Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas

We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing αVβ3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and αVβ3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0–60%) expressed LH39, while αVβ3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5–90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed

From Sound to Significance: Exploring the Mechanisms Underlying Emotional Reactions to Music

A common approach to studying emotional reactions to music is to attempt to obtain direct links between musical surface features such as tempo and a listener’s responses. however, such an analysis ultimately fails to explain why emotions are aroused in the listener. in this article we explore an alternative approach, which aims to account for musical emotions in terms of a set of psychological mechanisms that are activated by different types of information in a musical event. this approach was tested in 4 experiments that manipulated 4 mechanisms (brain stem reflex, contagion, episodic memory, musical expectancy) by selecting existing musical pieces that featured information relevant for each mechanism. the excerpts were played to 60 listeners, who were asked to rate their felt emotions on 15 scales. skin conductance levels and facial expressions were measured, and listeners reported subjective impressions of relevance to specific mechanisms. results indicated that the target mechanism conditions evoked emotions largely as predicted by a multimechanism framework and that mostly similar effects occurred across the experiments that included different pieces of music. we conclude that a satisfactory account of musical emotions requires consideration of how musical features and responses are mediated by a range of underlying mechanisms

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity

Exploring the similarities and differences between medical assessments of competence and criminal responsibility

The medical assessments of criminal responsibility and competence to consent to treatment are performed, developed and debated in distinct domains. In this paper I try to connect these domains by exploring the similarities and differences between both assessments. In my view, in both assessments a decision-making process is evaluated in relation to the possible influence of a mental disorder on this process. I will argue that, in spite of the relevance of the differences, both practices could benefit from the recognition of this similarity. For cooperative research could be developed directed at elucidating exactly how various mental disturbances can affect decision-making processes

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14–41%); the intent-to-treat response rate was 21% (CI 95%: 12–34%). Median time to neurologic progression was 49 days (range 1–515(+)); median survival was 88 days (range 1–515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians. © 2001 Cancer Research Campaign http://www.bjcancer.co

HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, β-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection

Deciding Together?:Best Interests and Shared Decision-Making in Paediatric Intensive Care

In the western healthcare, shared decision making has become the orthodox approach to making healthcare choices as a way of promoting patient autonomy. Despite the fact that the autonomy paradigm is poorly suited to paediatric decision making, such an approach is enshrined in English common law. When reaching moral decisions, for instance when it is unclear whether treatment or non-treatment will serve a child’s best interests, shared decision making is particularly questionable because agreement does not ensure moral validity. With reference to current common law and focusing on intensive care practice, this paper investigates what claims shared decision making may have to legitimacy in a paediatric intensive care setting. Drawing on key texts, I suggest these identify advantages to parents and clinicians but not to the child who is the subject of the decision. Without evidence that shared decision making increases the quality of the decision that is being made, it appears that a focus on the shared nature of a decision does not cohere with the principle that the best interests of the child should remain paramount. In the face of significant pressures toward the displacement of the child’s interests in a shared decision, advantages of a shared decision to decisional quality require elucidation. Although a number of arguments of this nature may have potential, should no such advantages be demonstrable we have cause to revise our commitment to either shared decision making or the paramountcy of the child in these circumstances