Differential sensitivity of normal and cystic fibrosis airway epithelial cells to epinephrine.

1. Exposure to epinephrine has been shown to have a range of effects on cells and tissues. A recent study suggested that the proliferative ability of CF epithelial cells, exposed to high concentrations of epinephrine (200 - 300 microM), was reduced when compared to that of normal cells. This approach could potentially provide a means to effectively separate cells with functional cyclic AMP-dependent Cl-ion transport from those defective in this pathway. 2. The sensitivity to killing by epinephrine is reported here for four different CF cell lines, three normal cell lines, and two CF epithelial cell lines complemented with wild-type (wt) CF transmembrane conductance regulator (CFTR) cDNA. 3. While each cell line exhibited varying sensitivity to 200 microM epinephrine, no predictable pattern was observed between the expression of wt-CFTR and cell survival following epinephrine exposure. Overall, normal cell lines did exhibit a greater resistance to epinephrine-induced cell death although, the most resistant cell line was derived from CF tracheal epithelium (SigmaCFTE29o-). 4. The expression of exogenous wt-CFTR increased the survival of one cell line (CFDEo-) when compared to the parent line, but in another complemented line, survival was reduced. 5. These findings suggest that while epinephrine induces cell killing, it is not consistently effective for preferential selection of normal over CF cells. Although CFTR may play a role in the mechanism(s) of epinephrine killing, other factors such as cell density, proliferative ability, cell type origin and phenotype are involved.     

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

Background

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.

Methods/design

The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment.

Discussion

The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.     

NEED FOR PRECISE PROTOCOL IN MAGNETIC RESONANCE IMAGING OF THE POST OPERATIVE SPINE

Gadolinium enhanced Magnetic Resonance Imaging (MRI) for the evaluation of the post operative lumbo-sacral spine is a sensitive and specific imaging technique. A need for establishing a specific protocol for Failed Back Surgery Syndrome (FBSS) for use in the service hospitals is highlighted for convenience of patient management and preservation of active manpower. The MR scan of 50 patients performed over a span of six months, who complained of persistent low backache even after surgery, were retrospectively analysed. The specificity of this series using MRI in indicating the exact cause of FBSS was clocked at only 30%. The conditions diagnosed were rectifiable. The balance of the patients who could not be offered any specific diagnosis towards the cause, were being managed conservatively / placed in low medical category for a considerable period. It was noted with concern that there was non prevalence of sequence like the fast spin echo with gadolinium enhancement as a routine.KEY WORDS: Gadolinium, Magnetic Resonance Imaging, Post-operative spine     

4-S-(5″-烃基-4″-氨基-1″,2″,4″-三唑-3″-基)-4-去氧-4′-去甲基表鬼臼毒素衍生物的合成及抗肿瘤活性

许多有显著抗肿瘤活性的鬼臼毒素类化合物,其母核C-4侧链上往往连接有刚性较强的脂环或芳香环结构,而且侧链多含有一定数量的杂原子［1～3］。另外,三氮唑类化合物大都有广泛的生物活性,如抗菌［4～5］、抗病毒［6］、抗肿瘤［7］等,据此,我们设计并合成了8个三氮唑杂环取代的表鬼臼毒素衍生物,以期寻找活性高、毒副作用小的鬼臼毒素类药物,并进一步考察此类化合物的构效关系。　合成路线如图1所示,三氮唑3a～3h和4′-去甲基-表鬼臼毒2分别按文献［8,9］方法合成;我们选择三氟乙酸作为缩合剂,基于它不仅能催化缩合反应,而且能保护三唑上的氨基官能团,使其不能充当进攻基团;最后一步缩合反应显然经历了一个SN1历程,4′-去甲基-表鬼臼毒 的C-4位上很容易形成一个苄基型碳正离子,由于C-1位有庞大的芳环,加之,进攻的基团也较大,可以预料,这个反应有很强的立体选择性,使C-4β-构型成为主要产物,事实确实如此,在TLC上几乎看不到C-4α-构型的产物。     

(-)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1 activity

Green tea polyphenols have been shown to inhibit cancer in a variety of tumor models, including ultraviolet B (UVB)-induced non-melanoma skin cancer. In green tea extracts, the major dry mass constituent is the family of catechins, of which (-)-epigallocatechin-(3)-gallate (EGCG) is considered to be important for the chemopreventive activity. EGCG has been shown to have antioxidant properties, but there has been little progress toward identifying the specific targets and mechanisms of its action. Using cultured human keratinocytes, we show that UVB- induced AP-1 activity is inhibited by EGCG in a dose range of 5.45 nM to 54.5 microM. EGCG is effective at inhibiting AP-1 activity when applied before, after or both before and after UVB irradiation. EGCG also inhibits AP-1 activity in the epidermis of a transgenic mouse model. This work begins to define a mechanism by which EGCG could be acting to inhibit UVB-induced tumor formation.      

Egg sharing and egg donation: attitudes of British egg donors and recipients

The question of payment to egg donors has recently focused the attention of both the Human Fertilisation and Embryology Authority (HFEA) and licensed clinics. An acute shortage of egg donors and the rising costs of assisted conception treatment are matters of grave concern to many patients. To understand the emotional and social effects of egg sharing and egg donation, we conducted a survey of attitudes in a group of women who had some knowledge or experience of egg donation. A total of 750 questionnaires were sent out of which 217 were returned within the specified time limit. From these, 107 respondents had experience of egg donation and 110 had made enquiries about donation. The data from these questionnaires were collated and tabulated by the National Opinion Polls (NOP) Research Group. An analysis of the data produced the following key findings: (i) donating or sharing eggs is a social issue, 94% discuss it with partners/family/friends; (ii) altruistic motives are not the prerogative of non-patient volunteers-egg share donors felt that helping the childless was as important as having a chance of in-vitro fertilization (IVF) for themselves; (iii) the treatment procedure causes the most anxiety for egg donors. The recipients were most concerned about delays, donor characteristics and how the eggs were allocated; (iv) most respondents (65%) with prior experience of egg sharing would do it again - 63% of egg share donors, 72% of egg share recipients; (v) cash rewards to egg donors and outright advertising for donors were rejected by 64 and 62% of the sample respectively; and (vi) counselling was highly valued and there were no instances of 'shattered lives' after treatment. The findings do not support the recently announced intentions of the HFEA to disallow payment to gamete donors on the grounds of devalued consent. There is no precedent in modern medicine for egg sharing. The patients surveyed drew a clear distinction between egg sharing and financial rewards. As long as egg donation is not covered by the National Health Service, it is fairer to offer egg sharing than to refuse treatment to those unable to pay.      

Pregnancy following intracytoplasmic sperm injection treatment with dead husband's spermatozoa: ethical and policy considerations

This paper describes the first pregnancy in a childless widow after intracytoplasmic sperm injection (ICSI) treatment with her deceased husband's spermatozoa which had been stored for nearly 3 years before use. Before his death the husband had received treatment for testicular cancer and he had given the appropriate written consent for the future use of his spermatozoa. Of the 10 eggs injected, six resulted in normal embryos. Three embryos were transferred and the remaining three embryos are currently stored for possible future use. The treatment resulted in a continuing singleton pregnancy. The case demonstrated the suitability of ICSI in those difficult cases where the sperm quality is extremely poor. This success is also compared with a widely debated case of another widow who was refused permission to use her deceased husband's spermatozoa. It is concluded that in the case of posthumous use of frozen spermatozoa, the current laws are conveniently applicable in a chronic illness but not so in an acute illness leading to death. In the light of the wide public debate on the issues raised by this legal case, the UK Government has also decided to conduct a review of consent procedures involving the storage and use of genetic material.