from 2 unrelated families who showed lifelong severe thrombocytopenia, bleeding diathesis, mental retardation, mitral valve prolapse, and jaundice. Whole-exome sequencing revealed 4 variants that affect GALE, 3 of those previously unreported (Pedigree A, p.Lys78ValfsX32 and p.Thr150Met; Pedigree B, p.Val128Met; and p.Leu223Pro). Platelet phenotype analysis showed giant and/or grey platelets, impaired platelet aggregation, and severely reduced alpha and dense granule secretion. Enzymatic activity of the UDP-galactose-4-epimerase enzyme was severely decreased in all patients. Immunoblotting of platelet lysates revealed reduced GALE protein levels, a significant decrease in N-acetyl-lactosamine (LacNAc), showing a hypoglycosylation pattern, reduced surface expression of gylcoprotein Ibα-IX-V (GPIbα-IX-V) complex and mature β1 integrin, and increased apoptosis. In vitro studies performed with patients-derived megakaryocytes showed normal ploidy and maturation but decreased proplatelet formation because of the impaired glycosylation of the GPIbα and β1 integrin, and reduced externalization to megakaryocyte and platelet membranes. Altered distribution of filamin A and actin and delocalization of the von Willebrand factor were also shown. Overall, this study expands our knowledge of GALE-related thrombocytopenia and emphasizes the critical role of GALE in the physiological glycosylation of key proteins involved in platelet production and function.This work was supported by grants from Instituto de Salud Carlos III (ISCIII) & Feder (PI17/01966, PI20/00926) and cofunded by European Union (ERDF/ESF, “Investing in your future”), Gerencia Regional de Salud (GRS2061/A/2019, GRS2135/A/2020, GRS2314/A/2021), Fundación Mutua Madrileña (FMM, AP172142019), Sociedad Española de Trombosis y Hemostasia (SETH-FETH; Premio López Borrasca 2019 and Ayuda a Grupos de Trabajo en Patología Hemorrágica 2020 and 2021), Fundación Castellano Leonesa de Hematología y Hemoterapia (FUCALHH 2020), Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD12/0036/0069), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233). Progetti di ricerca di rilevante interesse Nazionale (PRIN 2017Z5LR5Z), and the European Commission (H2020-FETOPEN-1-2016-2017-SilkFusion ID 767309). The author´s research on Inherited Platelet Disorders is conducted in accordance with the aims of the multicentric project “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” of Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC). A.M.-Q. is fully supported by an “Ayuda predoctoral de la Junta de Castilla y León” by the Fondo Social Europeo (JCYL- EDU/556/2019 PhD scholarship) and received an “Ayuda para breves estancias formativas” from the Sociedad Española de Hematología y Hemoterapia (SEHH-FEHH), and from the Sociedad Española de Trombosis y Hemostasia (SETH-FETH); E.V. is fully supported by an “Ayuda para contratos predoctorales de la Universidad de Salamanca cofinanciadas por el banco Santander,” programa propio III convocatoria 2018; I.S.-G. is supported by a contract from the University of Salamanca cofinanced by the Junta de Castilla y León (Council of Education) and FEDER-European Union [ref. SA0118P20 (2)]; S.S.-M. and C.M.-G. received funding from the European Research Council (ERC) under the ERA-Per-Med programme (ERAPERMED2018-275) SYNtherapy and ISCIII (AC18/00093) cofunded by ERDF/ESF, “Investing in your future”; I.G.-T. and R.B. are supported by a grant from the Universidad de Salamanca (“Contrato postdoctoral Universidad de Salamanca programa propio II, 2019”)Peer reviewe