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In 2005, religious authorities in Palestine warned publicly of a new phenomenon, one that was ‘foreign to Palestinian society’: ʿurfī marriages. They used this term to refer to ‘secret marriages,’ which they considered as linked to social breakdown, the result of the Israeli occupation. In the tales (similar to rumors) of young men and women throughout the West Bank and Gaza in the early 2010s, these marriages were often related to the colonial geographies of anxiety, of social and political fragmentation, and of the spatial segregation that Israel has imposed on Palestinians. Related concerns were expressed by the men of religion as they attempted to maintain their authority in highly uncertain times and in contested spaces. Still, in the very small number of concrete cases shariʿa judges continued to use the flexibility of Islamic jurisprudence to legally recognize ʿurfī marriages to work towards the most equitable solution in problematic situations.

A memorial tribute to Albert Aghazarian (1950–2020) recalling, often in his own words, how he grew up in the Old City of Jerusalem, his life-long passion for the city as a historian and activist, a...

This chapter focusses on efforts to enhance year-long study abroad (SA) for UK modern languages and cultures students through closer alignment of learning and assessment in a range of destinations worldwide with learning and assessment elsewhere in the programme, and through increased support for social and experiential learning before, during, and after residence abroad. It presents a new system of project-based, culturally focussed formal academic study and assessment and a parallel scheme to provide multimodal blended learning support to help students optimise their social and experiential learning, intercultural development, enterprise skills, and future employability. This chapter argues that acknowledging the importance of both formal and informal learning is needed to allow SA to consolidate its position at the centre of the modern languages degree.

Homeless people have complex problems. GP enhanced care (Pathway) has shown benefits. We performed a randomised, -parallel arm trial at two large inner city hospitals. Inpatient homeless adults were randomly allocated to either standard care (all management by the hospital-based clinical team) or enhanced care with input from a homeless care team. The hospital data system provided healthcare usage information, and we used questionnaires to assess quality of life. 206 patients were allocated to enhanced care and 204 to usual care. Length of stay (up to 90 days after admission) did not differ between groups (standard care 14.0 days, enhanced care 13.3 days). Average reattendance at the emergency department within a year was 5.8 visits in the standard care group and 4.8 visits with enhanced care, but this decrease was not significant. -Quality of life scores after discharge (in 108 patients) improved with enhanced care (EQ-5D-5L score increased by 0.12 [95% CI 0.032 to 0.22] compared wtih 0.03 [-0.1 to 0.15; p=0.076] with standard care). The proportion of people sleeping on the streets after discharge was 14.6% in the standard care arm and 3.8% in the enhanced care arm (p=0.034). The quality-of-life cost per quality-adjusted life-year was £26,000. The Pathway approach doesn't alter length of stay but improves quality of life and reduces street -homelessness.

In focus groups and individual interviews with the wives and mothers of Palestinian political prisoners, we find that their narratives describe a triple captivity—of the Israeli colonial system, the Israeli prison, and the post-Oslo Palestinian political landscape with its isolating effects in their own communities. Wives and mothers of prisoners mediate between prison and family life by navigating through the multiple dynamics of Israeli securitization and geographic incarceration, political invisibility in the Palestinian field, and social isolation in their communities. In particular, the visit from the West Bank to prisons inside Israel emerges as an ordeal that haunts and structures daily life. We draws on Jacques Ranciere’s notion to highlight the vanishing of the political, the dominance of policing, and the diminishing value of imprisonment in the post Oslo years, signaling an absence of the Palestinian emancipatory project.

Background: The epidermal growth factor receptor (EGFR) is expressed in ovarian cancer, but agents targeting this pathway have shown little effect as single agents. This may be due to the presence of alternative pathways, particularly activation of the PI3K/ Akt/MTOR pathway. Methods: We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the EGFR inhibitors erlotinib and gefitinib in ovarian cancer primary cell cultures. Results: The single-agent EGFR inhibitors showed little activity, although some activity was seen with the single-agent PI3K inhibitor, ZSTK474. Combinations of ZSTK474 with EGFR inhibitors showed enhanced activity with some evidence of synergy, whereas sirolimus combinations were less active. The results were not explicable on the basis of PIK3CA mutation or amplification, or PTEN loss, although one tumour with a KRAS mutation showed resistance to EGFR inhibitors. However, there was correlation of the EGFR expression with sensitivity to EGFR and resistance to PI3K active agents, and inverse correlation in the sensitivity of individual tumours to agents active against these pathways, suggesting a mechanism of action for the combination. Conclusion: Phase I/II clinical trials with these agents should include further pharmacodynamic endpoints and molecular characterisation to identify patients most likely to benefit from this strategy.

Low-trophic level species account for more than 30% of global fisheries production and contribute substantially to global food security. We used a range of ecosystem models to explore the effects of fishing low-trophic level species on marine ecosystems, including marine mammals and seabirds, and on other commercially important species. In five well-studied ecosystems, we found that fishing these species at conventional maximum sustainable yield (MSY) levels can have large impacts on other parts of the ecosystem, particularly when they constitute a high proportion of the biomass in the ecosystem or are highly connected in the food web. Halving exploitation rates would result in much lower impacts on marine ecosystems while still achieving 80% of MSY.

There are rising numbers of single women across the Arab world. While this is usually connected with delayed marriage, Palestine shows a unique pattern of early but not universal marriage. This article looks beneath the statistics to investigate the stories behind this trend. How do young unmarried women negotiate boundaries and understand and enact choice in the context of a society experiencing prolonged insecure and warlike conditions, political crisis and social fragmentation and where the high number of unmarried women can be an increasing locus of moral panic? In conducting focus groups with two generations of women, my research looks at the prevailing importance of education, civil society and security in negotiating space within women's lives and uncovers a long tradition of unmarried women leading full and significant lives which needs to be recovered from the past.

In our comparison of marriage arrangements and wedding celebrations during the first and the second intifada in Palestine, we focus on “political marriages” wherein the political activism and affiliation of the marital partners are of considerable importance. During the first intifada, political engagement became a major consideration in choice of marriage partner in some settings, and conventional boundaries of religion and class were transgressed. Simultaneously, marriage celebrations were transformed, whereby a widespread culture of austerity and mourning made weddings far more simple and inexpensive, as well as signaling solidarity and resistance. In the second intifada, marriage arrangements and wedding celebrations are very different. The changed political climate, with the hope and popular participation of the first intifada turned into the despair and exclusions of the second, transformed political engagement from a positive into a largely negative qualification. The material side of marriage has again become more important, public displays of consumption acceptable, and celebrations more expensive. These shift s are shaped by the effects of the post-Oslo transition, as well as by the warlike conditions on the ground. Although these conditions, from Israeli army intrusions to physical barriers to marriage, are more insecure and dangerous than in the earlier intifada, they function largely as external threats to the shaping of wedding arrangements and ceremonies, rather than generating internal transformations. For Maha Mustaqlem Nassar (1954–2008) whose committed life inspired us.

Referencing the ‘‘stereotypes of self’’ identified by Rosemary Sayigh in the life stories of Palestinian camp women in Lebanon who had lived through the Palestinian resistance, the author focuses on the narratives of two women in Ramallah9s Am9ari refugee camp since the outbreak of the al-Aqsa intifada to reflect on the Palestinian present. Though the women——and their goals and struggles——could not be more different, their narratives reveal significant shifts in self-representation that reflect both the impact of post-Oslo political realities and the new (unattainable) aspirations fueled by satellite television images and Ramallah cafee culture. The narratives also reflect, in very different ways, the national crisis, the impotence of Palestinian political groups and institutions, and the erosion of solidarities.

How do international human rights frameworks function in addressing violence against women in situations of prolonged political violence and colonial conflict? How do other voices, generated locally, take on, contest or interact with, these frameworks? These questions are addressed in the Palestinian context through examining two recent reports, the first, a problematic November 2006 report by Human Rights Watch, A Question of Security: Violence Against Palestinian Women and Girls, and the second, a report issued in March 2007 by the Palestinian Violence Against Women Forum, a network of local Palestinian NGOs. Data from the first Palestinian national survey on domestic violence (2005) are also scrutinized. Beginning with a specific incident of a recent honor crime in a Palestinian refugee camp, this initial intervention also probes the history of public debate research and activism on domestic violence in Palestine and argues for careful attention to the diversity of community responses.

Embryonic stem (ES) cells are thought to have unique chromatin structures responsible for their capacity for self-renewal and pluripotency. To examine this possibility, we sought nuclear proteins in mouse ES cells that specifically bind to histones using a pull-down assay with synthetic peptides of histone H3 and H4 tail domain as baits. Nuclear proteins preferentially bound to the latter. We identified 45 proteins associated with the histone H4 tail and grouped them into four categories: 10 chromatin remodeling proteins, five histone chaperones, two histone modification-related proteins, and 28 other proteins. mRNA expression levels of 20 proteins selected from these 45 proteins were compared between undifferentiated and retinoic acid (RA)-induced differentiated ES cells. All of the genes were similarly expressed in both states of ES cells, except nucleoplasmin 3 (NPM3) that was expressed at a higher level in the undifferentiated cells. NPM3 proteins were localized in the nucleoli and nuclei of the cells and expression was decreased during RA-induced differentiation. When transfected with NPM3 gene, ES cells significantly increased their proliferation compared with control cells. The present study strongly suggests that NPM3 is a chromatin remodeling protein responsible for the unique chromatin structure and replicative capacity of ES cells.

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFbeta1 and TGFbeta2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT-PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor beta receptor 1 (TGFbetaR1), and are therefore susceptible to TGFbeta1 and TGFbeta2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFbeta2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFbeta1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.

Leukotrienes derived from the 5-lipoxygenase pathway are proinflammatory lipid mediators that possibly play a role in inflammatory bowel diseases. The expression of 5-lipoxygenase pathway proteins has not previously been examined in colonic mucosa in inflammatory bowel disease.Quantitative immunohistochemical analyses showed that, compared to those of the control subjects (n = 9), colonic biopsies from patients with active inflammatory bowel disease (n = 17) had 3- to 7-fold higher mean counts of cells expressing 5-lipoxygenase (P = 0.03), 5-lipoxygenase-activating protein (P = 0.005), and the leukotriene A(4) hydrolase (P = 0.004), which make up the biosynthetic pathway of the potent neutrophil chemotaxin leukotriene B(4). Immunoexpression of the leukotriene C(4) synthase was unaltered (P0.2). The increased representation of leukotriene B(4)-pathway enzymes was associated with higher counts of neutrophils (P = 0.0001), macrophages (P = 0.03), eosinophils (P = 0.0004), CD8(+) T cells (P0.001), activated T cells (P0.05), and B cells (P0.05) but not of mast cells (P0.9). These eicosanoid and cellular changes were most marked in the subgroup of patients with ulcerative colitis (n = 9), and were absent in patients with quiescent disease (n = 6). The anomalies in the 5-lipoxygenase pathway were accompanied as expected by more cells immunostaining for cytokine-inducible COX-2 (P = 0.004, n = 17), but this study also revealed a greater number of cells expressing COX-1 in the samples from the patients in the ulcerative colitis subgroup (P = 0.03, n = 9).The 5-lipoxygenase data provide a cellular basis for increased tissue synthesis of the leukotriene B(4), as reflected in the colonic mucosa and rectal dialysates of patients with active inflammatory bowel disease, which contributes to neutrophil influx and colonic injury. The COX-1/COX-2 data highlight the ambiguous functional role of prostanoid pathways in inflammatory bowel diseases.

Background: Uveal melanoma arises in an immune-privileged site and can itself add to the immunosuppressive environment. Previous studies on cutaneous melanoma have shown the presence of tolerogenic dendritic cells (DCs), which could play an important role in the progression of the tumour. Aim: To examine the presence and functional status of DCs in a small series of uveal melanomas. Methods: 10 cases of uveal melanoma were examined for the expression of FXIIIa, CD68, human leucocyte antigen (HLA)-DR, CD40, CD83, transforming growth factor βR1 and indolamine 2,3 dioxygenase by immunohistochemical analysis on sections embedded in paraffin wax. Results: CD68-positive macrophages were present in all of the tumours and were evenly distributed throughout. DCs expressing FXIIIa-positive were seen in 7 cases, and were often found concentrated in foci within the tumour mass. These cells were dendritic and expressed high levels of HLA-DR. The DCs did not express the maturation markers CD83 or CD40. In one case, concentration of DCs around the area of tumour necrosis was observed, and some of these cells expressed CD83. Conclusion: Numerous tolerising antigen-presenting cells may play a role in melanoma-related immunosuppression in the eye, although activation of DCs may be associated with tumour necrosis.

The authors ground their reflections on gender and the complex realities of the second Palestinian intifada against Israeli occupation in the political processes unleashed by the signing of the Israeli–Palestinian rule, noting that the profound inequalities between Israel and Palestine during the interim period produced inequalities among Palestinians. The apartheid logic of the Oslo period – made explicit in Israel's policies of separation, seige and confinement of the Palestinian population during the intifada and before it – is shown to shape the forms, sites and levels of resistance which are highly restricted by gender and age. In addition, the authors argue that the Palestinian Authority and leadership have solved the contradictions and crisis of Palestinian nationalism in this period through a form of rule that the authors term ‘authoritarian populism’, that tends to disallow democractic politics and participation. The seeming absence of women and civil society from the highly unequal and violent confrontations is contrasted with the first Palestinian intifada (1987–91), that occurred in a context of more than a decade of democratic activism and the growth of mass-based organizations, including the Palestinian women's movement. The authors explore three linked crises in gender roles emerging from the conditions of the second intifada: a crisis in masculinity, a crisis in paternity and a crisis in maternity.

There is increasing evidence to suggest that the potent neutrophil chemoattractant interleukin-8 (IL-8) has an important role in the pathogenesis of inflammatory bowel disease. IL-8 mediates its actions via two cell surface receptors, CXCR1 and CXCR2. This paper describes the distribution of these IL-8 receptors in the normal gastrointestinal tract and how this is modified in ulcerative colitis (UC). Paraffin-embedded colonic resection specimens were stained with monoclonal antibodies directed against CXCR1 and CXCR2 in ten cases of total UC, 16 cases of appendicitis, and 11 histologically normal sections. A semiquantitative scale of 0-4 was used to assess the proportion and intensity of positively stained cells within certain defined areas of tissue. A comparative assessment was made of the distribution of various cell populations. Dual immunostaining was used to confirm the phenotype of positively staining cells. In the histologically normal colon, the antibody against CXCR1 stained a subpopulation of macrophages deep to the epithelium and germinal centre lymphocytes. A similar pattern of staining was seen in acute appendicitis, with in addition some positively stained neutrophil polymorphs. In UC, there was up-regulation of CXCR1, with a striking increase in positively stained macrophages throughout the mucosa and of B and T lymphocytes outside the germinal centre areas. There was also intense up-regulation of CXCR1 expression by the luminal epithelium, reflected in the epithelial staining score (mean+/-SE=1.8+/-0.44 for UC cases, vs. 0.23+/-0.16 for controls and 0.25+/-0.14 for acute appendicitis). CXCR2 was only expressed on a small population of lamina propria mononuclear cells and crypt epithelial cells, with no significant differences observed between the groups. These results suggest that IL-8 may, through CXCR1, have a role beyond neutrophil recruitment in mediating the immune response in UC and that this is not merely a consequence of the acute inflammation seen in UC.

Background The epidermal growth factor receptor family is expressed in breast cancer, and agents targeting this pathway have single agent effects (e.g. traztuzumab). Development of resistance may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway. We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the epidermal growth factor (EGFR) inhibitors erlotinib and gefitinib in breast MCF10a isogenic cell lines with EGFR, BRAF, AKT, and PI3K mutations. Results PI3K mutation conferred increased activity of EGFR inhibitors against MCF10a cells in comparison with the parental cell line and other mutations studied. Combination of EGFR inhibitors with either the PI3K inhibitor ZSTK474 or the MTOR inhibitor sirolimus showed increased activity. Conclusions These results are encouraging for the use of combinations targeting the PI3K and EGFR pathway simultaneously.

Purpose We sought to evaluate the efficacy of topical fibronectin ophthalmic solution, containing 3.5 mg/ml of human fibronectin, in the treatment of persistent epithelial defects of the cornea. Methods In a double-masked, randomized clinical trial, patients with a persistent, corneal epithelial defect of at least 14 days in duration, and at least 2 mm in width along the larger axis, were sought from the practices of 38 clinical investigators. After a 14-day washout period, 65 patients were randomly assigned to one of three treatment groups. One group (n = 20) received fibronectin drops; the second (n = 23) received drops of the vehicle from the fibronectin solution; and the third (n = 22) received a placebo. Results After 21 days of treatment, there was no difference in percentage reduction of the corneal epithelial defect size; the average percentage of reduction of defect area ranged from 46.5% to 54.3%. Fibronectin treatment showed a beneficial effect for patients with larger baseline defects (10 mm 2 or greater in area); however, no such effect was observed among patients with smaller defects. Defect duration before treatment had a significant effect on outcome (P = .007); defects of longer duration were less likely to decrease in size over the course of the study. Conclusions All three treatment groups showed similar reductions in defect size; therefore, this study provides no support for the efficacy of fibronectin treatment of persistent, corneal epithelial defects. Defect duration showed a negative association with reduction in defect size. Because strict control of topical applications during the washout and treatment periods resulted in beneficial responses, physicians should carefully consider the topical medications used by patients who have persistent, corneal epithelial defects.

Expert systems-computerized decision consultants-offer potential for human service professionals to share expertise and reduce variability in decision making. The development of such systems is particularly important in the field of child protection because of high staff turnover and complex decision making requirements. This paper presents a method for knowledge acquisition in building a prototype expert system in child welfare. Patterns of decision making are traced and translated into computer-based rules. Solutions to research problems in developing expert systems are presented. Continued refinement of research practice in this area can lead to the development of usable expert systems for the social services.

Background Chemotherapy benefits relatively few patients with cutaneous melanoma. The assessment of tumour chemosensitivity by the ATP-based tumour chemosensitivity assay (ATP-TCA) has shown strong correlation with outcome in cutaneous melanoma, but requires fresh tissue and dedicated laboratory facilities. Aim To examine whether the results of the ATP-TCA correlate with the expression of genes known to be involved in resistance to chemotherapy, based on the hypothesis that the molecular basis of chemosensitivity lies within known drug resistance mechanisms. Method The chemosensitivity of 47 cutaneous melanomas was assessed using the ATP-TCA and correlated with quantitative expression of 93 resistance genes measured by quantitative reverse transcriptase PCR (qRT-PCR) in a Taqman Array after extraction of total RNA from formalin-fixed paraffin-embedded tissue. Results Drugs susceptible to particular resistance mechanisms showed good correlation with genes linked to these mechanisms using signatures of up to 17 genes. Comparison of these signatures for DTIC, treosulfan and cisplatin showed several genes in common. HSP70 , at least one human epidermal growth factor receptor, genes involved in apoptosis ( IAP2 , PTEN ) and DNA repair ( ERCC1 , XPA , XRCC1 , XRCC6 ) were present for these agents, as well as genes involved in the regulation of proliferation ( Ki67 , p21, p27). The combinations tested included genes represented in the single agent signatures. Conclusions These data suggest that melanoma chemosensitivity is influenced by known resistance mechanisms, including susceptibility to apoptosis. Use of a candidate gene approach may increase understanding of the mechanisms underlying chemosensitivity to drugs active against melanoma and provide signatures with predictive value.

The article describes how the UK government has set about introducing IT into various curricula, within the National Curriculum. It looks at the opportunities the Internet offers for education, and how this can be expanded at the international level.

Immune avoidance mechanisms play a key role in the successful dissemination of melanoma. One mechanism whereby this could be achieved is by interfering with dendritic cell (DC) presentation of tumour-associated antigens to naive T cells. In particular, immature DCs characterized by the absence of accessory molecules are known to be immunosuppressive and to be involved in the induction of tolerance. The present study has investigated the presence and activation status of DCs within melanoma metastases in the regional lymph nodes. Using image analysis techniques, the expression of Factor XIIIa (FXIIIa), CD40, CD83 and HLA-DR and the morphological features of DCs were examined in paraffin sections from 26 lymph nodes containing melanoma metastases. DCs expressing FXIIIa were found in 70% of the lymph nodes. The number of DCs identified was generally small but there were more concentrated areas of DCs designated as hotspots. In these areas of high FXIIIa staining, the percentage area occupied by DCs varied between 0.1% and 10%. The majority of FXIIIa-positive cells did not express the DC maturation markers CD83 or CD40 and morphologically were rounded with few dendrites, indicating that they were immature. The cells did, however, express high levels of HLA-DR, suggesting that they have the ability to present antigen but lack the accessory molecules required to initiate an immune response. Immature DCs, characterized by phenotypic and morphological features, are therefore present within the tumour deposits in lymph nodes infiltrated by melanoma and may specifically modulate the anti-melanoma immune response. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. Methods Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. Results In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors. Conclusion This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy.

Background Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosine kinase inhibitor (TKI) targeted to the ATP-binding domain of EGFR (HER1; erbB1). Methods In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA) to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan) against a variety of solid tumours (n = 86), including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC) and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the IndexSUM was calculated based on the percentage tumour growth inhibition (TGI) at each test drug concentration (TDC). Gefitinib was tested at concentrations ranging from 0.0625–2 microM (TDC = 0.446 microg/ml). This study represents the first use of a TKI in the assay. Results There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86) of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76) of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45) had a >50% decrease in their IndexSUM). In 38% of tumours (29/76), the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76) there was no change observed. Conclusion The in vitro model suggests that gefitinib may have differential effects in response to concomitant cytotoxic chemotherapy with the agents tested during this study. The mechanism involved may relate to the effect of TKIs on growth rate versus their effect on the ability of the cell to survive the stimulus to apoptosis produced by chemotherapy.

The expression of P-glycoprotein (P-gp) has been demonstrated to confer resistance to several anticancer drugs, including anthracyclines, taxanes and vinca alkaloids. Tariquidar is a novel inhibitor of P-gp that has been shown to reverse resistance to cytotoxic drugs in tumor cell lines and mouse xenografts. We have used an ATP-based chemosensitivity assay (ATP-TCA) to compare the activity of cytotoxic drugs in combination with tariquidar against a variety of solid tumors (n = 37). The expression of P-gp was determined in a subset of solid tumor samples by immunohistochemistry (n = 16). Resistance was seen in 20 of 37 (54%) tumors tested with doxorubicin, in 27 of 34 (79%) samples tested with paclitaxel and 17 of 31 (55%) with vinorelbine. Tariquidar alone showed no activity over a wide range of concentrations up to 2 microM (n = 14). The median IC90s for doxorubicin, paclitaxel and vinorelbine, alone were 2.57, 27.4 and 15.5 microM. These decreased to 1.67 (p0.0005), 20.6 (p0.05) and 9.5 microM (p0.001), respectively, in combination with tariquidar. Tariquidar also significantly decreased resistance in 14 of 20 (70%), six of 27 (22%) and six of 17 (35%) samples tested with doxorubicin, paclitaxel and vinorelbine, respectively. Immunohistochemical staining for P-gp was positive in nine of 16 (56%) samples and in all of these cases addition of tariquidar improved the activity of the cytotoxic. The results show that tariquidar is able to decrease resistance in a number of solid tumors resistant to cytotoxic drugs known to be P-gp substrates. These data support the introduction of tariquidar in combination with chemotherapy to clinical trials of patients expressing P-gp.

Mucosal changes in inflammatory bowel disease (IBD) are characterized by ulcerative lesions accompanied by prominent cellular infiltrates in the bowel wall. Chemokines are chemotactic cytokines that are able to promote leukocyte migration to areas of inflammation and are also able to initiate cell activation events. They have recently been implicated in the pathophysiology of many disease states. The aim of this study was to detail the degree and distribution of specific chemokines, interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, -2, and -3, and macrophage inflammatory protein (MIP)-1alpha and -1beta, in IBD mucosa. Thirty-nine patients were included, ten controls, 20 ulcerative colitis (UC), and nine Crohn's disease (CD), with a range of disease activity. Colonic mucosal biopsies were collected from UC, CD, and control patients and embedded in glycol methacrylate. Two-micrometre-thick sections were cut and stained using immunohistochemistry for chemokine protein expression. Sections were analysed using a light microscope. Expression of all types of chemokine protein was detected in colonic mucosa from both control and IBD patients. Patterns of staining between IBD patients and controls differed significantly, but CD and UC patients demonstrated similar patterns of staining. Individual chemokine expression was found to be significantly up-regulated in IBD when patients were compared with the non-diseased group in all areas of the mucosal sections. Up-regulated chemokine expression correlated with increasing activity of the disease. It is concluded that human colonic chemokine expression is non-selectively up-regulated in IBD. The results supported the hypothesis that the degree of local inflammation and tissue damage in UC and CD is dependent on local expression of specific chemokines within IBD tissues.