Prolonged survival of patients receiving trastuzumab beyond disease progression for HER2 overexpressing metastatic breast cancer (MBC)

Background: The aim of this retrospective analysis was to evaluate the impact of trastuzumab-based regimens on the survival of patients with HER2-overexpressing metastatic breast cancer (MBC). The study specifically focussed on the influence of the continuation of trastuzumab-based treatment despite tumor progression on survival. Patients and Methods: Patients with HER2 overexpressing MBC were included in this retrospective analysis. HER2 overexpression was determined by the immunohistochemical staining score (DAKO Hercep Test (TM)). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Results: Among 136 HER2 overexpressing patients (DAKO score 3+), 66 patients received first-line trastuzumab, 47 patients received trastuzumab as second-line therapy and 23 patients received trastuzumab beyond disease progression. There was no significant difference regarding the duration of trastuzumab-based treatment (first-line: 29.5 weeks vs. second-line: 25 weeks). Moreover, there was no difference in the response rate (first-line: 37.9% vs. second-line: 35.7%) or the median survival (p = 0.47 log rank). Patients who received >= 2 trastuzumab-based regimens for MBC survived significantly longer compared to those who had received only 1 regimen (>= 2 regimens: 62.4 months vs. 1 regimen: 38.5 months; p = 0.01 log rank). Conclusions: Trastuzumab is highly effective in the treatment of HER2 overexpressing MBC. Compared to historical controls, overall survival appears to be markedly prolonged, particularly in patients who received sequential trastuzumab-based treatment beyond disease progression

Obesity-related perivascular adipose tissue damage is reversed by sustained weight loss in the rat

Objective – Perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been characterised following weight loss induced by caloric restriction, which is often the first line treatment for obesity. Approach and Results – Contractility studies were performed using wire myography on small mesenteric arteries with and without PVAT from control, diet-induced obese, calorie restricted and sustained weight loss rats. Changes in the PVAT environment were assessed using immunohistochemistry. PVAT from healthy animals elicited an anticontractile effect in response to norepinephrine. This was abolished in diet-induced obesity through a mechanism involving increased local TNFα and reduced nitric oxide bioavailability within PVAT. Sustained weight loss led to improvement in PVAT function associated with restoration of adipocyte size, reduced TNFα and increased nitric oxide synthase function. This was associated with reversal of obesity-induced hypertension and normalisation of plasma adipokine levels, including leptin and insulin. Conclusions – We have shown that diet-induced weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and increased nitric oxide synthase activity within PVAT. These data reveal inflammation and nitric oxide synthase, particularly eNOS, as potential targets for the treatment of PVAT dysfunction associated with obesity and the metabolic syndrome

Scaling up kangaroo mother care in South Africa: 'on-site' versus 'off-site' educational facilitation

Background Scaling up the implementation of new health care interventions can be challenging and demand intensive training or retraining of health workers. This paper reports on the results of testing the effectiveness of two different kinds of face-to-face facilitation used in conjunction with a well-designed educational package in the scaling up of kangaroo mother care. Methods : Thirty-six hospitals in the Provinces of Gauteng and Mpumalanga in South Africa were targeted to implement kangaroo mother care and participated in the trial. The hospitals were paired with respect to their geographical location and annual number of births. One hospital in each pair was randomly allocated to receive either 'on-site' facilitation (Group A) or 'off-site' facilitation (Group B). Hospitals in Group A received two on-site visits, whereas delegates from hospitals in Group B attended one off-site, 'hands-on' workshop at a training hospital. All hospitals were evaluated during a site visit six to eight months after attending an introductory workshop and were scored by means of an existing progress-monitoring tool with a scoring scale of 0-30. Successful implementation was regarded as demonstrating evidence of practice (score >10) during the site visit. Results : There was no significant difference between the scores of Groups A and B (p = 0.633). Fifteen hospitals in Group A and 16 in Group B demonstrated evidence of practice. The median score for Group A was 16.52 (range 00.00-23.79) and that for Group B 14.76 (range 07.50-23.29). Conclusion : A previous trial illustrated that the implementation of a new health care intervention could be scaled up by using a carefully designed educational package, combined with face-to-face facilitation by respected resource persons. This study demonstrated that the site of facilitation, either on site or at a centre of excellence, did not influence the ability of a hospital to implement KMC. The choice of outreach strategy should be guided by local circumstances, cost and the availability of skilled facilitators

Collaborative review of pilot projects to inform policy: A methodological remedy for pilotitis?

BACKGROUND In rural health and other health service development contexts, there is frustration with a reliance on pilot projects as a means of informing policy and service innovation. There is also an emerging recognition that existing research methods do not draw lessons from the failed sustainability that characterises many of these pilots and demonstration projects. DISCUSSION: This article describes critical aspects of the methodology of a successful collaborative, multi-method, systematic synthesis of exemplary primary health care pilot projects in rural and remote Australia, which synthesised principles from a number of pilot projects to inform policy makers and planners. Hallmarks of the method were: the nature of the source materials for the research, the subsequent research engagement with the actual pilot projects, the extent of collaboration throughout the study with end-users from policy and planning arenas, and the attention to procedural quality. SUMMARY: The methodology, while time consuming, has resulted in applied, policy-relevant findings, and evidence of consideration by policy-makers

Mindfulness-based interventions in epilepsy: a systematic review

Mindfulness based interventions (MBIs) are increasingly used to help patients cope with physical and mental long-term conditions (LTCs). Epilepsy is associated with a range of mental and physical comorbidities that have a detrimental effect on quality of life (QOL), but it is not clear whether MBIs can help. We systematically reviewed the literature to determine the effectiveness of MBIs in people with epilepsy. Medline, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Allied and Complimentary Medicine Database, and PsychInfo were searched in March 2016. These databases were searched using a combination of subject headings where available and keywords in the title and abstracts. We also searched the reference lists of related reviews. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Three randomised controlled trials (RCTs) with a total of 231 participants were included. The interventions were tested in the USA (n = 171) and China (Hong Kong) (n = 60). Significant improvements were reported in depression symptoms, quality of life, anxiety, and depression knowledge and skills. Two of the included studies were assessed as being at unclear/high risk of bias - with randomisation and allocation procedures, as well as adverse events and reasons for drop-outs poorly reported. There was no reporting on intervention costs/benefits or how they affected health service utilisation. This systematic review found limited evidence for the effectiveness of MBIs in epilepsy, however preliminary evidence suggests it may lead to some improvement in anxiety, depression and quality of life. Further trials with larger sample sizes, active control groups and longer follow-ups are needed before the evidence for MBIs in epilepsy can be conclusively determined

The Bajocian (Middle Jurassic): a key interval in the early Mesozoic phytoplankton radiation

Dinoflagellates and coccolithophores are two of the most important groups of phytoplankton in the modern oceans. These groups originated in the Triassic and radiated through the early Mesozoic, rising to ecological prominence. Within this long-term radiation, important shortterm intervals of evolutionary and ecological change can be recognised. The Bajocian (Middle Jurassic, ~170–168 Ma) was characterised by an important ecological transition within the coccolithophores, and the radiation of one of the principal families of cyst-forming dinoflagellates, the Gonyaulacaceae. During the Early Bajocian, the coccolith genus Watznaueria diversified and expanded ecologically to dominate coccolith floras, a situation which continued for the remainder of the Mesozoic. This pattern was paralleled within dinoflagellate cyst floras by the ecological dominance of the genus Dissiliodinium in the midpalaeolatitudes. These phenomena appear to be linked to a positive carbon isotope shift, and an interval of enhanced productivity driven by a shift to a more humid climate, enhanced continental weathering and nutrient flux, or by changes in ocean circulation and upwelling. The latest Early Bajocian to earliest Bathonian was then characterised by the rapid increase in diversity of dinoflagellate cysts within the family Gonyaulacaceae. Through this interval, the Gonyaulacaceae transitioned from being a relatively minor component of dinoflagellate cyst floras, to becoming one of the prominent groups of cyst-forming dinoflagellates, which has persisted to the Holocene. In Europe, the pattern of this radiation was strongly influenced by sea level, with the increase in gonyaulacacean diversity reflecting a major second-order transgression. On a finer scale, the main pulses of first appearances correlate with third-order transgressive episodes. A rise in sea level, coupled with changes in the tectonic configuration of ocean gateways, appears to have controlled the pattern of plankton diversification in Europe. These palaeoceanographic changes may have enhanced water-mass transfer between Europe, the northwest Tethys Ocean and the Hispanic Corridor, which promoted the floral interchange of dinoflagellates. Whilst sea level rise and associated large-scale palaeoenvironmental shifts appear to have controlled the pattern of dinoflagellate cyst appearances in several regions outside Europe, there is no direct correlation between dinoflagellate cyst diversity and sea level rise on a global scale. Although the Bajocian was transgressive in several regions, widespread flooded continental area was also present throughout the preceding Aalenian, an interval of low gonyaulacacean diversity. Moreover, although the Middle Jurassic was an interval of major climatic cooling, there was a ~5 myr gap between the onset of cooling and the radiation of gonyaulacaceans during the Bajocian. The Bajocian was, however, marked by a major evolutionary radiation in the pelagic realm, including ammonites, giant suspension feeding fishes and planktonic foraminifera. These phenomena may indicate an underlying ecological driver to the radiation of dinoflagellates during the Bajocian evolutionary explosion which could represent an extension of the Mesozoic Marine Revolution.This work has arisen from the PhD project of Nickolas J. Wiggan which was supported by NERC BGS DTG award reference BUFI S246, entitled The mid Jurassic plankton explosion. This was funded jointly between the British Geological Survey and the University of Cambridge. James B. Riding publishes with the approval of the Executive Director, British Geological Survey (NERC). We thank the Review Papers Coordinator, Tim Horscroft, for inviting this contribution. Nick Butterfield (Cambridge) is thanked for discussions and suggestions during NJW’s PhD project. We also thank Daniel Mantle and Fabienne Giraud, whose insightful reviews greatly improved the quality of this manuscript

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility