The failure of radical treatments to cure cancer: can less deliver more?

All too often attempts to deliver improved cancer cure rates by increasing the dose of a particular treatment are not successful enough to justify the accompanying increase in toxicity and reduction in quality of life suffered by a significant number of patients. In part, this drive for using higher levels of treatment derives from the nature of the process for testing and incorporation of new protocols. Indeed, new treatment regimens must now consider the key role of immunity in cancer control, a component that has been largely ignored until very recently. The recognition that some drugs developed for cytotoxicity at higher doses can display alternative anticancer activities at lower doses including through modulation of immune responses is prompting a significant re-evaluation of treatment protocol development. Given that tumours are remarkably heterogeneous and with inherent genetic instability it is probably only the adaptive immune response with its flexibility and extensive repertoire that can rise to the challenge of effecting significant control and ultimately elimination of a patient's cancer. This article discusses some of the elements that have limited higher levels of treatment outcomes and where too much proved less effective. We explore observations that less can often be as effective, if not more effective especially with some chemotherapy regimens, and discuss how this can be exploited in combination with immunotherapies to deliver nontoxic improved tumour responses

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

The formation of professional identity in medical students: considerations for educators

<b>Context</b> Medical education is about more than acquiring an appropriate level of knowledge and developing relevant skills. To practice medicine students need to develop a professional identity – ways of being and relating in professional contexts.<p></p> <b>Objectives</b> This article conceptualises the processes underlying the formation and maintenance of medical students’ professional identity drawing on concepts from social psychology.<p></p> <b>Implications</b> A multi-dimensional model of identity and identity formation, along with the concepts of identity capital and multiple identities, are presented. The implications for educators are discussed.<p></p> <b>Conclusions</b> Identity formation is mainly social and relational in nature. Educators, and the wider medical society, need to utilise and maximise the opportunities that exist in the various relational settings students experience. Education in its broadest sense is about the transformation of the self into new ways of thinking and relating. Helping students form, and successfully integrate their professional selves into their multiple identities, is a fundamental of medical education

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Papillomavirus Vaccines

The considerable morbidity and mortality associated with certain human papillomaviruses (HPV) has provided the impetus for HPV vaccine development. The design of such vaccines has evolved from an understanding of the nature of HPV infections and their consequences, together with evaluation of the efficacy of different approaches to vaccination in animal models. These studies have culminated in the production of several different vaccine preparations which are currently undergoing Phase I and II clinical trials. The justification for the widespread implementation of prophylactic HPV vaccines will depend on the outcome of larger scale studies of vaccine efficacy that take into account the epidemiology of HPV infections and associated disease. The usefulness of therapeutic HPV vaccines will require evidence that they can substantially augment or substitute for the effectiveness of currently available treatments

Electron and ion microprobe analysis of calcium distribution and transport in coral tissues.

It is shown by x-ray microanalysis that a gradient of total intracellular Ca concentration exists from the outer oral ectoderm to the inner skeletogenic calicoblastic ectoderm in the coral Galaxea fascicularis. This suggests an increase in intracellular Ca stores in relation to calcification. Furthermore, Ca concentration in the fluid-filled space of the extrathecal coelenteron is approximately twice as high as in the surrounding seawater and higher than in the mucus-containing seawater layer on the exterior of the oral ectoderm. This is indicative of active Ca2+ transport across the oral epithelium. Polyps were incubated in artificial seawater in which all 40Ca was replaced by 44Ca. Imaging Ca2+ transport across the epithelia by secondary ion mass spectroscopy (SIMS) using 44Ca as a tracer showed that Ca2+ rapidly entered the cells of the oral epithelium and that 44Ca reached higher concentrations in the mesogloea and extrathecal coelenteron than in the external seawater layer. Very little Ca2+ was exchanged in the mucocytes, cnidocytes or zooxanthellae. These observations again suggest that Ca2+ transport is active and transcellular and also indicate a hitherto unsuspected role in Ca2+ transport for the mesogloea. © 2007, Company of Biologist

Molecular evolution of HoxA13 and the multiple origins of limbless morphologies in amphibians and reptiles

Developmental processes and their results, morphological characters, are inherited through transmission of genes regulating development. While there is ample evidence that cis-regulatory elements tend to be modular, with sequence segments dedicated to different roles, the situation for proteins is less clear, being particularly complex for transcription factors with multiple functions. Some motifs mediating protein-protein interactions may be exclusive to particular developmental roles, but it is also possible that motifs are mostly shared among different processes. Here we focus on HoxA13, a protein essential for limb development. We asked whether the HoxA13 amino acid sequence evolved similarly in three limbless clades: Gymnophiona, Amphisbaenia and Serpentes. We explored variation in ω (dN/dS) using a maximum-likelihood framework and HoxA13sequences from 47 species. Comparisons of evolutionary models provided low ω global values and no evidence that HoxA13 experienced relaxed selection in limbless clades. Branch-site models failed to detect evidence for positive selection acting on any site along branches of Amphisbaena and Gymnophiona, while three sites were identified in Serpentes. Examination of alignments did not reveal consistent sequence differences between limbed and limbless species. We conclude that HoxA13 has no modules exclusive to limb development, which may be explained by its involvement in multiple developmental processes

Can computational efficiency alone drive the evolution of modularity in neural networks?

Some biologists have abandoned the idea that computational efficiency in processing multipart tasks or input sets alone drives the evolution of modularity in biological networks. A recent study confirmed that small modular (neural) networks are relatively computationally-inefficient but large modular networks are slightly more efficient than non-modular ones. The present study determines whether these efficiency advantages with network size can drive the evolution of modularity in networks whose connective architecture can evolve. The answer is no, but the reason why is interesting. All simulations (run in a wide variety of parameter states) involving gradualistic connective evolution end in non-modular local attractors. Thus while a high performance modular attractor exists, such regions cannot be reached by gradualistic evolution. Non-gradualistic evolutionary simulations in which multi-modularity is obtained through duplication of existing architecture appear viable. Fundamentally, this study indicates that computational efficiency alone does not drive the evolution of modularity, even in large biological networks, but it may still be a viable mechanism when networks evolve by non-gradualistic means

Terrestrial implications for the maritime geoarchaeological resource: A view from the Lower Palaeolithic

Stone tools and faunal remains have been recovered from the English Channel and the North Sea through trawling, dredging for aggregates, channel clearance, and coring. These finds highlight the potential for a maritime Lower Palaeolithic archaeological resource. It is proposed here that any Lower Palaeolithic artefacts, faunal remains, and sediments deposited in the maritime zone during dry, low-stand phases were once (and may still be) contextually similar to their counterparts in the terrestrial Lower Palaeolithic records of north-western Europe. Given these similarities, can interpretive models and analytical frameworks developed for terrestrial archaeology be profitably applied to an assessment of the potential value of any maritime resource? The terrestrial geoarchaeological resource for the Lower Palaeolithic is dominated by artefacts and ecofacts that have been fluvially reworked. The spatio-temporal resolution of these data varies from entire river valleys and marine isotope stages to river channel gravel bar surfaces and decadal timescales, thus supporting a variety of questions and approaches. However, the structure of the terrestrial resource also highlights two fundamental limitations in current maritime knowledge that can restrict the application of terrestrial approaches to any potential maritime resource: (i) how have the repetitive transgressions and regressions of the Middle and Late Pleistocene modified the terrace landforms and sediments associated with the river systems of the English Channel and southern North Sea basins?; and (ii) do the surviving submerged terrace landforms and fluvial sedimentary deposits support robust geochronological models, as is the case with the classical terrestrial terrace sequences? This paper highlights potential approaches to these questions, and concludes that the fluvial palaeogeography, Pleistocene fossils, and potential Lower Palaeolithic artefacts of the maritime geoarchaeological resource can be profitably investigated in future as derived, low-resolution data sets, facilitating questions of colonisation, occupation, demography, and material culture