Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing

We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

Somatostatin, its receptors and analogs, in lung cancer

Despite developments in diagnosis and treatment, lung cancer is the commonest cause of cancer death in Europe and North America. Due to increasing cigarette consumption, the incidence of the disease and resultant mortality is rising dramatically in women. Novel approaches to the management of lung cancer are urgently required. Somatostatin is a tetradecapeptide first identified in the pituitary and subsequently throughout the body particularly in neuroendocrine cells of the pancreas and gastrointestinal tract and the nervous system. The peptide has numerous functions including inhibition of hormone release, immunomodulation and neurotransmission and is an endogenous inhibitor of cell proliferation and angiogenesis. Somatostatin and its analogs, including octreotide (SMS 201-995), somatuline (BIM 23014) and vapreotide (RC-160), act by binding to specific somatostatin receptors (SSTR) of which there are 5 principal subtypes, SSTR-1-5. Although elevated plasma somatostatin levels may be detected in 14-15% of patients, tumor cell expression appears rare. SSTR may be expressed by lung tumors, particularly small cell lung cancer and bronchial carcinoid disease. [111In]pentetreotide scintigraphy may have a role to play in the localization and staging of lung cancers both before and following treatment, and in detecting relapsed disease. The potential role of radiolabelled somatostatin analogs as radiotherapeutic agents in the management of lung cancer is currently being explored. Somatostatin analog therapy results in significant growth inhibition of both SSTR-positive and SSTR-negative lung tumors in vivo. Recent work indicates that these agents may enhance the efficacy of chemotherapeutic agents in the treatment of solid tumors including lung cancer. Copyright © 2001 S. Karger AG, Basel.

Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer : potential targets for chemoprevention and systemic therapy

The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1β, Tumour Necrosis Factor (TNF)-α and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Osteogenic differentiation of murine embryonic stem cells is mediated by fibroblast growth factor receptors

The mechanisms involved in the control of embryonic stem (ES) cell differentiation are yet to be fully elucidated. However, it has become clear that the family of fibroblast growth factors (FGFs) are centrally involved. In this study we examined the role of the FGF receptors (FGFRs 1-4) during osteogenesis in murine ES cells. Single cells were obtained after the formation of embryoid bodies, cultured on gelatin-coated plates, and coaxed to differentiate along the osteogenic lineage. Upregulation of genes was analyzed at both the transcript and protein levels using gene array, relative-quantitative PCR (RQ-PCR), and Western blotting. Deposition of a mineralized matrix was evaluated with Alizarin Red staining. An FGFR1-specific antibody was generated and used to block FGFR1 activity in mES cells during osteogenic differentiation. Upon induction of osteogenic differentiation in mES cells, all four FGFRs were clearly upregulated at both the transcript and protein levels with a number of genes known to be involved in osteogenic differentiation including bone morphogenetic proteins (BMPs), collagen I, and Runx2. Cells were also capable of depositing a mineralized matrix, confirming the commitment of these cells to the osteogenic lineage. When FGFR1 activity was blocked, a reduction in cell proliferation and a coincident upregulation of Runx2 with enhanced mineralization of cultures was observed. These results indicate that FGFRs play critical roles in cell recruitment and differentiation during the process of osteogenesis in mES cells. In particular, the data indicate that FGFR1 plays a pivotal role in osteoblast lineage determination.

Gesturing elsewhere: the identity politics of the Balinese death/thrash metal scene

This essay explores the political significance of Balinese death/thrash fandom. In the early 1990s, the emergence of a death/thrash scene in Bali paralleled growing criticism of accelerated tourism development on the island. Specifically, locals protested the increasing ubiquity of Jakarta, 'the centre', cast as threatening to an authentically 'low', peripheral Balinese culture. Similarly, death/thrash enthusiasts also gravitated toward certain fringes, although they rejected dominant notions of Balinese-ness by gesturing elsewhere, toward a global scene. The essay explores the ways in which death/thrash enthusiasts engaged with local discourses by coveting their marginality, and aims to demonstrate how their articulations of 'alien-ness' contributed in important ways to a broader regionalism.

Factors associated with the wish to hasten death : a study of patients with terminal illness

Background. There is considerable debate regarding the clinical issues surrounding the wish to hasten death (WTHD) in the terminally ill. The clinical factors contributing to the WTHD need further investigation among the terminally ill in order to enhance understanding of the clinical assessment and treatment needs that underlie this problem. A more detailed understanding may assist with the development of appropriate therapeutic interventions. Method. A sample of terminally ill cancer patients (N=256) recruited from an in-patient hospice unit, home palliative care service and a general hospital palliative care consulting service from Brisbane Australia between 1998–2001 completed a questionnaire assessing psychological (depression and anxiety), social (family relationship, social support, level of burden on others) and the impact of physical symptoms. The association between these factors and the WTHD was investigated. Results. A high WTHD was reported by 14% of patients. A discriminant function analysis revealed that the following variables were associated with a high WTHD (P<0·001): higher levels of depressive symptoms, being admitted to an in-patient hospice setting, a greater perception of being a burden on others, lower family cohesion, lower levels of social support, higher levels of anxiety and greater impact of physical symptoms. Conclusions. Psychological and social factors are related to a WTHD among terminally ill cancer patients. Greater attention needs to be paid to the assessment of psychological and social issues in order to provide appropriate therapeutic interventions for terminally ill patients.

Doctors and their patients : A context for understanding the wish to hasten death

There is a paucity of research that has directly examined the role of the health professional in dealing with a terminally ill patient's wish to hasten death (WTHD) and the implications of this for the support and services needed in the care for a dying patient. Themes to emerge from a qualitative analysis of interviews conducted on doctors (n=24) involved in the treatment and care of terminally ill patients were (i) the doctors' experiences in caring for their patients (including themes of emotional demands/expectations, the duration of illness, and the availability of palliative care services); (ii) the doctors' perception of the care provided to their respective patients (comprising themes concerning satisfaction with the care for physical symptoms, for emotional symptoms, or overall care); (iii) the doctors' attitudes to euthanasia and (iv) the doctors' perception of their patients' views/beliefs regarding euthanasia and hastened death. When responses were categorised according to the patients' level of a WTHD, the theme concerning the prolonged nature of the patients' illnesses was prominent in the doctor group who had patients with the highest WTHD, whereas there was only a minority of responses concerning support from palliative care services and satisfaction with the level of emotional care in this group. This exploratory study presents a set of descriptive findings identifying themes among a small group of doctors who have been involved in the care of terminally ill cancer patients, to investigate factors that may be associated with the WTHD among these patients. The pattern of findings suggest that research investigating the doctor-patient interaction in this setting may add to our understanding of the problems (for patients and their doctors) that underpins the wish to hasten death in the terminally ill.

Terminally ill cancer patients’ wish to hasten death

This exploratory study investigated factors associated with the wish to hasten death among a sample of terminally ill cancer patients. Semi-structured interviews conducted on a total of 72 hospice and home palliative care patients were subjected to qualitative analysis using QSRNUDIST. The main themes to emerge suggested that patients with a high wish to hasten death had greater concerns with physical symptoms and psychologica l suffering, perceived themselves to be more of a burden to others, and experienced higher levels of demoralization, while also reporting less confidence in symptom control, fewer social supports, less satisfaction with life experiences and fewer religious beliefs when compared with patients who had a moderate or no wish to hasten death. The implications of these findings will be discussed.

Health, Death, and Indigenous Australians in the Coronial system

This paper details research conducted in Queensland during the first year of operation of the new Coroners Act 2003. Information was gathered from all completed investigations between December 2003 and December 2004 across five categories of death: accidental, suicide, natural, medical and homicide. It was found that 25 percent of the total number of Indigenous deaths recorded in 2004 were reported to, and investigated by, the Coroner, in comparison to 9.4 percent of non-Indigenous deaths. Moreover, Indigenous people were found to be over-represented in each category of death, except in death in a medical setting, where they were absent.

Teaching cause-of-death certification : lessons from international experience

The accuracy of cause-of-death statistics substantially depends on the quality of cause-of-death information in death certificates, primarily completed by medical doctors. Deficiencies in cause-of-death certification have been observed across the world, and over time. Despite educational interventions targeting to improve the quality of death certification, their intended impacts are rarely evaluated. This review aims to provide empirical evidence that could guide the modification of existing educational programs, or the development of new interventions, which are necessary to improve the capacity of certifiers as well as the quality of cause-of-death certification, and thereby, the quality of mortality statistics.