Palliative Care in Advanced Liver Disease: Similar or Different Palliative Care Needs in Patients with a Prospect of Transplantation? Prospective Study from a Portuguese University Hospital and Transplantation Center

Background and Aims: End-stage liver disease (ESLD) is an important cause of morbidity and mortality, comparable to a large extent to other organ insufficiencies. The need for palliative care (PC) in patients with ESLD is high. In Portugal, in the only identified study, more than 80% of patients hospitalized with ESLD had criteria for PC. No results specified which needs they identified or their transplantation prospect status. Methods: Prospective observational study including 54 ESLD patients who presented to a university hospital and transplantation center, between November 2019 and September 2020. Assessment of their PC needs through the application of NECPAL CCOMS-ICO© and IPOS, considering their transplantation perspective status. Results: Of the 54 patients, 5 (9.3%) were on active waiting list for transplantation and 8 (14.8%) under evaluation. NECPAL CCOMS-ICO© identified 23 patients (n = 42.6%) that would benefit from PC. Assessment of PC needs by clinicians, functional markers and significant comorbidities were the most frequent criteria (47.8%, n = 11). IPOS also revealed a different sort of needs: on average, each patient identified about 9 needs (8.9 ±2.8). Among the symptoms identified, weakness (77.8%), reduced mobility (70.3%), and pain (48.1%) stood out, as well as the psychoemotional symptoms of depression (66.7%) and anxiety (77.8%). There were no significant differences between the subgroups of patients analyzed. Only 4 patients (7.4%) were followed by the PC team. Conclusion: All the ESLD patients included, independently of the group they belonged to, presented with PC needs. No significant differences between the subgroups of patients were identified, confirming that even patients with a transplantation prospect have important needs for PC

Rotary orbital suspension culture of embryonic stem cell-derived neural stem/progenitor cells: impact of hydrodynamic culture on aggregate yield, morphology and cell phenotype

Embryonic stem (ES)-derived neural stem/progenitor cells (ES-NSPCs) constitute a promising cell source for application in cell therapies for the treatment of central nervous system disorders. In this study, a rotary orbital hydrodynamic culture system was applied to single-cell suspensions of ES-NSPCs, to obtain homogeneously-sized ES-NSPC cellular aggregates (neurospheres). Hydrodynamic culture allowed the formation of ES-NSPC neurospheres with a narrower size distribution than statically cultured neurospheres, increasing orbital speeds leading to smaller-sized neurospheres and higher neurosphere yield. Neurospheres formed under hydrodynamic conditions (72 h at 55 rpm) showed higher cell compaction and comparable percentages of viable, dead, apoptotic and proliferative cells. Further characterization of cellular aggregates provided new insights into the effect of hydrodynamic shear on ES-NSPC behaviour. Rotary neurospheres exhibited reduced protein levels of N-cadherin and ß-catenin, and higher deposition of laminin (without impacting fibronectin deposition), matrix metalloproteinase-2 (MMP-2) activity and percentage of neuronal cells. In line with the increased MMP-2 activity levels found, hydrodynamically-cultured neurospheres showed higher outward migration on laminin. Moreover, when cultured in a 3D fibrin hydrogel, rotary neurospheres generated an increased percentage of neuronal cells. In conclusion, the application of a constant orbital speed to single-cell suspensions of ES-NSPCs, besides allowing the formation of homogeneously-sized neurospheres, promoted ES-NSPC differentiation and outward migration, possibly by influencing the expression of cell–cell adhesion molecules and the secretion of proteases/extracellular matrix proteins. These findings are important when establishing the culture conditions needed to obtain uniformly-sized ES-NSPC aggregates, either for use in regenerative therapies or in in vitro platforms for biomaterial development or pharmacological screening.The authors would like to acknowledge Professor Domingos Henrique (Instituto de Medicina Molecular, Lisbon) for providing the ES 46C cell line. This study was supported by FEDER funds through the Programa Operacional Factores de Competitividade – COMPETE (Grant No. FCOMP‐01‐0124‐FEDER‐021125) and by National Funds through FCT – Fundação para a Ciência e a Tecnologia (Grant No. PTDC/SAU‐BMA/118869/2010). I. F. Amaral is supported by QREN through programme ON.2 (Grant No. NORTE‐07‐0124‐FEDER‐000005) and M. J. Oliveira is an Investigator FCT Fellow

Qualitative characterization of healthcare wastes

The biological hazard inherent in the clinical wastes should be considered during the management and treatment process as well as the disposal into the environment. In this chapter, the risks associated with the clinical wastes as well as the management of these wastes are discussed. The chapter focused on reviewing the types of healthcare wastes generated from hospitals and clinics as well as the regulations and management practices used for these wastes. Moreover, the health risk associated with the infectious agents which have the potential to be transmitted into the environment. It has appeared that the clinical wastes represent real hazards for the human health and the environment if they were not managed properly

CP properties of symmetry-constrained two-Higgs-doublet models

The two-Higgs-doublet model can be constrained by imposing Higgs-family symmetries and/or generalized CP symmetries. It is known that there are only six independent classes of such symmetry-constrained models. We study the CP properties of all cases in the bilinear formalism. An exact symmetry implies CP conservation. We show that soft breaking of the symmetry can lead to spontaneous CP violation (CPV) in three of the classes.Comment: 14 pages, 2 tables, revised version adapted to the journal publicatio

Predicting the safety and efficacy of butter therapy to raise tumour pHe: an integrative modelling study

Background: Clinical positron emission tomography imaging has demonstrated the vast majority of human cancers exhibit significantly increased glucose metabolism when compared with adjacent normal tissue, resulting in an acidic tumour microenvironment. Recent studies demonstrated reducing this acidity through systemic buffers significantly inhibits development and growth of metastases in mouse xenografts.\ud \ud Methods: We apply and extend a previously developed mathematical model of blood and tumour buffering to examine the impact of oral administration of bicarbonate buffer in mice, and the potential impact in humans. We recapitulate the experimentally observed tumour pHe effect of buffer therapy, testing a model prediction in vivo in mice. We parameterise the model to humans to determine the translational safety and efficacy, and predict patient subgroups who could have enhanced treatment response, and the most promising combination or alternative buffer therapies.\ud \ud Results: The model predicts a previously unseen potentially dangerous elevation in blood pHe resulting from bicarbonate therapy in mice, which is confirmed by our in vivo experiments. Simulations predict limited efficacy of bicarbonate, especially in humans with more aggressive cancers. We predict buffer therapy would be most effectual: in elderly patients or individuals with renal impairments; in combination with proton production inhibitors (such as dichloroacetate), renal glomular filtration rate inhibitors (such as non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors), or with an alternative buffer reagent possessing an optimal pK of 7.1–7.2.\ud \ud Conclusion: Our mathematical model confirms bicarbonate acts as an effective agent to raise tumour pHe, but potentially induces metabolic alkalosis at the high doses necessary for tumour pHe normalisation. We predict use in elderly patients or in combination with proton production inhibitors or buffers with a pK of 7.1–7.2 is most promising

Interactive models of communication at the nanoscale using nanoparticles that talk to one another

[EN] 'Communication' between abiotic nanoscale chemical systems is an almost-unexplored field with enormous potential. Here we show the design and preparation of a chemical communication system based on enzyme-powered Janus nanoparticles, which mimics an interactive model of communication. Cargo delivery from one nanoparticle is governed by the biunivocal communication with another nanoparticle, which involves two enzymatic processes and the interchange of chemical messengers. The conceptual idea of establishing communication between nanodevices opens the opportunity to develop complex nanoscale systems capable of sharing information and cooperating.A. L.-L. is grateful to 'La Caixa' Banking Foundation for his PhD fellowship. We wish to thank the Spanish Government (MINECO Projects MAT2015-64139-C4-1, CTQ2014-58989-P and CTQ2015-71936-REDT and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project PROMETEOII/2014/047) for support. The Comunidad de Madrid (S2013/MIT-3029, Programme NANOAVANSENS) is also gratefully acknowledged.Llopis-Lorente, A.; Díez, P.; Sánchez, A.; Marcos Martínez, MD.; Sancenón Galarza, F.; Martínez-Ruiz, P.; Villalonga, R.... (2017). Interactive models of communication at the nanoscale using nanoparticles that talk to one another. Nature Communications. 8:1-7. https://doi.org/10.1038/ncomms15511S178Tseng, R., Huang, J., Ouyang, J., Kaner, R. & Yang, Y. Polyaniline nanofiber/gold nanoparticle nonvolatile memory. Nano Lett. 5, 1077–1080 (2005).Liu, R. & Sen, A. Autonomous nanomotor based on copper-platinum segmented nanobattery. J. Am. Chem. Soc. 133, 20064–20067 (2011).Valov, I. et al. Nanobatteries in redox-based resistive switches require extension of memristor theory. Nat. Commun. 4, 1771 (2013).Tarn, D. et al. Mesoporous silica nanoparticle nanocarriers: biofunctionality and biocompatibility. Acc. Chem. Res. 46, 792–801 (2013).Kline, T. & Paxton, W. Catalytic nanomotors: remote-controlled autonomous movement of striped metallic nanorods. Angew. Chem. Int. Ed. 117, 754–756 (2005).Akyildiz, I. F., Brunetti, F. & Blázquez, C. Nanonetworks: a new communication paradigm. Comput. Netw. 52, 2260–2279 (2008).Suda, T., Moore, M., Nakano, T., Egashira, R. & Enomoto, A. Exploratory research on molecular communication between nanomachines. Nat. Comput. 25, 1–30 (2005).Malak, D. & Akan, O. B. Molecular communication nanonetworks inside human body. Nano Commun. Netw. 3, 19–35 (2012).Akyildiz, I. F., Jornet, J. M. & Pierobon, M. Nanonetworks: a new frontier in communications. Commun. ACM 54, 84–89 (2011).Nakano, T., Moore, M. J., Wei, F., Vasilakos, A. V. & Shuai, J. Molecular communication and networking: opportunities and challenges. IEEE Trans. Nanobiosci. 11, 135–148 (2012).Waters, C. M. & Bassler, B. L. Quorum sensing: cell-to-cell communication in bacteria. Annu. Rev. Cell Dev. Biol. 21, 319–346 (2005).Dickschat, J. S. Quorum sensing and bacterial biofilms. Nat. Prod. Rep. 27, 343–369 (2010).Kerényi, Á., Bihary, D., Venturi, V. & Pongor, S. Stability of multispecies bacterial communities: signaling networks may stabilize microbiomes. PLoS ONE 8, e57947 (2013).Gotti, C. & Clementi, F. Neuronal nicotinic receptors: from structure to pathology. Prog. Neurobiol. 74, 363–396 (2004).Betke, K. M., Wells, C. A. & Hamm, H. E. GPCR mediated regulation of synaptic transmission. Prog. Neurobiol. 96, 304–321 (2012).Qian, L., Winfree, E. & Bruck, J. Neural network computation with DNA strand displacement cascades. Nature 475, 368–372 (2011).Benenson, Y. Biomolecular computing systems: principles, progress and potential. Nat. Rev. Genet. 13, 455–468 (2012).Ball, P. Chemistry meets computing. Nature 406, 118–120 (2000).de Silva, A. P. & McClenaghan, N. D. Molecular-Scale Logic Gates. Chem. Eur. J. 10, 574–586 (2004).Condon, A. Automata make antisense. Nature 429, 351–352 (2004).Seelig, G., Soloveichik, D., Zhang, D. Y. & Winfree, E. Enzyme-free nucleic acid logic circuits. Science 314, 1585–1588 (2006).Douglas, S. M., Bachelet, I. & Church, G. M. A logic-gated nanorobot for targeted transport of molecular payloads. Science 335, 831–834 (2012).Angelos, S., Yang, Y. W., Khashab, N. M., Stoddart, J. F. & Zink, J. I. Dual-controlled nanoparticles exhibiting AND logic. J. Am. Chem. Soc. 131, 11344–11346 (2009).Liu, H. et al. Dual-responsive surfaces modified with phenylboronic acid-containing polymer brush to reversibly capture and release cancer cells. J. Am. Chem. Soc. 135, 7603–7609 (2013).Lee, J. W. & Klajn, R. Dual-responsive nanoparticles that aggregate under the simultaneous action of light and CO2 . Chem. Commun. 51, 2036–2039 (2015).Liu, D. et al. Resettable, multi-readout logic gates based on controllably reversible aggregation of gold nanoparticles. Angew. Chem. Int. Ed. 50, 4103–4107 (2011).Chitode, J. S. Communication Theory Technical Publications (2010).Wood, J. T. Communication in Our Lives Wadsworth (2009).Guardado-Alvarez, T. M., Sudha Devi, L., Russell, M. M., Schwartz, B. J. & Zink, J. I. Activation of snap-top capped mesoporous silica nanocontainers using two near-infrared photons. J. Am. Chem. Soc. 135, 14000–14003 (2013).Baeza, A., Guisasola, E., Ruiz-Hernández, E. & Vallet-Regí, M. Magnetically triggered multidrug release by hybrid mesoporous silica nanoparticles. Chem. Mater. 24, 517–524 (2012).Zhang, Z. et al. Biocatalytic release of an anticancer drug from nucleic-acids-capped mesoporous SiO2 using DNA or molecular biomarkers as triggering stimuli. ACS Nano 7, 8455–8468 (2013).Tang, F., Li, L. & Chen, D. Mesoporous silica nanoparticles: synthesis, biocompatibility and drug delivery. Adv. Mater. 24, 1504–1534 (2012).Li, Z., Barnes, J. C., Bosoy, A., Stoddart, J. F. & Zink, J. I. Mesoporous silica nanoparticles in biomedical applications. Chem. Soc. Rev. 41, 2590–2605 (2012).Coll, C., Bernardos, A., Martínez-Máñez, R. & Sancenón, F. Gated silica mesoporous supports for controlled release and signaling applications. Acc. Chem. Res. 46, 339–349 (2013).Aznar, E. et al. Gated materials for on-command release of guest molecules. Chem. Rev. 116, 561–718 (2016).Díez, P. et al. Toward the design of smart delivery systems controlled by integrated enzyme-based biocomputing ensembles. J. Am. Chem. Soc. 136, 9116–9123 (2014).Villalonga, R. et al. Enzyme-controlled sensing-actuating nanomachine based on Janus Au-mesoporous silica nanoparticles. Chem. Eur. J. 19, 7889–7894 (2013).Jerez, G., Kaufman, G., Prystai, M., Schenkeveld, S. & Donkor, K. K. Determination of thermodynamic pKa values of benzimidazole and benzimidazole derivatives by capillary electrophoresis. J. Sep. Sci. 32, 1087–1095 (2009).Sheffner, A. L. The reduction in vitro in viscosity of mucoprotein solutions by a new mucolytic agent, N-acetyl-L-cysteine. Ann. N. Y. Acad. Sci. 106, 298–310 (1963).Turkevich, J., Stevenson, P. C. & Hillier, J. A study of the nucleation and growth processes in the synthesis of colloidal gold. Discuss. Faraday Soc. 11, 55–75 (1951).Frens, G. Controlled Nucleation for the Regulation of the Particle Size in Monodisperse Gold Suspensions. Nature 241, 20–22 (1973).Yousef, F. O., Zughul, M. B. & Badwan, A. A. The modes of complexation of benzimidazole with aqueous β-cyclodextrin explored by phase solubility, potentiometric titration, 1H-NMR and molecular modeling studies. J. Incl. Phenom. Macrocycl. Chem. 57, 519–523 (2007).Sánchez, A., Díez, P., Martínez-Ruíz, P., Villalonga, R. & Pingarrón, J. M. Janus Au-mesoporous silica nanoparticles as electrochemical biorecognition-signaling system. Electrochem. Commun. 30, 51–54 (2013).Akyildiz, I. F., Pierobon, M., Balasubramaniam, S. & Koucheryavy, Y. The internet of Bio-Nano things. IEEE Commun. Mag. 53, 32–40 (2015).Sancenón, F., Pascual, L., Oroval, M., Aznar, E. & Martínez-Máñez, R. Gated silica mesoporous materials in sensing applications. ChemistryOpen 4, 418–437 (2015).Akyildiz, I. & Jornet, J. The Internet of nano-things. IEEE Wirel. Commun. 17, 58–63 (2010).Giménez, C. et al. Towards chemical communication between gated nanoparticles. Angew. Chem. Int. Ed. 53, 12629–12633 (2014).Davis, B. G., Lloyd, R. C. & Jones, J. B. Controlled site-selective glycosylation of proteins by a combined site-directed mutagenesis and chemical modification approach. J. Org. Chem. 63, 9614–9615 (1998)

A general reaction-diffusion model of acidity in cancer invasion

We model the metabolism and behaviour of a developing cancer tumour in the context of its microenvironment, with the aim of elucidating the consequences of altered energy metabolism. Of particular interest is the Warburg Effect, a widespread preference in tumours for cytosolic glycolysis rather than oxidative phosphorylation for glucose breakdown, as yet incompletely understood. We examine a candidate explanation for the prevalence of the Warburg Effect in tumours, the acid-mediated invasion hypothesis, by generalising a canonical non-linear reaction–diffusion model of acid-mediated tumour invasion to consider additional biological features of potential importance. We apply both numerical methods and a non-standard asymptotic analysis in a travelling wave framework to obtain an explicit understanding of the range of tumour behaviours produced by the model and how fundamental parameters govern the speed and shape of invading tumour waves. Comparison with conclusions drawn under the original system—a special case of our generalised system—allows us to comment on the structural stability and predictive power of the modelling framework