Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells

Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induced cell death in melanoma. ESOM rapidly induced accumulation of reactive oxygen species (ROS) through mitochondrial dysfunctions and involvement of NADPH oxidase. The ROS scavenger N-acetyl--cysteine (NAC) and inhibition of NADPH oxidase significantly reduced ESOM-induced cell death, consistent with inhibition of cytosolic acidification. Autophagy, a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, represents a defence mechanism in cancer cells under metabolic stress. ESOM induced the early accumulation of autophagosomes, at the same time reducing the autophagic flux, as observed by WB analysis of LC3-II accumulation and by fluorescence microscopy. Moreover, ESOM treatment decreased mammalian target of rapamycin signalling, as reduced phosphorylation of p70-S6K and 4-EBP1 was observed. Inhibition of autophagy by knockdown of Atg5 and Beclin-1 expression significantly increased ESOM cytotoxicity, suggesting a protective role for autophagy in ESOM-treated cells. The data presented suggest that autophagy represents an adaptive survival mechanism to overcome drug-induced cellular stress and cytotoxicity, including alteration of pH homeostasis mediated by proton pump inhibition

Microwave sensor system for continuous monitoring of adhesive curing processes

A microwave sensor system has been developed for monitoring adhesive curing processes. The system provides continuous, real-time information about the curing progress without interfering with the reaction. An open-coaxial resonator is used as the sensor head, and measurements of its resonance frequency and quality factor are performed during cure to follow the reaction progress. Additionally, the system provides other interesting parameters such as reaction rate or cure time. The adhesive dielectric properties can also be computed off-line, which gives additional information about the process. The results given by the system correlate very well with conventional measurement techniques such as differential scanning calorimetry, combining accuracy and rate with simplicity and an affordable cost. © 2012 IOP Publishing Ltd.The authors thank Rut Benavente Martinez for her assistance in the DSC experiments. The contract of BG-B is financed by the Ministry of Science and Innovation of Spain, through the 'Torres Quevedo' Sub-programme, which is also co-financed by the European Social Fund (ESF). This work has been financed by the Ministry of Science and Innovation of Spain through the project MONIDIEL (TEC2008-04109).García Baños, B.; Catalá Civera, JM.; Penaranda-Foix, FL.; Canós Marín, AJ.; Sahuquillo Navarro, O. (2012). Microwave sensor system for continuous monitoring of adhesive curing processes. Measurement Science and Technology. 23(3). https://doi.org/10.1088/0957-0233/23/3/035101S233Jost, M., & Sernek, M. (2008). Shear strength development of the phenol–formaldehyde adhesive bond during cure. Wood Science and Technology, 43(1-2), 153-166. doi:10.1007/s00226-008-0217-2Costa, M. L., Botelho, E. C., Paiva, J. M. F. de, & Rezende, M. C. (2005). Characterization of cure of carbon/epoxy prepreg used in aerospace field. Materials Research, 8(3), 317-322. doi:10.1590/s1516-14392005000300016Chen, J., & Hojjati, M. (2007). Microdielectric analysis and curing kinetics of an epoxy resin system. Polymer Engineering & Science, 47(2), 150-158. doi:10.1002/pen.20687Sernek, M., & Kamke, F. A. (2007). Application of dielectric analysis for monitoring the cure process of phenol formaldehyde adhesive. International Journal of Adhesion and Adhesives, 27(7), 562-567. doi:10.1016/j.ijadhadh.2006.10.004Núñez, L., Gómez-Barreiro, S., Gracia-Fernández, C. A., & Núñez, M. R. (2004). Use of the dielectric analysis to complement previous thermoanalytical studies on the system diglycidyl ether of bisphenol A/1,2 diamine cyclohexane. Polymer, 45(4), 1167-1175. doi:10.1016/j.polymer.2003.12.024Lefebvre, D. R., Han, J., Lipari, J. M., Long, M. A., McSwain, R. L., & Wells, H. C. (2006). Dielectric analysis for in-situ monitoring of gelatin renaturation and crosslinking. Journal of Applied Polymer Science, 101(5), 2765-2775. doi:10.1002/app.21631Cordovez, M., Li, Y., & Karbhari, V. M. (2004). Assessment of Dielectrometry for Characterization of Processing and Moisture Absorption in FRP Composites. Journal of Reinforced Plastics and Composites, 23(4), 445-456. doi:10.1177/0731684404031980Das, N. K., Voda, S. M., & Pozar, D. M. (1987). Two Methods for the Measurement of Substrate Dielectric Constant. IEEE Transactions on Microwave Theory and Techniques, 35(7), 636-642. doi:10.1109/tmtt.1987.1133722Fioretto, D., Livi, A., Rolla, P. A., Socino, G., & Verdini, L. (1994). The dynamics of poly(n-butyl acrylate) above the glass transition. Journal of Physics: Condensed Matter, 6(28), 5295-5302. doi:10.1088/0953-8984/6/28/007Givot, B. L., Krupka, J., & Belete, D. Y. (s. f.). Split post dielectric resonator technique for dielectric cure monitoring of structural adhesives. 13th International Conference on Microwaves, Radar and Wireless Communications. MIKON - 2000. Conference Proceedings (IEEE Cat. No.00EX428). doi:10.1109/mikon.2000.913931Canos, A. J., Catala-Civera, J. M., Penaranda-Foix, F. L., & Reyes-Davo, E. (2006). A novel technique for deembedding the unloaded resonance frequency from measurements of microwave cavities. IEEE Transactions on Microwave Theory and Techniques, 54(8), 3407-3416. doi:10.1109/tmtt.2006.877833Marks, R. B., & Williams, D. F. (1992). A general waveguide circuit theory. Journal of Research of the National Institute of Standards and Technology, 97(5), 533. doi:10.6028/jres.097.024Harrington, R. F. (1967). Matrix methods for field problems. Proceedings of the IEEE, 55(2), 136-149. doi:10.1109/proc.1967.5433Baker-Jarvis, J., Janezic, M. D., Domich, P. D., & Geyer, R. G. (1994). Analysis of an open-ended coaxial probe with lift-off for nondestructive testing. IEEE Transactions on Instrumentation and Measurement, 43(5), 711-718. doi:10.1109/19.328897Taylor, B. N. (1994). Guidelines for evaluating and expressing the uncertainty of NIST measurement results. doi:10.6028/nist.tn.1297Casalini, R., Corezzi, S., Livi, A., Levita, G., & Rolla, P. A. (1997). Dielectric parameters to monitor the crosslink of epoxy resins. Journal of Applied Polymer Science, 65(1), 17-25. doi:10.1002/(sici)1097-4628(19970705)65:13.0.co;2-tPreu, H., & Mengel, M. (2007). Experimental and theoretical study of a fast curing adhesive. International Journal of Adhesion and Adhesives, 27(4), 330-337. doi:10.1016/j.ijadhadh.2006.06.004Harper, D. P., Wolcott, M. P., & Rials, T. G. (2001). Evaluation of the cure kinetics of the wood/pMDI bondline. International Journal of Adhesion and Adhesives, 21(2), 137-144. doi:10.1016/s0143-7496(00)00045-2Garcia-Banos, B., Canos, A. J., Penaranda-Foix, F. L., & Catala-Civera, J. M. (2011). Noninvasive Monitoring of Polymer Curing Reactions by Dielectrometry. IEEE Sensors Journal, 11(1), 62-70. doi:10.1109/jsen.2010.2050475He, Y. (2001). DSC and DEA studies of underfill curing kinetics. Thermochimica Acta, 367-368, 101-106. doi:10.1016/s0040-6031(00)00654-7Núñez-Regueira, L., Gracia-Fernández, C. A., & Gómez-Barreiro, S. (2005). Use of rheology, dielectric analysis and differential scanning calorimetry for gel time determination of a thermoset. Polymer, 46(16), 5979-5985. doi:10.1016/j.polymer.2005.05.06

Mechanisms and models of somatic cell reprogramming

Whitehead Institute for Biomedical Research (Jerome and Florence Brill Graduate Student Fellowship)National Institutes of Health (U.S.) (US NIH grant RO1-CA087869)National Institutes of Health (U.S.) (US NIH grant R37-CA084198)National Science Foundation (U.S.) (NSF Graduate Research Fellowship)National Institutes of Health (U.S.) ((NIH) Kirschstein National Research Service Award,1 F32 GM099153-01A1)Vertex Pharmaceuticals Incorporated (Vertex Scholar

HTLV-1 infection in solid organ transplant donors and recipients in Spain

Background: HTLV-1 infection is a neglected disease, despite infecting 10–15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. Methods: All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. Results: A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. Conclusion: The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopath

Rapid subacute myelopathy following kidney transplantation from HTLV-1 donors: role of immunosuppresors and failure of antiretrovirals

Two kidney transplant recipients from a single donor became infected with HTLV-1 (human T-lymphotropic virus type 1) in Spain. One developed myelopathy 8 months following surgery despite early prescription of antiretroviral therapy. The allograft was removed from the second recipient at month 8 due to rejection and immunosuppressors discontinued. To date, 3 years later, this patient remains infected but asymptomatic. HTLV-1 infection was recognized retrospectively in the donor, a native Spaniard who had sex partners from endemic regions. Our findings call for a reappraisal of screening policies on donor-recipient organ transplantation. Based on the high risk of disease development and the large flux of persons from HTLV-1 endemic regions, pre-transplant HTLV-1 testing should be mandatory in Spain

HIV Aspartyl Peptidase Inhibitors Interfere with Cellular Proliferation, Ultrastructure and Macrophage Infection of Leishmania amazonensis

Submitted by Sandra Infurna ([email protected]) on 2019-01-08T13:43:09Z No. of bitstreams: 1 Ellenf_Altoe_etal_IOC_2009.pdf: 1452755 bytes, checksum: 77127a59920cef6bca71296107f6ec63 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-01-08T13:51:34Z (GMT) No. of bitstreams: 1 Ellenf_Altoe_etal_IOC_2009.pdf: 1452755 bytes, checksum: 77127a59920cef6bca71296107f6ec63 (MD5)Made available in DSpace on 2019-01-08T13:51:34Z (GMT). No. of bitstreams: 1 Ellenf_Altoe_etal_IOC_2009.pdf: 1452755 bytes, checksum: 77127a59920cef6bca71296107f6ec63 (MD5) Previous issue date: 2009Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ. Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Microbiologia Geral,. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ. Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Microbiologia Geral,. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Microbiologia Prof. Paulo de Góes. Departamento de Microbiologia Geral,. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ. Brasil.Leishmania is the etiologic agent of leishmanisais, a protozoan disease whose pathogenic events are not well understood. Current therapy is suboptimal due to toxicity of the available therapeutic agents and the emergence of drug resistance. Compounding these problems is the increase in the number of cases of Leishmania-HIV coinfection, due to the overlap between the AIDS epidemic and leishmaniasis

Multiwavelength study of the galactic PeVatron candidate LHAASO J2108+5157

Context. Several new ultrahigh-energy (UHE) γ-ray sources have recently been discovered by the Large High Altitude Air Shower Observatory (LHAASO) collaboration. These represent a step forward in the search for the so-called Galactic PeVatrons, the enigmatic sources of the Galactic cosmic rays up to PeV energies. However, it has been shown that multi-TeV γ-ray emission does not necessarily prove the existence of a hadronic accelerator in the source; indeed this emission could also be explained as inverse Compton scattering from electrons in a radiation-dominated environment. A clear distinction between the two major emission mechanisms would only be made possible by taking into account multi-wavelength data and detailed morphology of the source. Aims. We aim to understand the nature of the unidentified source LHAASO J2108+5157, which is one of the few known UHE sources with no very high-energy (VHE) counterpart. Methods. We observed LHAASO J2108+5157 in the X-ray band with XMM-Newton in 2021 for a total of 3.8 hours and at TeV energies with the Large-Sized Telescope prototype (LST-1), yielding 49 hours of good-quality data. In addition, we analyzed 12 years of Fermi-LAT data, to better constrain emission of its high-energy (HE) counterpart 4FGL J2108.0+5155. We used naima and jetset software packages to examine the leptonic and hadronic scenario of the multi-wavelength emission of the source. Results. We found an excess (3.7σ) in the LST-1 data at energies E > 3 TeV. Further analysis of the whole LST-1 energy range, assuming a point-like source, resulted in a hint (2.2σ) of hard emission, which can be described with a single power law with a photon index of Σ = 1.6 ± 0.2 the range of 0.3 - 100 TeV. We did not find any significant extended emission that could be related to a supernova remnant (SNR) or pulsar wind nebula (PWN) in the XMM-Newton data, which puts strong constraints on possible synchrotron emission of relativistic electrons. We revealed a new potential hard source in Fermi-LAT data with a significance of 4σ and a photon index of Σ = 1.9 ± 0.2, which is not spatially correlated with LHAASO J2108+5157, but including it in the source model we were able to improve spectral representation of the HE counterpart 4FGL J2108.0+5155. Conclusions. The LST-1 and LHAASO observations can be explained as inverse Compton-dominated leptonic emission of relativistic electrons with a cutoff energy of 100-30+70 TeV. The low magnetic field in the source imposed by the X-ray upper limits on synchrotron emission is compatible with a hypothesis of a PWN or a TeV halo. Furthermore, the spectral properties of the HE counterpart are consistent with a Geminga-like pulsar, which would be able to power the VHE-UHE emission. Nevertheless, the lack of a pulsar in the neighborhood of the UHE source is a challenge to the PWN/TeV-halo scenario. The UHE γ rays can also be explained as π0 decay-dominated hadronic emission due to interaction of relativistic protons with one of the two known molecular clouds in the direction of the source. Indeed, the hard spectrum in the LST-1 band is compatible with protons escaping a shock around a middle-aged SNR because of their high low-energy cut-off, but the origin of the HE γ-ray emission remains an open question

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Gaia Early Data Release 3 Acceleration of the Solar System from Gaia astrometry

Context. Gaia Early Data Release 3 (Gaia EDR3) provides accurate astrometry for about 1.6 million compact (QSO-like) extragalactic sources, 1.2 million of which have the best-quality five-parameter astrometric solutions. Aims. The proper motions of QSO-like sources are used to reveal a systematic pattern due to the acceleration of the solar systembarycentre with respect to the rest frame of the Universe. Apart from being an important scientific result by itself, the acceleration measured in this way is a good quality indicator of the Gaia astrometric solution. Methods. Theeffect of the acceleration was obtained as a part of the general expansion of the vector field of proper motions in vector spherical harmonics (VSH). Various versions of the VSH fit and various subsets of the sources were tried and compared to get the most consistent result and a realistic estimate of its uncertainty. Additional tests with the Gaia astrometric solution were used to get a better idea of the possible systematic errors in the estimate. Results. Our best estimate of the acceleration based on Gaia EDR3 is (2.32 +/- 0.16) x 10(-10) m s(-2) (or 7.33 +/- 0.51 km s(-1) Myr-1) towards alpha = 269.1 degrees +/- 5.4 degrees, delta = -31.6 degrees +/- 4.1 degrees, corresponding to a proper motion amplitude of 5.05 +/- 0.35 mu as yr(-1). This is in good agreement with the acceleration expected from current models of the Galactic gravitational potential. We expect that future Gaia data releases will provide estimates of the acceleration with uncertainties substantially below 0.1 mu as yr(-1).Peer reviewe