In vitro cell cytotoxicity profile and morphological response to polyoxometalate-stabilised gold nanoparticles

The size and redox properties of molecular polyoxometalates (POMs) make them extremely relevant for bioapplications: from disrupting tumour growth and enzyme inhibition, to DNA-intercalating agents and antimicrobial applications. Their unique ability to reversibly dominate and receive electrons, coupled with their high anionic charge, also makes them suitable for the preparation of zero-valent state metal nanoparticles (NPs) from molecular precursors. Polyoxometalate-stabilised nanoparticles (NPs@POM) are therefore an ideal delivery vehicle for bioactive POMs. Here we show how POM-stabilised gold NPs (AuNPs@POM) are massively internalised into Vero (kidney epithelial) and B16 (skin melanoma) cell lines with variable cytotoxic effects. Cell viability assays and quantification of cytoplasmic membrane composition revealed that the Vero cell line was unaltered by the internalisation of these hybrid particles; while their internalisation in B16 tumour cells produced mild cytotoxic effects and an antiproliferative cell cycle arrest in the G0/G1 and G2/M phases. The observed perturbation of the tumour cell line combined with the high degree of internalisation means that these (or similar) NPs@POM could serve as candidates for a range of bioapplications in diagnostics or therapy

Nanoparticles engineered to bind cellular motors for efficient delivery

Background: Dynein is a cytoskeletal molecular motor protein that transports cellular cargoes along microtubules. Biomimetic synthetic peptides designed to bind dynein have been shown to acquire dynamic properties such as cell accumulation and active intra- and inter-cellular motion through cell-to-cell contacts and projections to distant cells. On the basis of these properties dynein-binding peptides could be used to functionalize nanoparticles for drug delivery applications. Results: Here, we show that gold nanoparticles modified with dynein-binding delivery sequences become mobile, powered by molecular motor proteins. Modified nanoparticles showed dynamic properties, such as travelling the cytosol, crossing intracellular barriers and shuttling the nuclear membrane. Furthermore, nanoparticles were transported from one cell to another through cell-to-cell contacts and quickly spread to distant cells through cell projections. Conclusions: The capacity of these motor-bound nanoparticles to spread to many cells and increasing cellular retention, thus avoiding losses and allowing lower dosage, could make them candidate carriers for drug delivery

Magnetic-Responsive Release Controlled by Hot Spot Effect

Magnetically triggered drug delivery nanodevices have attracted great attention in nanomedicine, as they can feature as smart carriers releasing their payload at clinician's will. The key principle of these devices is based on the properties of magnetic cores to generate thermal energy in the presence of an alternating magnetic field. Then, the temperature increase triggers the drug release. Despite this potential, the rapid heat dissipation in living tissues is a serious hindrance for their clinical application. It is hypothesized that magnetic cores could act as hot spots, this is, produce enough heat to trigger the release without the necessity to increase the global temperature. Herein, a nanocarrier has been designed to respond when the temperature reaches 43 degrees C. This material has been able to release its payload under an alternating magnetic field without the need of increasing the global temperature of the environment, proving the efficacy of the hot spot mechanism in magnetic-responsive drug delivery devices

Estudio del bypass gástrico en Y de Roux y de la gastrectomía tubular sobre el metabolismo de la glucosa y la secreción de hormonas intestinales. Estudio prospectivo y randomizado

Introducció: El bypass gàstric en Y de Roux laparoscòpic (BGYRL) és la tècnica quirúrgica d'elecció per al tractament de l'obesitat mòrbida. La gastrectomia tubular laparoscòpica (GTL) és una tècnica bariàtrica restrictiva amb resultats molt prometedors en relació a la pèrdua de pes, però se'n desconeixen els efectes metabòlics i endocrins. L'objectiu d'aquest estudi és l'avaluació de les diferències en la resposta del metabolisme de la glucosa i la secreció d'hormones intestinals entre ambdós procediments. Material i mètodes: Es va dissenyar un estudi prospectiu i aleatoritzat per la realització del BGYRL i la GTL, ambdós realitzats via laparoscòpica. Totes les pacients es varen avaluar abans, i als 3 i 12 mesos de la intervenció. Se'ls va prendre una mostra de sang venosa després d'un dejuni de 12 hores i als 10 i 60 minuts després de la ingesta d'Ensure® 420 kcal per realitzar les determinacions dels nivells plasmàtics de glucosa, insulina, grelina, leptina, pèptid relacionat amb glucagó (GLP-1), pèptid YY (PYY) i polipèptid pancreàtic (PP). Resultats: Es varen incloure 15 pacients (totes de gènere femení, edat mitja de 48±9 anys, IMC de 44±2.7 kg/m2 amlitat preoperatòria) dels quals 7 van ser aleatoritzats a BGYRL i 8 a GTL. No hi van haver diferències entre ambdós grups en edat, IMC preoperatori, classificació ASA i determinacions hormonals preoperatòries. Després de la cirurgia, s'observa un descens de la glicèmia i insulinèmia, amb una reducció de l'índex HOMA-IR en ambdós grups. Postoperatòriament, es detecta una disminución de les concentracions de la leptina en dejú i després de la ingesta, significativament menor en el grup de BGYRL. Mentre que els nivells de grelina en dejú només descendeixen de forma significativa en el grup de la GTL. Després de la ingesta es produeix una augment dels nivells de GLP-1, significativament major en el grup de BGYRL. Conclusions: Tan el BGYRL como la GTL s'associen a una significativa pèrdua de pes, encara que aquesta fou significativament superior en el BGYRL. Ambdós procediments han millorat notablement l'homeostasi de la glucosa. Només la GTL va rehuir els nivells de grelina tan en dejú com després de la ingesta, mentre que els nivells de GLP-1 i PYY s'elevaren després de la cirurgia, sense diferències estadísticament significatives entre ambdues tècniques.Introducción: El bypass gástrico en Y de Roux laparoscópico (BGYRL) es la técnica quirúrgica de elección para el tratamiento de la obesidad mórbida. La gastrectomía tubular laparoscópica (GTL) es una técnica bariátrica restrictiva con resultados muy prometedores con relación a la pérdida de peso, pero se desconocen, sin embargo, sus efectos metabólicos y endocrinos. El objetivo de nuestro estudio es evaluar las diferencias en la respuesta del metabolismo de la glucosa y la secreción de hormonas intestinales entre ambos procedimientos. Material y métodos: Se diseñó un estudio prospectivo y aleatorizado tras la realización del BGYRL y la GTL, ambos realizados por vía laparoscópica. Todas las pacientes se evaluaron antes y a los 3 y 12 meses de la intervención. Se les tomó una muestra de sangre venosa tras un ayuno de 12 horas y a los 10 y 60 minutos tras la ingesta de Ensure® 420 kcal para realizar las determinaciones de los niveles plasmáticos de glucosa, insulina, grelina, leptina, péptido relacionado con glucagón (GLP-1), péptido YY (PYY) y polipéptido pancreático (PP).Resultados: Se incluyeron 15 pacientes (todas del género femenino, edad media de 48±9 años, IMC de 44±2.7 kg/m2 con comorbilidad preoperatoria) de los cuales 7 fueron aleatorizados a BGYRL y 8 a GTL. No hubo diferencias entre ambos grupos en la edad, IMC preoperatorio, clasificación de ASA y determinaciones hormonales preoperatorias. Después de la cirugía, se observa un descenso de la glicemia e insulinemia, con una reducción del índice HOMA-IR en ambos grupos. Postoperatoriamente, se detecta una disminución de las concentraciones de leptina en ayunas y tras la ingesta, significativamente menor en el grupo de BGYRL. Mientras que los niveles de grelina en ayunas sólo descienden de forma significativa en el grupo de la GTL. Tras la ingesta se produjo un aumento de los niveles de GLP-1, significativamente mayor en el grupo de BGYRL. Conclusiones: Tanto el BGYRL como la GTL se asociaron a una significativa pérdida de peso, aunque ésta fue significativamente superior en el BGYRL. Ambos procedimientos han mejorado notablemente la homeostasis de la glucosa. Sólo la GTL redujo los niveles de grelina tanto en ayunas como tras la ingesta. Mientras que los niveles de GLP-1 y PYY se elevaron tras la cirugía, sin diferencias estadísticamente significativas entre ambas técnicas

Septic shock in pregnancy due to pyogenic sacroiliitis: a case report

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Coastal primary productivity changes over the last millennium: a case study from the Skagerrak (North Sea)

A comprehensive multi-proxy study on two sediment cores from the western and central Skagerrak was performed in order to detect the variability and causes of marine primary productivity changes in the investigated region over the last 1100 years. The cores were dated by Hg pollution records and AMS 14C dating and analysed for palaeoproductivity proxies such as total organic carbon, δ13C, total planktonic foraminifera, benthic foraminifera (total assemblages as well as abundance of Brizalina skagerrakensis and other palaeoproductivity taxa) and palaeothermometers such as Mg∕Ca and δ18O. Our results reveal two periods with changes in productivity in the Skagerrak region: (i) a moderate productivity at  ∼ &thinsp;CE&thinsp;900–1700 and (ii) a high productivity at  ∼ &thinsp;CE&thinsp;1700–present. During  ∼ &thinsp;CE&thinsp;900–1700, moderate productivity was likely driven by the nutrients transported with the warm Atlantic water inflow associated with a tendency for a persistent positive NAO phase during the warm climate of the Medieval Climate Anomaly, which continues into the LIA until  ∼ &thinsp;CE&thinsp;1450. The following lower and more variable temperature period at  ∼ &thinsp;CE&thinsp;1450–1700 was likely caused by a reduced contribution of warm Atlantic water, but stronger deep-water renewal, due to a generally more negative NAO phase and a shift to the more variable and generally cooler climate conditions of the Little Ice Age. The productivity and fluxes of organic matter to the seafloor did not correspond to the temperature and salinity changes recorded in the benthic Melonis barleeanus shells. For the period from  ∼ &thinsp;CE&thinsp;1700 to the present day, our data point to an increased nutrient content in the Skagerrak waters. This increased nutrient content was likely caused by enhanced inflow of warm Atlantic water, increased Baltic outflow, intensified river runoff, and enhanced human impact through agricultural expansion and industrial development. Intensified human impact likely increased nutrient transport to the Skagerrak and caused changes in the oceanic carbon isotope budget, known as the Suess effect, which is clearly visible in our records as a negative shift in δ13C values from  ∼ &thinsp;CE&thinsp;1800. In addition, a high appearance of S. fusiformis during the last 70 years at both studied locations suggests increased decaying organic matter at the sea floor after episodes of enhanced primary production.</p

Development of Targeted Alpha Particle Therapy for Solid Tumors

Abstract: Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to dat

Impact of the clinical context on the 14-3-3 test for the diagnosis of sporadic CJD

BACKGROUND: The 14-3-3 test appears to be a valuable aid for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in selected populations. However, its usefulness in routine practice has been challenged. In this study, the influence of the clinical context on the performance of the 14-3-3 test for the diagnosis of sCJD is investigated through the analysis of a large prospective clinical series. METHODS: Six hundred seventy-two Spanish patients with clinically suspected sCJD were analyzed. Clinical classification at sample reception according to the World Health Organization's (WHO) criteria (excluding the 14-3-3 test result) was used to explore the influence of the clinical context on the pre-test probabilities, and positive (PPV) and negative (NPV) predictive values of the 14-3-3 test. RESULTS: Predictive values of the test varied greatly according to the initial clinical classification: PPV of 98.8%, 96.5% and 45.0%, and NPV of 26.1%, 66.6% and 100% for probable sCJDi (n = 115), possible sCJDi (n = 73) and non-sCJDi (n = 484) cases, respectively. According to multivariate and Bayesian analyses, these values represent an improvement of diagnostic certainty compared to clinical data alone. CONCLUSION: In three different contexts of sCJD suspicion, the 14-3-3 assay provides useful information complementary to clinical and electroencephalographic (EEG) data. The test is most useful supporting a clinical impression, whilst it may show deceptive when it is not in agreement with clinical data