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‣ Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent

Pantziarka, Pan; Bouche, Gauthier; Meheus, Lydie; Sukhatme, Vidula; Sukhatme, Vikas P
Fonte: Cancer Intelligence Publicador: Cancer Intelligence
Tipo: Artigo de Revista Científica
Português
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Mebendazole, a well-known anti-helminthic drug in wide clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types. Significantly, there are also two case reports of anti-cancer activity in humans. The data are summarised and discussed in relation to suggested mechanisms of action. Based on the evidence presented, it is proposed that mebendazole would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of mebendazole as an anti-cancer therapeutic is warranted. A number of possible combinations with other drugs are discussed in the Appendix.

‣ A polymorphism in the TC21 promoter associates with an unfavorable tamoxifen treatment outcome in breast cancer

Rokavec, M.; Schroth, W.; Amaral, S.; Fritz, P.; Antoniadou, L.; Glavac, D.; Simon, W.; Schwab, M.; Eichelbaum, M.; Brauch, H.
Fonte: American Association for Cancer Research Publicador: American Association for Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Tamoxifen therapy is a standard in the treatment of estrogen receptor (ER)-positive breast cancer; however, its efficacy varies widely among patients. In addition to interpatient differences in the tamoxifen-metabolizing capacity, there is growing evidence that crosstalk between ER and growth factor signaling contributes to tamoxifen resistance. We focused on TC21, a member of the Ras superfamily, to investigate the influence of the TC21 –582C>T promoter polymorphism on TC21 expression and treatment outcome. Immunohistochemical analyses of breast tumors revealed a higher TC21 expression in ER-negative compared with ER-positive tumors. Expression in ER-positive tumors was higher in carriers of the T allele in an allele dose–dependent manner. Quantitative real-time PCR analyses showed that TC21 mRNA expression is decreased after transfection of ER in ER-negative breast cancer cells MDA-MB-231, UACC893, and BT-20. In MCF7 ER-positive cells, TC21 expression decreased with 17β-estradiol treatment and increased after treatment with tamoxifen metabolites, 4-OH-tamoxifen, or endoxifen. In patients treated with adjuvant mono tamoxifen, high cytoplasmic TC21 tumor expression or the carriership of the –582T allele conferred increased recurrence rates [n = 45: hazard ratio (HR)...

‣ Attitudes Towards and Beliefs about Colorectal Cancer and Screening using the Faecal Occult Blood Test within the Italian-Australian Community

Severino, G.; Wilson, C.; Turnbull, D.; Duncan, A.; Gregory, T.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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Studies with minority ethnic communities worldwide reveal important differences in the content of beliefs about cancer and attitudes towards screening. Current initiatives in colorectal cancer (CRC) screening highlight the importance of identifying any illness-specific beliefs that might influence participation rates within the targeted age-range. We conducted semi-structured interviews with 20 Italian-Australians aged between 50 and 78 years, living in Adelaide, South Australia. Qualitative data from the interviews were analysed using framework analysis. Participants articulated specific beliefs about the nature of cancer, risk factors, prevention possibilities, and variety of potential barriers and benefits to faecal occult blood testing (FOBT). Although participants’ beliefs overlapped with conventional medical models of cancer, the results also demonstrated the presence of specific cultural perceptions that might influence FOBT participation. Our results suggest that models used to inform communication about cancer need to be sensitive to culture specific concerns. Within the context of the older Italian-Australian community, there is a suggestion that self and response efficacy may be serious barriers to screening behavior and that bi-lingual...

‣ Cancer in aboriginal and Torres Strait Islander people of Australia

Roder, D.; Currow, D.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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Aboriginal and Torres Strait Islander Australians have a cancer incidence for all sites combined equivalent to or slightly lower than for other Australians. They have a higher incidence of cancers of the cervix, liver and gallbladder, oesophagus, unknown primary site, mouth and throat, lung and pancreas, but a lower incidence of cancers of the prostate, female breast, colon/rectum and skin (melanoma). Case survivals are lower for Aboriginal and Torres Strait Islander patients, partly due to an excess of cancer types with a high case fatality, relatively low numbers with a low case fatality, and due to more advanced cancer stages at diagnosis. After accounting for these factors, Aboriginal and Torres Strait Islander Australians still fare worse, probably due to elevated comorbidity and less complete care resulting from geographic remoteness, limited access to transport and accommodation services, and sometimes a cultural disconnect with mainstream services.; David Roder and David Currow

‣ Circulating steroid hormone levels and risk of breast cancer for postmenopausal women

Baglietto, L.; Severi, G.; English, D.; Krishnan, K.; Hopper, J.; McLean, C.; Morris, H.; Tilley, W.; Giles, G.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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Epidemiologic studies have consistently reported that endogenous steroid hormone levels are associated with postmenopausal breast cancer risk, but little is known on the associations by tumor grade, hormone receptor status, or age at diagnosis. We performed a case-cohort study of naturally postmenopausal women within the Melbourne Collaborative Cohort Study that included a random sample of 857 women and 197 breast cancer cases diagnosed during a mean of 9.2 years of follow-up. Concentrations of total estradiol, estrone sulfate, testosterone, DHEA sulfate, androstenedione, and sex hormone binding globulin were measured in plasma collected at baseline before diagnosis; free estradiol plasma concentration was calculated. Cox regression was used to estimate associations adjusted for known and potential confounders. The HR for breast cancer comparing fourth and first quartiles was 1.44 [95% confidence interval (95% CI), 0.89-2.35] for total estradiol, 1.75 (95% CI, 1.06, 2.89) for free estradiol, 2.05 (95% CI, 1.24-3.37) for estrone sulfate, 1.25 (95% CI, 0.78-2.01) for testosterone, 1.41 (95% CI, 0.88-2.27) for DHEA sulfate, 1.49 (95% CI, 0.91-2.44) for androstenedione, and 0.33 (95% CI, 0.19-0.55) for sex hormone binding globulin. These associations did not differ by tumor grade and estrogen receptor/progesterone receptor status (all test for heterogeneity...

‣ Exploring differences in survival from cancer among indigenous and non-indigenous Australians: Implications for health service delivery and research

Chong, A.; Roder, D.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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The aim of this study is to compare cancer survivals of Indigenous and non-Indigenous Australians and consider health-service and research implications Cancer registry data from South Australia were used to calculate disease-specific survivals for Indigenous (n=671) and sampled non-Indigenous (n=15,799) patients diagnosed during 1977-2007, using Kaplan-Meier estimates and Cox proportional hazards regression. Indigenous and non-Indigenous five-year survivals were respectively: 40% and 57% for all cancer sites combined; 61% and 80% for female breast; 34% and 56% for colon/rectum; and 63% and 73% for cervix; whereas one-year survivals for cancers of unknown primary site were 5% and 22% respectively. Conversely, although not statistically significant (p=0.262), lung cancer survival tended to be higher in Indigenous than non-Indigenous patients. For all sites combined, Indigenous patients had lower survivals up to 70-79 years. The relative risk of death in Indigenous compared with non-Indigenous patients was 2.0 after adjusting for socio-demographic factors and diagnostic period, reducing to 1.4 when also adjusting for prognosis by primary site. Relative risks were 3.7 and 2.7 respectively for Indigenous compared with non-Indigenous patients from Far North remote communities. We conclude that relative risks for Indigenous compared with non-Indigenous patients for all cancers combined are elevated...

‣ Translating evidence into practice in low resource settings: cervical cancer screening tests are only part of the solution in rural India

Isaac, R.; Finkel, M.; Olver, I.; Annie, I.; Prashanth, H.; Subhashini, J.; Viswanathan, P.; Trevena, L.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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BACKGROUND: The majority of women in rural India have poor or no access to cervical cancer screening services, although one.quarter of all cervical cancers in the world occur there. Several large trials have proven the efficacy of low-tech cervical cancer screening methods in the Indian context but none have documented the necessary components and processes of implementing this evidence in a low-resource setting. METHODS: This paper discusses a feasible model of implementation of cervical cancer screening programme in low-resource settings developed through a pilot research project carried out in rural Tamilnadu, India. The programme used visual inspection of cervix after acetic acid application (VIA) as a screening tool, nurses in the primary care centres as the primary screeners and peer educators within Self-Help Women groups to raise community awareness. RESULTS: The uptake of screening was initially low despite the access to a screening programme. However, the programme witnessed an incremental increase in the number of women accessing screening with increasing community awareness. CONCLUSIONS: The investigators recommend 4 key components to programme implementation in low-resource setting: 1) Evidence-based, cost-effective test and treatment available within the reach of the community; 2) Appropriate referral pathways; 3) Skilled health workers and necessary equipment; and 4) Optimisation of health literacy...

‣ Survival from synchronous bilateral breast cancer: The experience of surgeons participating in the breast audit of the Society of Breast Surgeons of Australia and New Zealand

Roder, D.; De Silva, P.; Zorbas, H.; Kollias, J.; Malycha, P.; Pyke, C.; Campbell, I.; Webster, F.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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Background: Previous studies generally indicate that synchronous bilateral breast cancers (SBBC) have an equivalent or moderately poorer survival compared with unilateral cases. The prognostic characteristics of SBBC would be relevant when planning adjuvant therapies and follow-up medical surveillance. The frequency of SBBC among early breast cancers in clinical settings in Australia and New Zealand was investigated, plus their prognostic significance, using the Breast Cancer Audit Database of the Society of Breast Surgeons of Australia and New Zealand, which covered an estimated 60% of early invasive lesions in those countries. Design: Rate ratios (95% confidence limits) of SBBC were investigated among 35,370 female breast cancer cases by age of woman, histology type, grade, tumour diameter, nodal status, lymphatic/vascular invasion and oestrogen receptor status. Univariate and multivariable disease-specific survival analyses were undertaken. Results: 2.3% of cases were found to be SBBC (i.e., diagnoses occurring within 3 months). The figure increased from 1.4% in women less than 40 years to 4.1% in those aged 80 years or more. Disease-specific survivals did not vary by SBBC status (p=0.206). After adjusting for age, histology type...

‣ Risk factors for poorer breast cancer outcomes in residents of remote areas of Australia

Roder, D.; Zorbas, H.; Kollias, J.; Pyke, C.; Walters, D.; Campbell, I.; Taylor, C.; Webster, F.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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To investigate patient, cancer and treatment characteristics in females with breast cancer from more remote areas of Australia, to better understand reasons for their poorer outcomes, bi-variable and multivariable analyses were undertaken using the National Breast Cancer Audit database of the Society of Breast Surgeons of Australia and New Zealand. Results indicated that patients from more remote areas were more likely to be of lower socio-economic status and be treated in earlier diagnostic epochs and at inner regional and remote rather than major city centres. They were also more likely to be treated by low case load surgeons, although this finding was only of marginal statistical significance in multivariable analysis (p=0.074). Patients from more remote areas were less likely than those from major cities to be treated by breast conserving surgery, as opposed to mastectomy, and less likely to have adjuvant radiotherapy when having breast conserving surgery. They had a higher rate of adjuvant chemotherapy. Further monitoring will be important to determine whether breast conserving surgery and adjuvant radiotherapy utilization increase in rural patients following the introduction of regional cancer centres recently funded to improve service access in these areas.; David Roder...

‣ Epidemiology of Oral Cancer in Asia in the Past Decade- An Update (2000-2012)

Krishna Rao, S.; Mejia, G.; Roberts-Thomson, K.; Logan, R.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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The prevalence of oral cancers (OC) is high in Asian countries, especially in South and Southeast Asia. Asian distinct cultural practices such as betel-quid chewing, and varying patterns of tobacco and alcohol use are important risk factors that predispose to cancer of the oral cavity. The aim of this review is to provide an update on epidemiology of OC between 2000 and 2012. A literature search for this review was conducted on Medline for articles on OC from Asian countries. Some of the articles were also hand searched using Google. High incidence rates were reported from developing nations like India, Pakistan, Bangladesh, Taiwan and Sri Lanka. While an increasing trend has been observed in Pakistan, Taiwan and Thailand, a decreasing trend is seen in Philippines and Sri Lanka. The mean age of occurrence of cancer in different parts of oral cavity is usually between 51-55 years in most countries. The tongue is the leading site among oral cancers in India. The next most common sites in Asian countries include the buccal mucosa and gingiva. The 5 year survival rate has been low for OC, despite improvements in diagnosis and treatment. Tobacco chewing, smoking and alcohol are the main reasons for the increasing incidence rates. Low socioeconomic status and diet low in nutritional value lacking vegetables and fruits contribute towards the risk. In addition...

‣ Colorectal cancer treatment and survival : the experience of major public hospitals in South Australia over three decades

Roder, D.; Karapetis, C.S.; Wattchow, D.; Moore, J.; Singhal, N.; Joshi, R.; Keefe, D.; Fusco, K.; Powell, K.; Eckert, M.; Price, T.J.
Fonte: National Cancer Center Publicador: National Cancer Center
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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BACKGROUND: Registry data from four major public hospitals indicate trends in clinical care and survival from colorectal cancer over three decades, from 1980 to 2010. MATERIALS AND METHODS: Kaplan-Meier product- limit estimates and Cox proportional hazards models were used to investigate disease-specific survival and multiple logistic regression analyses to explore first-round treatment trends. RESULTS: Five-year survivals increased from 48% for 1980-1986 to 63% for 2005-2010 diagnoses. Survival increases applied to each ACPS stage (Australian Clinico-Pathological Stage), and particularly stage C (an increase from 38% to 68%). Risk of death from colorectal cancer halved (hazards ratio: 0.50 (0.45, 0.56)) over the study period after adjusting for age, sex, stage, differentiation, primary sub-site, health administrative region, and measures of socioeconomic status and geographic remoteness. Decreases in stage were not observed. Survivals did not vary by sex or place of residence, suggesting reasonable equity in service access and outcomes. Of staged cases, 91% were treated surgically with lower surgical rates for older ages and more advanced stage. Proportions of surgical cases having adjuvant therapy during primary courses of treatment increased for all stages and were highest for stage C (an increase from 5% in 1980-1986 to 63% for 2005-2010). Radiotherapy was more common for rectal than colonic cases. Proportions of rectal cases receiving radiotherapy increased...

‣ Gynecological conditions and the risk of endometrial cancer

Rowlands, I.J.; Nagle, C.M.; Spurdle, A.B.; Webb, P.M.; Oehler, M.K.; Australian National Endometrial Cancer Study Group; Australian Ovarian Cancer Study Group
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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Abstract not available; Ingrid J. Rowlands, Christina M. Nagle, Amanda B. Spurdle, Penelope M. Webb, Australian National Endometrial Cancer Study Group, Australian Ovarian Cancer Study Group; Martin Oehler is a member of the Australian National Endometrial Cancer Study Group and the Australian Ovarian Cancer Study Group

‣ Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development

Bianco-Miotto, T.; Chiam, K.; Buchanan, G.; Jindal, S.; Day, T.; Thomas, M.; Pickering, M.; O'Loughlin, M.; Ryan, N.; Raymond, W.; Horvath, L.; Kench, J.; Stricker, P.; Marshall, V.; Sutherland, R.; Henshall, S.; Gerald, W.; Scher, H.; Risbridger, G.; Cle
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
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BACKGROUND: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. METHODS: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. RESULTS: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. CONCLUSIONS: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. IMPACT: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover...

‣ Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer – a population-based study

Jordan, S.; Steer, C.; DeFazio, A.; Quinn, M.; Obermair, A.; Friedlander, M.; Francis, J.; O'Brien, S.; Goss, G.; Wyld, D.; Australian Ovarian Cancer Study Group; Webb, P.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Abstract not available; S. Jordan, C. Steer, A. DeFazio, M. Quinn, A. Obermair, M. Friedlander, J. Francis, S. O'Brien, G. Goss, D. Wyld, Australian Ovarian Cancer Study Group, P. Webb, for the Ovarian Cancer Patterns of Care Study Group; Martin K. Oehler is a member of the Australian Ovarian Cancer Study Group and the Patterns of Care Study Group

‣ Adherence to recommended treatments for early invasive breast cancer: decisions of women attending surgeons in the Breast Cancer Audit of Australia and New Zealand

Roder, D.; De Silva, P.; Zorbas, H.; Webster, F.; Kollias, J.; Pyke, C.; Campbell, I.
Fonte: Asian Pacific Organization for Cancer Prevention Publicador: Asian Pacific Organization for Cancer Prevention
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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AIM: The study aim was to determine the frequency with which women decline clinicians' treatment recommendations and variations in this frequency by age, cancer and service descriptors. DESIGN: The study included 36,775 women diagnosed with early invasive breast cancer in 1998-2005 and attending Australian and New Zealand breast surgeons. Rate ratios for declining treatment were examined by descriptor, using bilateral and multiple logistic regression analyses. Proportional hazards regression was used in exploratory analyses of associations with breast cancer death. RESULTS: 3.4% of women declined a recommended treatment of some type, ranging from 2.6% for women under 40 years to 5.8% for those aged 80 years or more, and with parallel increases by age presenting for declining radiotherapy (p<0.001) and axillary surgery (p=0.006). Multiple regression confirmed that common predictors of declining various treatments included low surgeon case load, treatment outside major city centres, and older age. Histological features suggesing a favourable prognosis were often predictive of declining various treatments, although reverse findings also applied with women with positive nodal status being more likely to decline a mastectomy and those with larger tumours more likely to decline chemotherapy. While survival anlsysi lacked statistical power due to small numbers...

‣ A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells

Butt, Alison J; Roberts, Caroline G; Seawright, Alan A; Oelrichs, Peter B; MacLeod, John; Liaw, Tracy Y E; Kavallaris, Maria; Somers-Edgar, Tiffany J; Lehrbach, Gillian M; Watts, Colin K; Sutherland, Robert L
Fonte: American Association for Cancer Research Publicador: American Association for Cancer Research
Tipo: Artigo de Revista Científica
Português
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Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and

‣ Comparison of quality of life after stereotactic body radiotherapy and surgery for early-stage prostate cancer

Katz, Alan; Ferrer Forés, Maria Montserrat; Suárez Novo, José Francisco
Fonte: Universidade Autônoma de Barcelona Publicador: Universidade Autônoma de Barcelona
Tipo: Artigo de Revista Científica Formato: application/pdf
Publicado em //2012 Português
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Background: As the long-term efficacy of stereotactic body radiation therapy (SBRT) becomes established and other prostate cancer treatment approaches are refined and improved, examination of quality of life (QOL) following prostate cancer treatment is critical in driving both patient and clinical treatment decisions. We present the first study to compare QOL after SBRT and radical prostatectomy, with QOL assessed at approximately the same times pre- and post-treatment and using the same validated QOL instrument. Methods: Patients with clinically localized prostate cancer were treated with either radical prostatectomy (n = 123 Spanish patients) or SBRT (n = 216 American patients). QOL was assessed using the Expanded Prostate Cancer Index Composite (EPIC) grouped into urinary, sexual, and bowel domains. For comparison purposes, SBRT EPIC data at baseline, 3 weeks, 5, 11, 24, and 36 months were compared to surgery data at baseline, 1, 6, 12, 24, and 36 months. Differences in patient characteristics between the two groups were assessed using Chi-squared tests for categorical variables and t-tests for continuous variables. Generalized estimating equation (GEE) models were constructed for each EPIC scale to account for correlation among repeated measures and used to assess the effect of treatment on QOL. Results: The largest differences in QOL occurred in the first 1–6 months after treatment...

‣ Mouse models of colorectal cancer as preclinical models

McIntyre, Rebecca E.; Buczacki, Simon J. A.; Arends, Mark J.; Adams, David J.
Fonte: Cancer Research UK Cambridge Institute, University of Cambridge Publicador: Cancer Research UK Cambridge Institute, University of Cambridge
Tipo: Article; published version
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This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/bies.201500032; In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative ?omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection.; REM, SJAB, MJA and DJA are funded by Cancer Research UK.

‣ Risk prediction models for colorectal cancer: a systematic review

Usher-Smith, Juliet A.; Walter, Fiona M.; Emery, Jon D.; Win, Aung K.; Griffin, Simon J.
Fonte: American Association for Cancer Research Publicador: American Association for Cancer Research
Tipo: Article; accepted version
Português
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This is the author accepted manuscript. The final version is available from American Association for Cancer Research via http://dx.doi.org/10.1158/1940-6207.CAPR-15-0274; Colorectal cancer (CRC) is the second leading cause of cancer-related death in Europe and the United States. Survival is strongly related to stage at diagnosis and population-based screening reduces CRC incidence and mortality. Stratifying the population by risk offers the potential of improving the efficiency of screening. In this systematic review we searched Medline, EMBASE and the Cochrane Library for primary research studies reporting or validating models to predict future risk of primary CRC for asymptomatic individuals. 12,808 papers were identified from the literature search and nine through citation searching. 52 risk models were included. Where reported (n=37), half the models had acceptable-to-good discrimination (c-statistic>0.7) in the derivation sample. Calibration was less commonly assessed (n=21), but overall acceptable. In external validation studies, 10 models showed acceptable discrimination (c-statistic 0.71-0.78). These include two with only three variables (age, gender and BMI; age, gender and family history of CRC). A small number of prediction models developed from case-control studies of genetic biomarkers also show some promise but require further external validation using population-based samples. Further research should focus on the feasibility and impact of incorporating such models into stratified screening programmes.; J Usher-Smith is funded by a National Institute of Health Research (NIHR) Clinical Lectureship and F Walter by an NIHR Clinician Scientist award. J Emery is funded by an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship. A Wong has an NHMRC Early Career Fellowship. The views expressed in this publication are those of the authors and not necessarily those of the NHS...

‣ Human GINS, a conserved DNA replication factor and candidate cancer marker

Marinsek, Nina
Fonte: University of Cambridge; MRC Cancer Cell Unit; Department of Oncology Publicador: University of Cambridge; MRC Cancer Cell Unit; Department of Oncology
Tipo: Thesis; doctoral; PhD
Português
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The GINS complex (a heterotetramer of Sld5, Psf1, Psf2 and Psf3) is a highly conserved DNA replication factor required for the initiation and elongation of DNA replication. GINS is believed to associate with Cdc45 and MCM proteins on replicating DNA. The interaction between GINS and MCM is also conserved in archaea. In my thesis, I explore the subcellular localisation of the GINS complex in relation to the MCM proteins and sites of DNA replication by high-resolution confocal microscopy. For these studies, I generated and carefully validated purified rabbit polyclonal and mouse monoclonal antibodies; these show a specific staining pattern by immunohistochemistry, immunoblotting and immunofluorescence. At high-resolution, all GINS antibodies produced a focal nuclear pattern, similar to that seen for the MCMs. However, confusingly, colocalisation between GINS and MCMs and between the GINS subunits themselves is poor. Investigations are continuing to understand this conundrum. Given the value of MCM proteins as specific and sensitive markers for cancer screening, I investigated whether GINS subunits also have potential diagnostic value. Sld5 and Psf3 expression is restricted to the proliferative compartment in normal tissue, but is found in the majority of cells in a wide range of dysplastic and malignant tissues...