Cancer survival in Australia 1992–1997 : geographic categories and socioeconomic status

Cancer Survival in Australia 1992-1997 is the first national analysis of how cancer survival varies by socioeconomic status and geographic region. It presents an analysis of five-year relative survival proportions by geographic category and socioeconomic status for persons diagnosed with cancer during the years 1992-1997.This analysis is presented by age and sex for all cancers (Excluding non-melanocytic skin cancers) combined and for the following National Health Priority Area cancers - colorectal cancer, cancer of the lung, melanoma, cancer of the breast (females only), cancer of the cervix, cancer of the prostate, and non-Hodgkin's lymphoma.This report is the third in a series of three reports on relative survival after being diagnosed with cancer. It is an important reference for all those interested in the health of Australians.

RNAi mediated Tiam1 gene knockdown inhibits invasion of retinoblastoma

T lymphoma invasion and metastasis protein (Tiam1) is up-regulated in variety of cancers and its expression level is related to metastatic potential of the type of cancer. Earlier, Tiam1 was shown to be overexpressed in retinoblastoma (RB) and we hypothesized that it was involved in invasiveness of RB. This was tested by silencing Tiam1 in RB cell lines (Y79 and Weri-Rb1) using siRNA pool, targeting different regions of Tiam1 mRNA. The cDNA microarray of Tiam1 silenced cells showed gene regulations altered by Tiam1 were predominantly on the actin cytoskeleton interacting proteins, apoptotic initiators and tumorogenic potential targets. The silenced phenotype resulted in decreased growth and increased apoptosis with non-invasive characteristics. Transfection of full length and N-terminal truncated construct (C1199) clearly revealed membrane localization of Tiam1 and not in the case of C580 construct. F-actin staining showed the interaction of Tiam1 with actin in the membrane edges that leads to ruffling, and also imparts varying invasive potential to the cell. The results obtained from our study show for the first time that Tiam1 modulates the cell invasion, mediated by actin cytoskeleton remodeling in RB.

Radiotherapy in the Barwon South Western Region: a rural perspective

Introduction: Cancer-related mortality rates are higher in rural areas compared with urban regions. Whether there are corresponding geographical variations in radiotherapy utilisation rates (RURs) is the subject of this study. Methods: RURs for the regional centre of Geelong and rural areas of the Barwon South Western Region were calculated using a population-based database (2009). Results: Lower RURs were observed for rural patients compared with the Geelong region for prostate cancer (15.7% vs 25.8%, P = 0.02), rectal cancer (32.8% vs 44.7%, P = 0.11), lymphoma (9.4% vs 26.2%, P = 0.05), and all cancers overall (25.6% vs 28.9%, P = 0.06). This lower rate was significant in men (rural, 19.9%; Geelong, 28.3%; P = 0.00) but not in women (rural, 33.6%; Geelong, 29.7%; P = 0.88). Time from diagnosis to radiotherapy was not significantly different for patients from the two regions. Tumour staging within the rural and Geelong regions was not significantly different for the major tumour streams of rectal, prostate and lung cancer (P = 0.61, P = 0.79, P = 0.43, respectively). A higher proportion of tumours were unstaged or unstageable in the rural region for lung (44% vs 18%, P < 0.01) and prostate (73% vs 57%, P < 0.01) cancer. Conclusion: Lower RURs were observed in our rural region. Differences found within tumour streams and in men suggest a complexity of relationships that will require further study.

Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (> 50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

Postchemotherapy and tumor-selective targeting with the La-specific DAB4 monoclonal antibody relates to apoptotic cell clearance

Early identification of tumor responses to treatment is crucial for devising more effective and safer cancer treatments. No widely applicable, noninvasive method currently exists for specifically detecting tumor cell death after cytotoxic treatment and thus for predicting treatment outcomes.

Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to-mesenchymal transition and stemness in esophageal squamous cancer cells

Natural and synthetic triterpenoids have been shown to kill cancer cells via multiple mechanisms. The therapeutic effect and underlying mechanism of the synthetic triterpenoid bardoxolone methyl (C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; CDDO-Me) on esophageal cancer are unclear. Herein, we aimed to investigate the anticancer effects and underlying mechanisms of CDDO-Me in human esophageal squamous cell carcinoma (ESCC) cells. Our study showed that CDDO-Me suppressed the proliferation and arrested cells in G2/M phase, and induced apoptosis in human ESCC Ec109 and KYSE70 cells. The G2/M arrest was accompanied with upregulated p21Waf1/Cip1 and p53 expression. CDDO-Me significantly decreased B-cell lymphoma-extra large (Bcl-xl), B-cell lymphoma 2 (Bcl-2), cleaved caspase-9, and cleaved poly ADP ribose polymerase (PARP) levels but increased the expression level of Bcl-2-associated X (Bax). Furthermore, CDDO-Me induced autophagy in both Ec109 and KYSE70 cells via suppression of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. There were interactions between the autophagic and apoptotic pathways in Ec109 and KYSE70 cells subject to CDDO-Me treatment. CDDO-Me also scavenged reactive oxygen species through activation of the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) pathway in Ec109 and KYSE70 cells. CDDO-Me inhibited cell invasion, epithelial-mesenchymal transition, and stemness in Ec109 and KYSE70 cells. CDDO-Me significantly downregulated E-cadherin but upregulated Snail, Slug, and zinc finger E-box-binding homeobox 1 (TCF-8/ZEB1) in Ec109 and KYSE70 cells. CDDO-Me significantly decreased the expression of octamer-4, sex determining region Y-box 2 (Sox-2), Nanog, and B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), all markers of cancer cell stemness, in Ec109 and KYSE70 cells. Taken together, these results indicate that CDDO-Me is a promising anticancer agent against ESCC. Further studies are warranted to explore the molecular targets, efficacy and safety of CDDO-Me in the treatment of ESCC.

The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells

Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.

Molecular insights and oligonucleotide based targeted gene therapy against cancer

The thesis helps to unravel the function of T lymphoma invasion and metastasis protein (TIAM1) and nucleolin, a nucleolar protein in retinoblastoma tumorigenesis. Aptamer based targeted imaging; drug and gene delivery to retinoblastoma and epithelial cancer cells was attained. The work work finally opened up avenues for cancer stem cell targeting using aptamers, imaging of cancer cells using novel bio-orthogonal agent and use of aptamer for blocking the miRNA-17-92 cluster maturation.

Cancer Treatment Survey (CaTS): development and validation of a new instrument to measure patients' preparation for chemotherapy and radiotherapy

Objective: Cancer patients experience high levels of pre-treatment anxiety. Chemotherapy and radiotherapy are threatening medical procedures. Preparation for these procedures should include the provision of sensory and procedural information, and addressing fears. The aim of this study was to develop a cancer treatment survey (CaTS) to assess the preparation for chemotherapy and radiotherapy in cancer patients.

Methods: Drawing on evidence for how to prepare patients for threatening procedures, items were generated by psychosocial/clinical experts and pilot tested with cancer patients. The 36-item draft CaTS was administered to 192 cancer patients commencing chemotherapy for lymphoma, breast or colon cancer. Participants also completed the Hospital Anxiety and Depression Scale (HADS) and basic medical and demographic information was recorded.

Results: A systematic process of item selection removed 11 items. Factor analysis indicated a two-factor solution, with 11 items representing sensory/psychological concerns and 14 items representing procedural concerns. The two subscales demonstrated excellent internal reliability with Cronbach's alpha both over 0.90 and the average inter-item correlation for each scale exceeded 0.30. Divergent validity was established for both CaTS subscales with the HADS-A and-T (all r<0.30). Younger participants (under 65 years of age) had significantly greater procedural concerns (p = 0.001; medium effect).

Conclusions: The CaTS is a two factor, 25-item measure that assesses sensory/psychological concerns and procedural concerns relating to cancer treatment. The instrument provides a reliable and valid outcome measure for interventions to prepare cancer patients for chemotherapy and radiotherapy.

A novel aggregate gene selection method for microarray data classification

This paper introduces a novel method for gene selection based on a modification of analytic hierarchy process (AHP). The modified AHP (MAHP) is able to deal with quantitative factors that are statistics of five individual gene ranking methods: two-sample t-test, entropy test, receiver operating characteristic curve, Wilcoxon test, and signal to noise ratio. The most prominent discriminant genes serve as inputs to a range of classifiers including linear discriminant analysis, k-nearest neighbors, probabilistic neural network, support vector machine, and multilayer perceptron. Gene subsets selected by MAHP are compared with those of four competing approaches: information gain, symmetrical uncertainty, Bhattacharyya distance and ReliefF. Four benchmark microarray datasets: diffuse large B-cell lymphoma, leukemia cancer, prostate and colon are utilized for experiments. As the number of samples in microarray data datasets are limited, the leave one out cross validation strategy is applied rather than the traditional cross validation. Experimental results demonstrate the significant dominance of the proposed MAHP against the competing methods in terms of both accuracy and stability. With a benefit of inexpensive computational cost, MAHP is useful for cancer diagnosis using DNA gene expression profiles in the real clinical practice.

NDRG2 promotes myoblast proliferation and caspase 3/7 activities during differentiation, and attenuates hydrogen peroxide - but not palmitate-induced toxicity

The function of the stress-responsive N-myc downstream-regulated gene 2 (NDRG2) in the control of myoblast growth, and the amino acids contributing to its function, are not well characterized. Here, we investigated the effect of increased NDRG2 levels on the proliferation, differentiation and apoptosis in skeletal muscle cells under basal and stress conditions. NDRG2 overexpression increased C2C12 myoblast proliferation and the expression of positive cell cycle regulators, cdk2, cyclin B and cyclin D, and phosphorylation of Rb, while the serine/threonine-deficient NDRG2, 3A-NDRG2, had less effect. The onset of differentiation was enhanced by NDRG2 as determined through the myogenic regulatory factor expression profiles and myocyte fusion index. However, the overall level of differentiation in myotubes was not different. While NDRG2 up-regulated caspase 3/7 activities during differentiation, no increase in apoptosis was measured by TUNEL assay or through cleavage of caspase 3 and PARP proteins. During H2O2 treatment to induce oxidative stress, NDRG2 helped protect against the loss of proliferation and ER stress as measured by GRP78 expression with 3A-NDRG2 displaying less protection. NDRG2 also attenuated apoptosis by reducing cleavage of PARP and caspase 3 and expression of pro-apoptotic Bax while enhancing the pro-survival Bcl-2 and Bcl-xL levels. In contrast, Mcl-1 was not altered, and NDRG2 did not protect against palmitate-induced lipotoxicity. Our findings show that NDRG2 overexpression increases myoblast proliferation and caspase 3/7 activities without increasing overall differentiation. Furthermore, NDRG2 attenuates H2O2-induced oxidative stress and specific serine and threonine amino acid residues appear to contribute to its function in muscle cells.

Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation

 OBJECTIVE: Evidence indicates an increased risk of certain cancers among people with type 2 diabetes. Evidence for rarer cancers and for type 1 diabetes is limited. We explored the excess risk of site-specific cancer incidence and mortality among people with type 1 and type 2 diabetes, compared with the general Australian population. RESEARCH DESIGN AND METHODS: Registrants of a national diabetes registry (953,382) between 1997 and 2008 were linked to national death and cancer registries. Standardized incidence and mortality ratios (SIRs/SMRs) are reported. RESULTS: For type 1 diabetes, significant elevated SIRs were observed for pancreas, liver, esophagus, colon and rectum (females only [F]), stomach (F), thyroid (F), brain (F), lung (F), endometrium, and ovary, and decreased SIRs were observed for prostate in males. Significantly increased SMRs were observed for pancreas, liver, and kidney (males only), non-Hodgkin's lymphoma, brain (F), and endometrium. For type 2 diabetes, significant SIRs were observed for almost all site-specific cancers, with highest SIRs observed for liver and pancreas, and decreased risks for prostate and melanoma. Significant SMRs were observed for liver, pancreas, kidney, Hodgkin's lymphoma, gallbladder (F), stomach (F), and non-Hodgkin's lymphoma (F). Cancer risk was significantly elevated throughout follow-up time but was higher in the first 3 months postregistration, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias. We suggest that screening for cancers in diabetic patients is important.

Increasing BMI was associated with increasing risk for overall cancer incidence and mortality in middle-aged women

Question: In middle-aged women, what is the association between body mass index (BMI) and cancer incidence and mortality?METHODSDesign: Prospective cohort study with mean follow-up of 5.4 years for cancer incidence and 7.0 years for cancer mortality.Setting: Population-based study in England and Scotland, United Kingdom.Patients: 1 222 630 women 55 to 64 years of age (mean 56 y) who had no history of cancer at baseline.Risk factors: BMI at baseline, divided into 5 categories (< 22.5, 22.5 to 24.9, 25.0 to 27.4, 27.5 to 29.9, and ≥ 30 kg/m2).Outcomes: Cancer incidence and mortality, overall and for 17 specific types of cancer, identified through linkage with the National Health Service central registers.Main results: Increasing BMI was associated with increasing risks for all cancers, endometrial cancer, esophageal adenocarcinoma, kidney cancer, leukemia, postmenopausal breast cancer, multiple myeloma, pancreatic cancer, non-Hodgkin lymphoma, and ovarian cancer; and with decreasing risks for esophageal squamous cell carcinoma, lung cancer, and premenopausal breast cancer (Table). Risks for stomach, colorectal, cervical, bladder, and brain cancer and malignant melanoma did not vary by BMI. Patterns for cancer mortality were similar to those for cancer incidence: Relative risk for death from any type of cancer was 1.06 (95% CI 1.02 to 1.10) per 10-unit increase in BMI. In postmenopausal women, the estimated proportion of cancer attributable to being overweight or obese (BMI ≥ 25 kg/m2) was 5% for all cancers and about 50% for endometrial cancer and esophageal adenocarcinoma.Conclusions: In middle-aged women, increasing body mass index was associated with increasing risk for cancer incidence and mortality overall. High body mass index increased risk for some types of cancer but reduced risk for other types.

Modified AHP for gene selection and cancer classification using type-2 fuzzy logic

This paper proposes a modification to the analytic hierarchy process (AHP) to select the most informative genes that serve as inputs to an interval type-2 fuzzy logic system (IT2FLS) for cancer classification. Unlike the conventional AHP, the modified AHP allows us to process quantitative factors that are ranking outcomes of individual gene selection methods including t-test, entropy, receiver operating characteristic curve, Wilcoxon test, and signal-to-noise ratio. The IT2FLS is introduced for the classification task due to its great ability for handling nonlinear, noisy, and outlier data, which are common problems in cancer microarray gene expression profiles. An unsupervised learning strategy using the fuzzy c-means clustering is employed to initialize parameters of the IT2FLS. Other classifiers such as multilayer perceptron network, support vector machine, and fuzzy ARTMAP are also implemented for comparisons. Experiments are carried out on three well-known microarray datasets: diffuse large B-cell lymphoma, leukemia cancer, and prostate. Rather than the traditional cross validation, leave-one-out cross-validation strategy is applied for the experiments. Results demonstrate the performance dominance of the IT2FLS against the competing classifiers. More noticeably, the modified AHP improves the classification performance not only of the IT2FLS but of all other classifiers as well. Accordingly, the proposed combination between the modified AHP and IT2FLS is a powerful tool for cancer classification and can be implemented as a real clinical decision support system that is useful for medical practitioners.