Functional role of cell surface CUB domain-containing protein 1 in tumour cell dissemination

The function of CUB domain-containing protein 1 (CDCP1), a recently described transmembrane protein expressed on the surface of hematopoietic stem cells and normal and malignant cells of different tissue origin, is not well defined. The contribution of CDCP1 to tumor metastasis was analyzed by using HeLa carcinoma cells overexpressing CDCP1 (HeLa-CDCP1) and a high-disseminating variant of prostate carcinoma PC-3 naturally expressing high levels of CDCP1 (PC3-hi/diss). CDCP1 expression rendered HeLa cells more aggressive in experimental metastasis in immunodeficient mice. Metastatic colonization by HeLa-CDCP1 was effectively inhibited with subtractive immunization-generated, CDCP1-specific monoclonal antibody (mAb) 41-2, suggesting that CDCP1 facilitates relatively late stages of the metastatic cascade. In the chick embryo model, time- and dose-dependent inhibition of HeLa-CDCP1 colonization by mAb 41-2 was analyzed quantitatively to determine when and where CDCP1 functions during metastasis. Quantitative PCR and immunohistochemical analyses indicated that CDCP1 facilitated tumor cell survival soon after vascular arrest. Live cell imaging showed that the function-blocking mechanism of mAb 41-2 involved enhancement of tumor cell apoptosis, confirmed by attenuation of mAb 41-2–mediated effects with the caspase inhibitor z-VAD-fmk. Under proapoptotic conditions in vitro, CDCP1 expression conferred HeLa-CDCP1 cells with resistance to doxorubicin-induced apoptosis, whereas ligation of CDCP1 with mAb 41-2 caused additional enhancement of the apoptotic response. The functional role of naturally expressed CDCP1 was shown by mAb 41-2–mediated inhibition of both experimental and spontaneous metastasis of PC3-hi/diss. These findings confirm that CDCP1 functions as an antiapoptotic molecule and indicate that during metastasis CDCP1 facilitates tumor cell survival likely during or soon after extravasation.

Managing wetlands sustainably as ecosystems : The contribution of the law (part 1)

The ways in which a society set standards of behaviour and of conduct for its members vary hugely. For example, accepted practices, recognised customs, spiritually or morally inspired norms, judicially declared rules, executively formulated edicts, formal legislative enactments or constitutionally embedded rights and duties. Whatever form they assume, these standards are the artificial construction of the human mind. Accordingly the law - whatever its form - can do no more and no less than regulate or set standards for human behaviour, human conduct, and human decision-making. The law cannot regulate the environment. It can only regulate human activities that impact directly or indirectly upon the environment. This applies as much to wetlands as components of the environment as it does to any other components of the environment or the environment at large. The capacity of the law to protect the environment and therefore wetlands is thus totally dependent upon the capacity of the law to regulate human behaviour, human conduct and human decision-making. At the same time the law needs to reflect the specific nature, functions and locations of wetlands. A wetland is an ecosystem by itself; it comprises a range of ecosystems within it; and it is part of a wider set of ecosystems. Hence, the significant ecological functions performed by wetlands. Then there are the benefits flowing to humans from wetlands. These may be social, economic, cultural, aesthetic, or a combination of some or of all of these. It is a challenge for a society acting through its legal system to find the appropriate balance between these ecological and these human values. But that is what sustainability requires.The ways in which a society set standards of behaviour and of conduct for its members vary hugely. For example, accepted practices, recognised customs, spiritually or morally inspired norms, judicially declared rules, executively formulated edicts, formal legislative enactments or constitutionally embedded rights and duties. Whatever form they assume, these standards are the artificial construction of the human mind. Accordingly the law - whatever its form - can do no more and no less than regulate or set standards for human behaviour, human conduct, and human decision-making. The law cannot regulate the environment. It can only regulate human activities that impact directly or indirectly upon the environment. This applies as much to wetlands as components of the environment as it does to any other components of the environment or the environment at large. The capacity of the law to protect the environment and therefore wetlands is thus totally dependent upon the capacity of the law to regulate human behaviour, human conduct and human decision-making. At the same time the law needs to reflect the specific nature, functions and locations of wetlands. A wetland is an ecosystem by itself; it comprises a range of ecosystems within it; and it is part of a wider set of ecosystems. Hence, the significant ecological functions performed by wetlands. Then there are the benefits flowing to humans from wetlands. These may be social, economic, cultural, aesthetic, or a combination of some or of all of these. It is a challenge for a society acting through its legal system to find the appropriate balance between these ecological and these human values. But that is what sustainability requires.

Halogen bonding between an isoindoline nitroxide and 1,4-diiodotetrafluorobenzene: new tools and tectons for self-assembling organic spin systems

Halogen bonding has been observed for the first time between an isoindoline nitroxide and an iodoperfluorocarbon (see figure), which cocrystallize to form a discrete 2:1 supramolecular compound in which NO.⋅⋅⋅I halogen bonding is the dominant intermolecular interaction. This illustrates the potential use of halogen bonding and isoindoline nitroxide tectons for the assembly of organic spin systems...

Feasibility of brief psychological distress screening by a community-based telephone helpline for cancer patients and carers

Background Up to one-third of people affected by cancer experience ongoing psychological distress and would benefit from screening followed by an appropriate level of psychological intervention. This rarely occurs in routine clinical practice due to barriers such as lack of time and experience. This study investigated the feasibility of community-based telephone helpline operators screening callers affected by cancer for their level of distress using a brief screening tool (Distress Thermometer), and triaging to the appropriate level of care using a tiered model. Methods Consecutive cancer patients and carers who contacted the helpline from September-December 2006 (n = 341) were invited to participate. Routine screening and triage was conducted by helpline operators at this time. Additional socio-demographic and psychosocial adjustment data were collected by telephone interview by research staff following the initial call. Results The Distress Thermometer had good overall accuracy in detecting general psychosocial morbidity (Hospital Anxiety and Depression Scale cut-off score ≥ 15) for cancer patients (AUC = 0.73) and carers (AUC = 0.70). We found 73% of participants met the Distress Thermometer cut-off for distress caseness according to the Hospital Anxiety and Depression Scale (a score ≥ 4), and optimal sensitivity (83%, 77%) and specificity (51%, 48%) were obtained with cut-offs of ≥ 4 and ≥ 6 in the patient and carer groups respectively. Distress was significantly associated with the Hospital Anxiety and Depression Scale scores (total, as well as anxiety and depression subscales) and level of care in cancer patients, as well as with the Hospital Anxiety and Depression Scale anxiety subscale for carers. There was a trend for more highly distressed callers to be triaged to more intensive care, with patients with distress scores ≥ 4 more likely to receive extended or specialist care. Conclusions Our data suggest that it was feasible for community-based cancer helpline operators to screen callers for distress using a brief screening tool, the Distress Thermometer, and to triage callers to an appropriate level of care using a tiered model. The Distress Thermometer is a rapid and non-invasive alternative to longer psychometric instruments, and may provide part of the solution in ensuring distressed patients and carers affected by cancer are identified and supported appropriately.

Long term survival following the detection of circulating tumour cells in head and neck squamous cell carcinoma

Background Techniques for detecting circulating tumor cells in the peripheral blood of patients with head and neck cancers may identify individuals likely to benefit from early systemic treatment. Methods Reconstruction experiments were used to optimise immunomagnetic enrichment and RT-PCR detection of circulating tumor cells using four markers (ELF3, CK19, EGFR and EphB4). This method was then tested in a pilot study using samples from 16 patients with advanced head and neck carcinomas. Results Seven patients were positive for circulating tumour cells both prior to and after surgery, 4 patients were positive prior to but not after surgery, 3 patients were positive after but not prior to surgery and 2 patients were negative. Two patients tested positive for circulating cells but there was no other evidence of tumor spread. Given this patient cohort had mostly advanced disease, as expected the detection of circulating tumour cells was not associated with significant differences in overall or disease free survival. Conclusion For the first time, we show that almost all patients with advanced head and neck cancers have circulating cells at the time of surgery. The clinical application of techniques for detection of spreading disease, such as the immunomagnetic enrichment RT-PCR analysis used in this study, should be explored further.