Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes

Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population

Genetic Incorporation of Human Metallothionein into the Adenovirus Protein IX for Non-Invasive SPECT Imaging

As the limits of existing treatments for cancer are recognized, clearly novel therapies must be considered for successful treatment; cancer therapy using adenovirus vectors is a promising strategy. However tracking the biodistribution of adenovirus vectors in vivo is limited to invasive procedures such as biopsies, which are error prone, non-quantitative, and do not give a full representation of the pharmacokinetics involved. Current non-invasive imaging strategies using reporter gene expression have been applied to analyze adenoviral vectors. The major drawback to approaches that tag viruses with reporter genes is that these systems require initial viral infection and subsequent cellular expression of a reporter gene to allow non-invasive imaging. As an alternative to conventional vector detection techniques, we developed a specific genetic labeling system whereby an adenoviral vector incorporates a fusion between capsid protein IX and human metallothionein. Our study herein clearly demonstrates our ability to rescue viable adenoviral particles that display functional metallothionein (MT) as a component of their capsid surface. We demonstrate the feasibility of 99mTc binding in vitro to the pIX-MT fusion on the capsid of adenovirus virions using a simple transchelation reaction. SPECT imaging of a mouse after administration of a 99mTc-radiolabeled virus showed clear localization of radioactivity to the liver. This result strongly supports imaging using pIX-MT, visualizing the normal biodistribution of Ad primarily to the liver upon injection into mice. The ability we have developed to view real-time biodistribution in their physiological milieu represents a significant tool to study adenovirus biology in vivo

Recull de propostes per minimitzar l'impacte negatiu de gènere del sistema de teletreball a l'Ajuntament de Barcelona

Finançat amb el projecte "Impacto de GÉnero del TEletrabajo y rutinas de COnfinamiento: más allá de lo obvio" (Ref. SUPERACOVID19_2.2.IGETECO) i a través de l'Ajuntament de Barcelona pel Servei d'Estudi sobre propostes per minimitzar l'impacte negatiu de gènere del sistema de teletreball a l'Ajuntament de Barcelona (exp.20002682)El present document recull les propostes d'actuació contingues a l'estudi Propostes per minimitzar l'impacte negatiu de gènere del sistema de teletreball a l'Ajuntament de Barcelona realitzat pel Centre d'Estudis Sociològics sobre la Vida Quotidiana i el Treball (QUIT) de la Universitat Autònoma de Barcelona. L'emergència sanitària provocada per la Covid19 i el necessari confinament de la població per combatre la pandèmia ha significat, des del punt de vista de l'organització del treball, un canvi molt important cap a l'impuls de formes de treball a distància. Però aquest impuls del teletreball ha estat una resposta fruit de l'emergència, lògica davant la situació viscuda i, com a tal, no ha pogut ser planificada amb el temps i els mitjans necessaris

In vivo gene transfer of inducible nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits

Background and Purpose-Hypercholesterolemia is associated with endothelial dysfunction. Inducible nitric oxide synthase (iNOS) is upregulated in atherosclerotic vessels. However, its role in the regulation of vascular function is not completely understood. We examined the effect of adenovirus-mediated gene transfer of iNOS to the hypercholesterolemic rabbit carotid artery in vivo. Methods-Rabbits were fed a high-cholesterol or chow diet for 10 weeks. Two doses (1 x 10(8) and 1 x 10(9) plaque-forming units [pfu]/mL) of adenoviral vectors encoding iNOS (AdiNOS) or beta-galactosidase (Adbetagal) were luminally delivered to the carotid arteries from chow- and cholesterol-fed animals. Vascular reactivity and superoxide levels were assessed in Adbetagal- and AdiNOS-transduced vessels from chow- and cholesterol-fed animals after 3 days. Results-Endothelium-dependent vasorelaxation was impaired in the carotid artery from cholesterol-fed animals. In AdiNOS-transduced arteries, transgene expression was demonstrated by positive immunostaining in the endothelium. Transduction with low-dose (1 x 10(8) pfu/mL) AdiNOS did not affect vascular reactivity in arteries from chow- and cholesterol-fed animals. In contrast, high-dose (1 x 10(9) pfu/mL) AdiNOS significantly reduced endothelium-dependent relaxation in vessels from cholesterol-but not chow- fed rabbits. After both low- and high-dose iNOS gene transfer, levels of O-2(.-) were significantly (P<0.05) elevated in carotid arteries from cholesterol-fed animals. Incubation with an O-2(.-) scavenger did not reverse vascular dysfunction in these arteries. Conclusions-Adenoviral- mediated overexpression of iNOS results in increased production of O-2(.-) in carotid arteries from cholesterol-but not chow- fed animals. High-dose AdiNOS gene transfer is associated with reduced endothelium-dependent and -independent relaxation in vessels from cholesterol-fed animals

Inhibitory effect of recombinant inos gene expression on vasomotor function of canine basilar artery

The present study was designed to determine the effect of recombinant inducible nitric oxide (NO) synthase (iNOS) gene expression on vasomotor function in cerebral arteries. Isolated canine basilar arteries were exposed ex vivo (30 min at 37degreesC) to an adenoviral vector [10(7), 10(8), or 10(9) plaque-forming units (pfu)/ml] encoding either the iNOS gene or the beta-galactosidase reporter gene. Twenty-four hours after transduction, Western blot analysis demonstrated expression of iNOS protein only in iNOS (10(9) pfu/ml)-transduced arteries. Immunohistochemical analysis localized iNOS expression predominantly in adventitia. Vascular reactivity of isolated basilar arteries was studied by isometric force recording. Concentration-response curves to UTP (10(-9)-10(-3) M) and diethylaminodiazen-1-ium-1,2-dioate (10(-10)-10(-5) M) were significantly shifted to the right in iNOS gene (109 pfu/ml)-transduced rings compared with control and beta-galactosidase-transduced rings (P < 0.05, n = 5-6). Endothelium-dependent relaxation to bradykinin was significantly attenuated in iNOS-transduced rings (P < 0.001, n = 8). The basal level of cGMP and superoxide anion (O-2(-).) production were elevated in iNOS-transduced rings (P < 0.05, n = 7 for cGMP; P < 0.01, n = 6-9 for O-2(-). production). Our results suggest that expression of recombinant iNOS in cerebral arteries reduces vasomotor reactivity to both vasoconstrictor and vasodilator agonists. Attenuation of contractions is most likely due to functional antagonism between UTP and cGMP. Reduction of endothelium-dependent relaxation to bradykinin appears to be mediated in part by reduced reactivity of smooth muscle cells to NO