Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane

Poly-(γ-l-glutamylglutamine)–paclitaxel (PGG–PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked to the polymer via ester bonds. PGG–PTX is of interest because it spontaneously forms very small nanoparticles in plasma. In mouse models, PGG–PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor. In this study, the efficacy of PGG–PTX was compared to that of Abraxane, an established nanoparticular formulation of PTX, in three different tumor models. Efficacy was quantified by delay in tumor growth of NCI H460 human lung cancer, 2008 human ovarian cancer and B16 melanoma xenografts growing in athymic mice following administration of equitoxic doses of PGG–PTX and Abraxane administered on either a single dose or every 7 day schedule. Toxicity was assessed by change in total body weight. The efficacy and toxicity of PGG–PTX was shown to increase with dose in the H460 model. PGG–PTX was ~1.5-fold less potent than Abraxane. PGG–PTX produced statistically significantly greater inhibition of tumor growth than Abraxane in all three tumor models when mice were given single equitoxic doses of drug. When given every 7 days for 3 doses, PGG–PTX produced greater inhibition of tumor growth while generating much less weight loss in mice bearing H460 tumors. PGG–PTX has activity that is superior to that of Abraxane in multiple tumor models. PGG–PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens

A Filmless Radiology Department in a Full Digital Regional Hospital: Quantitative Evaluation of the Increased Quality and Efficiency

Reggio Emilia hospital installed Picture Archiving and Communications Systems (PACS) as the final step towards a completely digital clinical environment completing the HIS/EMR and 1,400 web/terminals for patient information access. Financial benefits throughout the hospital were assessed upfront and measured periodically. Key indicators (radiology exam turnaround time, number of radiology procedures performed, inpatients length of stay before and after the PACS implementation, etc.) were analyzed and values were statistically tested to assess workflow and productivity improvements. The hospital went “filmless” in 28 weeks. Between the half of 2004 and the respective period in 2003, overall Radiology Department productivity increased by 12%, TAT improved by more than 60%. Timelier patient care resulted in decreased lengths of stay. Neurology alone experienced a 12% improvement in average patient stay. To quantify the impact of PACS on the average hospital stays and the expected productivity benefits to inpatient productivity were used a “high level” and a “detailed” business model. Annual financial upsides have exceeded $1.9 millions/year. A well-planned PACS deployment simplifies imaging workflow and improves patient care throughout the hospital while delivering substantial financial benefits. Staff buy-in was the key in this process and on-going training and process monitoring are a must

Imbibition in Disordered Media

The physics of liquids in porous media gives rise to many interesting phenomena, including imbibition where a viscous fluid displaces a less viscous one. Here we discuss the theoretical and experimental progress made in recent years in this field. The emphasis is on an interfacial description, akin to the focus of a statistical physics approach. Coarse-grained equations of motion have been recently presented in the literature. These contain terms that take into account the pertinent features of imbibition: non-locality and the quenched noise that arises from the random environment, fluctuations of the fluid flow and capillary forces. The theoretical progress has highlighted the presence of intrinsic length-scales that invalidate scale invariance often assumed to be present in kinetic roughening processes such as that of a two-phase boundary in liquid penetration. Another important fact is that the macroscopic fluid flow, the kinetic roughening properties, and the effective noise in the problem are all coupled. Many possible deviations from simple scaling behaviour exist, and we outline the experimental evidence. Finally, prospects for further work, both theoretical and experimental, are discussed.Comment: Review article, to appear in Advances in Physics, 53 pages LaTe

Affecting solidarities: bringing feeling into feminism, empathy in employment and compassion in academic communities of crises

While a wider context of crisis and neoliberal practices engulfing academia has triggered a variety of debilitating impacts on both education and academic working lives, tourism academia remains an insulated workplace, slowly responding to efforts corresponding to a politics of care, diversity and inclusivity. In highlighting attention to the issue of gender equity in tourism academia, this paper draws on netnographic analysis from one global electronic mailing list and analyses empirical data on the issues of ‘gender’, ‘women’ and ‘diversity’. The case study brings to the fore the urgency of addressing these issues as regards tourism academia. The latter is a space that we argue would benefit from enactments that nurture affectivities of solidarity. These are exemplified in the form of caring, compassionate and feeling fuelled inclusive workplaces. This paper aims to stimulate further debate in underscoring the need to introduce what we term ‘unbounded feminisms of solidarity and compassion’

Achtsamkeitstraining für die Firma? Gerne, aber bitte nachhaltig

Die weltweite Nachfrage nach Achtsamkeitstrainingskursen in Unternehmen hat in den letzten Jahren enorm zugenommen. Das große Interesse an Achtsamkeit liegt an der Hoffnung vieler Unternehmen weltweit, damit Stress im Firmenalltag abzubaün, mehr Gleichgewicht einzuleiten sowie in der Folge sogar Produktivitätssteigerungen realisieren zu können, aber auf sanfte, nachhaltige Art. Dennoch ist die Nachhaltigkeit von Achtsamkeitskursen in Unternehmen längst nicht so eingehend erforscht wie es die Popularität dieses Themas nahe legt. Das liegt hauptsächlich daran, dass bei vielen Kursen in Firmen Achtsamkeit mit Meditation gleichgestellt wird. Meditieren ist jedoch nur eine von vielen Methoden, um Achtsamkeit zu lernen und im Arbeitsalltag anzuwenden, und die Meditation ist nicht immer der beste Weg in die Achtsamkeit. In diesem Kapitel wird Schritt für Schritt erklärt, was Achtsamkeit ist und wie sie funktioniert, warum sie nicht dasselbe ist wie Achtsamkeitsmeditation und wie man Unternemen helfen kann, Achtsamkeit nachhaltig in ihre Firmenkultur einzubetten und somit langfristig zu erreichen, was sie sich durch Achtsamkeitskurse erhoffen

Pharmacokinetics and tissue distribution of PGG–paclitaxel, a novel macromolecular formulation of paclitaxel, in nu/nu mice bearing NCI-460 lung cancer xenografts

PGG–PTX is a water-soluble formulation of paclitaxel (PTX), made by conjugating PTX to poly(l-γ-glutamylglutamine) acid (PGG) via ester bonds, that spontaneously forms a nanoparticle in aqueous environments. The purpose of this study was to compare the pharmacokinetics and tissue distribution of PTX following injection of either free PTX or PGG–PTX in mice. Both [3H]PTX and PGG–[3H]PTX were administered as an IV bolus injection to mice bearing SC NCI-H460 lung cancer xenografts at a dose of 40-mg PTX equivalents/kg. Plasma, tumor, major organs, urine, and feces were collected at intervals out to 340 h. Total taxanes, taxane extractable into ethyl acetate, and native PTX were quantified by liquid scintillation counting and HPLC. Conjugation of PTX to the PGG polymer increased plasma and tumor C max, prolonged plasma half-life and the period of accumulation in tumor, and reduced washout from tumor. In plasma injection of PGG–PTX increased total taxane AUC0–340 by 23-fold above that attained with PTX. In tumors, it increased the total taxane by a factor of 7.7, extractable taxane by 5.7, and native PTX by a factor of 3.5-fold. Conjugation delayed and reduced total urinary and fecal excretion of total taxanes. Incorporation of PTX into the PGG–PTX polymer significantly prolonged the half-life of total taxanes, extractable taxane, and native PTX in both the plasma and tumor compartments. This resulted in a large increase in the amount of active PTX delivered to the tumor. PGG–PTX is an attractive candidate for further development

Commercial hospitality in destination experiences: McDonald's and tourists' consumption of space

This paper examines the multiple roles that globalised, branded spaces of hospitality can play in tourists' experiences in destinations. It is argued that previous studies have not considered adequately how such commercial hospitality services and spaces interact with and influence tourists' experiences of places. Drawing on a netnographic analysis of online discussions of McDonald's, this study explores how tourists perceive these hospitality venues, and how they use them to engage with foreign destinations and negotiate the ‘work of tourism’. The data show how tourists (re)construct their identities through reflections on consuming McDonald's. The data also demonstrate that tourists critically evaluate discourses of authenticity and the (in)authenticity of consuming McDonald's. The paper concludes by discussing the implications for the marketing and management of McDonald's and similar branded commercial hospitality venues, the marketing and management of destinations, and it outlines avenues for further research

Decellularised skeletal muscles allow functional muscle regeneration by promoting host cell migration

Pathological conditions affecting skeletal muscle function may lead to irreversible volumetric muscle loss (VML). Therapeutic approaches involving acellular matrices represent an emerging and promising strategy to promote regeneration of skeletal muscle following injury. Here we investigated the ability of three different decellularised skeletal muscle scaffolds to support muscle regeneration in a xenogeneic immune-competent model of VML, in which the EDL muscle was surgically resected. All implanted acellular matrices, used to replace the resected muscles, were able to generate functional artificial muscles by promoting host myogenic cell migration and differentiation, as well as nervous fibres, vascular networks, and satellite cell (SC) homing. However, acellular tissue mainly composed of extracellular matrix (ECM) allowed better myofibre three-dimensional (3D) organization and the restoration of SC pool, when compared to scaffolds which also preserved muscular cytoskeletal structures. Finally, we showed that fibroblasts are indispensable to promote efficient migration and myogenesis by muscle stem cells across the scaffolds in vitro. This data strongly support the use of xenogeneic acellular muscles as device to treat VML conditions in absence of donor cell implementation, as well as in vitro model for studying cell interplay during myogenesis

Non-Linear Elasticity of Extracellular Matrices Enables Contractile Cells to Communicate Local Position and Orientation

Most tissue cells grown in sparse cultures on linearly elastic substrates typically display a small, round phenotype on soft substrates and become increasingly spread as the modulus of the substrate increases until their spread area reaches a maximum value. As cell density increases, individual cells retain the same stiffness-dependent differences unless they are very close or in molecular contact. On nonlinear strain-stiffening fibrin gels, the same cell types become maximally spread even when the low strain elastic modulus would predict a round morphology, and cells are influenced by the presence of neighbors hundreds of microns away. Time lapse microscopy reveals that fibroblasts and human mesenchymal stem cells on fibrin deform the substrate by several microns up to five cell lengths away from their plasma membrane through a force limited mechanism. Atomic force microscopy and rheology confirm that these strains locally and globally stiffen the gel, depending on cell density, and this effect leads to long distance cell-cell communication and alignment. Thus cells are acutely responsive to the nonlinear elasticity of their substrates and can manipulate this rheological property to induce patterning

A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment

<p>Abstract</p> <p>Background</p> <p>About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.</p> <p>Methods/design</p> <p>The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life.</p> <p>Conclusion</p> <p>The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00394992</p