Cytotoxic chemotherapy: Still the mainstay of clinical practice for all subtypes metastatic breast cancer

Cytotoxic chemotherapy remains central to the treatment of all subtypes of metastatic breast cancer (MBC). We review evidence-based chemotherapy options for women with MBC after an anthracycline and a taxane including re-challenge with anthracycline or taxane, capecitabine, eribulin and ixabepilone as a single agent or combination with capecitabine (not approved in the EU); and the vinca alkaloid vinflunine as single agent or combined with either capecitabine/gemcitabine (also not approved EU or USA). Etirinotecan pegol, comprising irinotecan bound to polyethylene glycol by a biodegradable linker, is a new cytotoxic agent for patients with MBC that has achieved encouraging response rates in phase II studies; it has been further evaluated in the phase III BEACON trial. New cytotoxics should address novel targets or modes of delivery, achieve meaningful improvements in outcomes and seek to identify predictive biomarker(s)

Precision pharmacology: Mass spectrometry imaging and pharmacokinetic drug resistance

Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as “pharmacokinetic drug resistance”. To understand whether a drug is being adequately delivered to the tumour, “precision pharmacology” techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research

Drug delivery in a tumour cord model: a computational simulation

YesThe tumour vasculature and microenvironment is complex and heterogeneous, contributing to reduced delivery of cancer drugs to the tumour. We have developed an in silico model of drug transport in a tumour cord to explore the effect of different drug regimes over a 72 h period and how changes in pharmacokinetic parameters affect tumour exposure to the cytotoxic drug doxorubicin. We used the model to describe the radial and axial distribution of drug in the tumour cord as a function of changes in the transport rate across the cell membrane, blood vessel and intercellular permeability, flow rate, and the binding and unbinding ratio of drug within the cancer cells. We explored how changes in these parameters may affect cellular exposure to drug. The model demonstrates the extent to which distance from the supplying vessel influences drug levels and the effect of dosing schedule in relation to saturation of drug-binding sites. It also shows the likely impact on drug distribution of the aberrant vasculature seen within tumours. The model can be adapted for other drugs and extended to include other parameters. The analysis confirms that computational models can play a role in understanding novel cancer therapies to optimize drug administration and delivery

Robust coefficients of a higher order AR modelling in a speech enhancement system using parameterized Wiener filtering

We study some speech enhancement algorithms based on the iterative Wiener filtering method due to Lim-Oppenheim (1978), where the AR spectral estimation of the speech is carried out using a second-order analysis. But in our algorithms we consider an AR estimation by means of cumulant analysis. This work extends some preceding papers due to the authors, providing a generalization of third- and fourth-order algorithms by means of adding two parameters in the general expression of Wiener filtering. These parameters allow a better control of their performance. Some results are presented considering AWGN but listening tests give similar performance when other noises (diesel engine) are considered.Peer ReviewedPostprint (published version

Injuries in elite male kitesurfers

El kitesurf como deporte extremo relativamente nuevo, presenta una literatura escasa en comparación con otros deportes del mar de mayor tradición. En la actualidad, el patrón y la frecuencia de las lesiones en kitesurf no están nada claros. El objetivo de este estudio fue identificar los patrones lesivos comunes, así como las áreas potenciales sobre las que se podrían aplicar medidas de prevención en kitesurfistas profesionales masculinos. Se diseñó un estudio epidemiológico descriptivo. Se suministró un cuestionario de carácter retrospectivo a 38 kitesurfistas de elite, participantes en la Copa del Mundo disputada en Fuerteventura (2008). El tobillo fue la zona corporal con mayor porcentaje de lesiones p<0.01, y la modalidad de Course Race presenta el 68.4% de lesiones, frente a los 31.6% del Freestyle. Dichas lesiones se produjeron más durante los entrenamientos (76.3%; p<0.01), que en las competiciones y las más comunes fueron las agudas. Estos resultados indican la necesidad de establecer nuevas metodologías de prevención, sobre todo para las piernas, especialmente en la modalidad de Course Race y en la zona del tobillo, así como el uso de materiales para la protección del pie.A relatively new extreme sport, kitesurf hasn’t received the kind of scientific scrutiny found with other more traditional sports. Currently, the pattern and rate of kiteboarding injuries are largely unclear. The objective was to identify common injury patterns as well as potential areas in which prevention measures might be instituted. A descriptive epidemiological study was designed and a retrospective questionnaire was performed on 38 elite kitesurfers taking part in the World Cup Fuerteventura 2008. The ankle is the part of the body most affected by injury p<0.01, whilst the Course Race category accounted for 68.4% of injuries, compared with 31.6% in the Freestyle category. Said injuries occurred more frequently when training (76.3%; p<0.01) than during competitions and acute injuries were the most common. These results show the need to establish new prevention methodologies, above all for the legs and specifically for the ankle area and in the Course Race category, as well as the use of foot protections

An evaluation of hedonic responses in taste-potentiated odor aversion using the analysis of licking microstructure and orofacial reactivity

Two experiments examined the hedonic responses conditioned to odor cues in the phenomenon of taste-potentiated odor aversion. Experiment 1 analyzed the microstructure of licking behavior during voluntary consumption. A tasteless odor (amyl acetate) was delivered to rats either diluted in water or mixed with saccharin before being injected with LiCl. At test, subjects which had received the odor-taste compound during conditioning showed both lower odor consumption and lick cluster size, a result indicating an increased negative evaluation of the odor. Experiment 2 examined the orofacial reactions elicited by the odor as index of its hedonic impact. During conditioning, the rats were intraorally infused with either the odor alone or the odor-saccharin compound before being injected with LiCl. At test, they were infused with the odor and their orofacial responses video recorded. More aversive orofacial responses were elicited by the odor cue in rats that had compound conditioning, again a result indicating a strengthened negative hedonic reactivity compared to animals experiencing odor aversion conditioning alone. Taken together, these results indicate that taste-mediated potentiation of odor aversion conditioning impacts on the acquisition of conditioned hedonic reactions as well as consumption

Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

S31-201 (NSC 74859) is a chemical probe inhibitor of Stat3 activity, which was identified from the National Cancer Institute chemical libraries by using structure-based virtual screening with a computer model of the Stat3 SH2 domain bound to its Stat3 phosphotyrosine peptide derived from the x-ray crystal structure of the Stat3 beta homodimer. S31-201 inhibits Stat3-Stat3 complex formation and Stat3 DNA-binding and transcriptional activities. Furthermore, S31-201 inhibits growth and induces apoptosis preferentially in tumor cells that contain persistently activated Stat3. Constitutively climerized and active Stat3C and Stat3 SH2 domain rescue tumor cells from S31-201-induced apoptosis. Finally, S31-201 inhibits the expression of the Stat3-regulated genes encoding cyclin D1, BcI-xL, and survivin and inhibits the growth of human breast tumors in vivo. These findings strongly suggest that the antitumor activity of S31-201 is mediated in part through inhibition of aberrant Stat3 activation and provide the proof-of-concept for the potential clinical use of Stat3 inhibitors such as S31-201 in tumors harboring aberrant Stat3

Procés d'atenció social de treball social sanitari individual i familiar

Treball social; GestióTrabajo social; GestiónSocial work; ManagementDocument que identifica i avalua les necessitats socials i familiars, i el malestar psicosocial derivat d'aquestes que poden dificultar el procés de salut, disminuint la capacitat de maneig del problema de salut, i condicionar la utilització dels serveis sanitaris.Document that identifies and evaluates social and family needs, and the psychosocial discomfort derived from these that can hinder the health process, reduce the ability to manage health problems, and condition the use of health services.Documento que identifica y evalúa las necesidades sociales y familiares, y el malestar psicosocial derivado de estos que pueden dificultar el proceso de salud, disminuir la capacidad de manejo de los problemas de salud, y condicionar la utilización de los servicios sanitarios

A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

Background Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM. Methods Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored. Results The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK. Conclusions With personalised dosing, nabiximols had acceptable safety and tolerability with no drug–drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial. Clinical trial registration ClinicalTrials.gov: Part 1– NCT01812603; Part 2– NCT01812616

Lipidomic profiling identifies signatures of metabolic risk

BACKGROUND: Metabolic syndrome (MetS), the clustering of metabolic risk factors, is associated with cardiovascular disease risk. We sought to determine if dysregulation of the lipidome may contribute to metabolic risk factors. METHODS: We measured 154 circulating lipid species in 658 participants from the Framingham Heart Study (FHS) using liquid chromatography-tandem mass spectrometry and tested for associations with obesity, dysglycemia, and dyslipidemia. Independent external validation was sought in three independent cohorts. Follow-up data from the FHS were used to test for lipid metabolites associated with longitudinal changes in metabolic risk factors. RESULTS: Thirty-nine lipids were associated with obesity and eight with dysglycemia in the FHS. Of 32 lipids that were available for replication for obesity and six for dyslipidemia, 28 (88%) replicated for obesity and five (83%) for dysglycemia. Four lipids were associated with longitudinal changes in body mass index and four were associated with changes in fasting blood glucose in the FHS. CONCLUSIONS: We identified and replicated several novel lipid biomarkers of key metabolic traits. The lipid moieties identified in this study are involved in biological pathways of metabolic risk and can be explored for prognostic and therapeutic utility.The Framingham Heart Study is funded by National Institutes of Health (NIH) contract N01-HC-25195. This study was made possible by a CRADA between BG Medicine, Inc., Boston University, and the NHLBI, and the laboratory work for this research was supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI). Analytical work was funded by the Division of Intramural Research of NHLBI as well as the Center for Information Technology, NIH, Bethesda, MD. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. The PESA study is supported by a non-competitive unrestricted grant shared between the National Center for Cardiovascular Research Carlos III (CNIC) and the Bank of Santander. The PESA study is a noncommercial study independent of the health and pharmaceutical industry. The CNIC is supported by the Spanish Ministry of Science, Innovation and Universities, the Instituto de Salud Carlos III, and the proCNIC Foundation. The study was partially funded by a grant from AstraZeneca (TANSNIP project). JMO is supported by the US Department of Agriculture, under agreement no. 8050-51000-098-00D. MPO and MJ acknowledge an Institute of Health Carlos III grant (PI 17-00134). This research was in part funded by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI14/00328), co-financed by FEDER funds from the European Union ('A way to built Europe'), and the Generalitat of Catalonia, Department of Health(SLT002/16/00250) and Department of Business and Knowledge(2017SGR696) to R.P. MJ is a Serra Hunter Fellow.S