Fibroblast growth factor-2, chemoresistance and colorectal cancer

Introduction: The role of fibroblast growth factor-2 (FGF-2) on colorectal cancer (CRC) cells exposed to chemotherapy has not been studied extensively. This thesis investigated whether FGF-2 mediates chemoresistance in primary (SW480) and metastatic (SW620) colon adenocarcinoma cell lines. Methods: Proliferation assays were used to assess the response of SW480 and SW620 colon cancer cell lines to varying concentrations of FGF-2 and to optimise the dose of 5- FU at which 50% cell death was observed. Cell survival assays were performed following 96 hours exposure to 5-FU ± FGF-2. Levels of chemotherapy induced apoptosis were determined using Caspase-3/7 assay. Expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) and FGFRs at both protein and gene level were determined to see if these contributed to the difference in chemoprotection observed. Results: At 0.25 ng/ml, FGF-2 did not affect proliferation in either cell lines. 25μM of 5-FU resulted in 50% kill in both cell lines. Significant cell survival was observed when FGF-2 (0.25 ng/ml) pre-treated SW620 cells were exposed to 5-FU (25 μM) compared to cells exposed to 5-FU alone (81% vs 60%, p=0.015). This chemoresistance was associated with attenuation of cellular apoptosis (p=0.04) with no significant change in expression of Bcl-2 and Bcl-XL at gene or protein level. This survival advantage was not seen in SW480 cells (59% vs 55%, p=0.35). There were no observed differences in the expression of FGFR1-4 in either cell lines. Conclusion: FGF-2 offers chemoresistance to SW620 and not to SW480 cells exposed to 5-FU. Both cell lines expressed fgf2 and fgfr1-4 genes, suggesting that fgfr expression does not account for the difference in chemoresistance. FGF-2 offered protection by causing significant reduction in chemotherapy induced apoptosis in SW620 colon cancer cell line; however this was not due to increased expression of anti-apoptotic proteins. The molecular mechanisms for this selective chemoprotection need to be investigated further

Fibroblast growth factor-2, chemoresistance and colorectal cancer

Introduction: The role of fibroblast growth factor-2 (FGF-2) on colorectal cancer (CRC) cells exposed to chemotherapy has not been studied extensively. This thesis investigated whether FGF-2 mediates chemoresistance in primary (SW480) and metastatic (SW620) colon adenocarcinoma cell lines. Methods: Proliferation assays were used to assess the response of SW480 and SW620 colon cancer cell lines to varying concentrations of FGF-2 and to optimise the dose of 5- FU at which 50% cell death was observed. Cell survival assays were performed following 96 hours exposure to 5-FU ± FGF-2. Levels of chemotherapy induced apoptosis were determined using Caspase-3/7 assay. Expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) and FGFRs at both protein and gene level were determined to see if these contributed to the difference in chemoprotection observed. Results: At 0.25 ng/ml, FGF-2 did not affect proliferation in either cell lines. 25μM of 5-FU resulted in 50% kill in both cell lines. Significant cell survival was observed when FGF-2 (0.25 ng/ml) pre-treated SW620 cells were exposed to 5-FU (25 μM) compared to cells exposed to 5-FU alone (81% vs 60%, p=0.015). This chemoresistance was associated with attenuation of cellular apoptosis (p=0.04) with no significant change in expression of Bcl-2 and Bcl-XL at gene or protein level. This survival advantage was not seen in SW480 cells (59% vs 55%, p=0.35). There were no observed differences in the expression of FGFR1-4 in either cell lines. Conclusion: FGF-2 offers chemoresistance to SW620 and not to SW480 cells exposed to 5-FU. Both cell lines expressed fgf2 and fgfr1-4 genes, suggesting that fgfr expression does not account for the difference in chemoresistance. FGF-2 offered protection by causing significant reduction in chemotherapy induced apoptosis in SW620 colon cancer cell line; however this was not due to increased expression of anti-apoptotic proteins. The molecular mechanisms for this selective chemoprotection need to be investigated further.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Management of acute and chronic iliofemoral venous outflow obstruction: a multidisciplinary team consensus.

The aim of this manuscript was to establish a consensus for the management of acute and chronic venous obstruction among specialists in the UK. Specialist physicians representing vascular surgery, interventional radiology and hematology were invited to 3 meetings to discuss management of acute and chronic iliofemoral obstruction. The meetings outlined controversial areas, included a topic-by-topic review; and on completion reached a consensus when greater than 80% agreement was reached on each topic. Physicians from 19 UK hospitals agreed on treatment protocols and highlighted areas that need development. Potential standard treatment algorithms were created. It was decided to establish a national registry of venous patients led by representatives from the treating multidisciplinary teams. Technical improvements have facilitated invasive treatment of patients with acute and chronic venous obstruction; however, the evidence guiding treatment is weak. Treatment should be conducted in centers with multi-disciplinary input; robust, coordinated data collection; and regular outcome analysis to ensure safe and effective treatment and a basis for future evolvement

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially