Expression Profiling of Nucleotide Metabolism-Related Genes in Human Breast Cancer Cells After Treatment with 5-Fluorouracil

5-Fluorouracil (5-FU) is one of the most widely used drugs for treatment of cancers, including breast cancer that exhibits its anticancer activity by inhibiting DNA synthesis and also incorporated into DNA and RNA. The objective of this investigation was to find out the total nucleotide metabolism genes regulated by 5-FU in breast cancer cell line. The breast cancer cell line MCF-7 was treated with the drug 5-FU. To analyze the expression of genes, we have conducted the experiment using 1.7k and 19k human microarray slide and confirmed the expression of genes by semiquantitative reverse transcription-polymerase chain reaction. The expression of 44 genes involved in the nucleotide metabolism pathway was quantified. Of these 44 genes analyzed, transcription of 6 genes were upregulated and 9 genes were downregulated. Earlier studies revealed that the transcription of genes for key enzymes like thymidylate synthase, thymidinekinase, and dihydropyrimidine dehydrogenase are regulated by 5-FU. This study identified some novel genes like thioredoxin reductase, ectonucleotide triphosphate dephosphorylase, and CTP synthase are regulated by 5-FU. The data also reveal large-scale perturbation in transcription of genes not involved directly in the known mechanism of action of 5-FU.

Glucosinolate composition and anti-cancer potential of daikon and radish sprouts

Daikon and radish sprouts contain high levels of glucoraphenin, a glucosinolate which hydrolyses to form sulphoraphene. Sulphoraphene, like sulphoraphane from broccoli, is a potent inducer of phase 2 detoxification enzymes and consequently has potential anti-cancer action. Unlike broccoli however, daikon and radish do not possess epithiospecifier protein, a protein that inhibits conversion of glucosinolates to isothiocyanates, and consequently they may represent more suitable sources of phyto-chemicals with anti-cancer potential. Concentrations of glucoraphenin were highest in the seed, declining exponentially with sprout development. The rate of decline was observed to vary considerably between varieties of daikon and radish, with some varieties maintaining significantly high levels of glucoraphenin. Varieties maintaining a high level of glucoraphenin included 'Cherry Belle' and 'French Breakfast'.

CBCT-guided radiotherapy for locally advanced head and cancer: dosimetric impact of weight loss on VMAT and IMRT plans for selected organs at risk structures (OARs)

Purpose: It is common for head and neck patients to be affected by time trend errors as a result of weight loss during a course of radiation treatment. The objective of this planning study was to investigate the impact of weight loss on Volumetric Modulated Arc Therapy (VMAT) as well as Intensity modulated radiation therapy (IMRT) for locally advanced head and neck cancer using automatic co-registration of the CBCT. Methods and Materials: A retrospective analysis of previously treated IMRT plans for 10 patients with locally advanced head and neck cancer patients was done. A VMAT plan was also produced for all patients. We calculated the dose–volume histograms (DVH) indices for spinal cord planning at risk volumes (PRVs), the brainstem PRVs (SC+0.5cm and BS+0.5cm, respectively) as well as mean dose to the parotid glands. Results: The results show that the mean difference in dose to the SC+0.5cm was 1.03% and 1.27% for the IMRT and VMAT plans, respectively. As for dose to the BS+0.5, the percentage difference was 0.63% for the IMRT plans and 0.61% for the VMAT plans. The analysis of the parotid gland doses shows that the percentage change in mean dose to left parotid was -8.0% whereas that of the right parotid was -6.4% for the IMRT treatment plans. In the VMAT plans, the percentages change for the left and the right parotid glands were -6.6% and -6.7% respectively. Conclusions: This study shows a clinically significant impact of weight loss on DVH indices analysed in head and neck organs at risk. It highlights the importance of adaptive radiotherapy in head and neck patients if organ at risk sparing is to be maintained.

Epithelial-mesenchymal axis in head and neck cancer cell lines

Objectives: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumour type which necessitates multiple invitro models to attain an appreciation of its multiple subtypes. The phenomenon of epithelial-mesenchymal transition (EMT) isimportant to the development of a metastatic cancer cell phenotype being relevant to the ability of cancer cells to intravasate intovasculature and to invade tissues. The role of EMT in human papilloma virus (HPV) positive HNSCC is not well understood. Thispaper aims to characterize seven HNSCC cell lines (FaDu, SCC-25, SCC-15, CAL27, RPMI2650) including two new HPV-16positive HNSCC cell lines (UD-SCC2, 93-VU-147T) for their epithelial and mesenchymal properties. Materials and methods: A panel of HNSCC cell lines from multiple head and neck anatomical sites were profiled for basalexpression of epithelial and mesenchymal characteristics at mRNA, protein and functional levels (proliferative, migratory andinvasive properties). Furthermore, 3D spheroid forming capabilities were investigated. Results: We found that the HPV-16 positive cell line, in particular UD-SCC2 demonstrated a more invasive and mesenchymalphenotype at the molecular and functional levels suggesting HPV infection may mediate some of these cellular properties.Moreover, HPV-negative cell lines were not strictly epithelial presenting with a dynamic range of expression. Conclusions: This study presents the molecular and phenotypic diversity of HNSCC cell lines. It highlights the need formore studies in this field and a scoring system where HNSCC cell lines are ranked according to their respective epithelial andmesenchymal nature. This data will be useful to anyone modelling HNSCC behaviour, providing a molecular context which willenable them to decipher cell phenotypes and to develop therapies which block EMT progression.

Adipocytes promote prostate cancer stem cell self-renewal through amplification of the cholecystokinin autocrine loop

Obesity has long been linked with prostate cancer progression, although the underlying mechanism is still largely unknown. Here, we report that adipocytes promote the enrichment of prostate cancer stem cells (CSCs) through a vicious cycle of autocrine amplification. In the presence of adipocytes, prostate cancer cells actively secrete the peptide hormone cholecystokinin (CCK), which not only stimulates prostate CSC self-renewal, but also induces cathepsin B (CTSB) production of the adipocytes. In return, CTSB facilitates further CCK secretion by the cancer cells. More importantly, inactivation of CCK receptor not only suppresses CTSB secretion by the adipocytes, but also synergizes the inhibitory effect of CTSB inhibitor on adipocyte-promoted prostate CSC self-renewal. In summary, we have uncovered a novel mechanism underlying the mutual interplay between adipocytes and prostate CSCs, which may help explaining the role of adipocytes in prostate cancer progression and provide opportunities for effective intervention.

Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1

Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgenindependent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers.

The impact of inter-fraction set-up errors on the probability of pulmonary and cardiac complication in left-sided breast cancer patients

Purpose This study evaluated the impact of patient set-up errors on the probability of pulmonary and cardiac complications in the irradiation of left-sided breast cancer. Methods and Materials Using the CMS XiO Version 4.6 (CMS Inc., St Louis, MO) radiotherapy planning system's NTCP algorithm and the Lyman -Kutcher-Burman (LKB) model, we calculated the DVH indices for the ipsilateral lung and heart and the resultant normal tissue complication probabilities (NTCP) for radiation-induced pneumonitis and excess cardiac mortality in 12 left-sided breast cancer patients. Results Isocenter shifts in the posterior direction had the greatest effect on the lung V20, heart V25, mean and maximum doses to the lung and the heart. Dose volume histograms (DVH) results show that the ipsilateral lung V20 tolerance was exceeded in 58% of the patients after 1cm posterior shifts. Similarly, the heart V25 tolerance was exceeded after 1cm antero-posterior and left-right isocentric shifts in 70% of the patients. The baseline NTCPs for radiation-induced pneumonitis ranged from 0.73% - 3.4% with a mean value of 1.7%. The maximum reported NTCP for radiation-induced pneumonitis was 5.8% (mean 2.6%) after 1cm posterior isocentric shift. The NTCP for excess cardiac mortality were 0 % in 100% of the patients (n=12) before and after setup error simulations. Conclusions Set-up errors in left sided breast cancer patients have a statistically significant impact on the Lung NTCPs and DVH indices. However, with a central lung distance of 3cm or less (CLD <3cm), and a maximum heart distance of 1.5cm or less (MHD<1.5cm), the treatment plans could tolerate set-up errors of up to 1cm without any change in the NTCP to the heart.

A dosimetric retrospective planning study comparing volumetric arc therapy (VMAT) and stereotactic body radiotherapy (SBRT) treatment plans for non-small cell lung cancer (NSCLC)

Purpose A retrospective planning study comparing volumetric arc therapy (VMAT) and stereotactic body radiotherapy (SBRT) treatment plans for non-small cell lung cancer (NSCLC). Methods and materials Five randomly selected early stage lung cancer patients were included in the study. For each patient, four plans were created: the SBRT plan and three VMAT plans using different optimisation methodologies. A total of 20 different plans were evaluated. The dose parameters of dose conformity results and the target dose constraints results were compared for these plans. Results The mean planning target volume (PTV) for all the plans (SBRT and VMAT) was 18·3 cm3, with a range from 15·6 to 20·1 cm3. The maximum dose tolerance to 1 cc of all the plans was within 140% (84 Gy) of the prescribed dose, and 95% of the PTV of all the plans received 100% of the prescribed dose (60 Gy). In all the plans, 99% of the PTV received a dose >90% of the prescribed dose, and the mean dose in all the plans ranged from 67 to 72 Gy. The planning target dose conformity for the SBRT and the VMAT (0°, 15° collimator single arc plans and dual arc) plans showed the tightness of the prescription isodose conformity to the target. Conclusions SBRT and VMAT are radiotherapy approaches that increase doses to small tumour targets without increasing doses to the organs at risk. Although VMAT offers an alternative to SBRT for NSCLC and the potential advantage of VMAT is the reduced treatment times over SBRT, the statistical results show that there was no significant difference between the SBRT and VMAT optimised plans in terms of dose conformity and organ-at-risk sparing.

Psychological consequences of cancer from the salutogenic and dyadic perspective

Previous empirical research has shown that positive, i.e. salutogenic, psychological resources and social support, have health-promoting effects in stressful life situations. In the present study the associations between sense of coherence (SOC), dispositional optimism, partner support, psychological distress, and quality of life among cancer patients and their partners were examined. The data was collected from Helsinki University Central Hospital in 1997 2000 by self-report questionnaires approximately 2, 8, and 14 months post diagnosis. Participants in studies I-IV were 155, 123, 153, and 147 cancer patients and their partners, respectively. The sample of the present study consisted of physically relatively well-functioning patients, whose overall psychological wellbeing was generally good as compared to the healthy population. Partners in this study, however, reacted more strongly to their partners illness and treatment. The partners displayed e.g. higher levels of anxiety and depression than the patients. The results of this study indicated that cancer patients and their partners with strong SOC and who are optimistic report fewer symptoms of distress. Moreover, patients who display an optimistic attitude to life, who receive support from their partner, and who control how they express anger have a better quality of life. The findings also confirmed that the role of the partner is significant in coping with cancer. The symptoms of depression and anxiety in patients and partners were associated, and the partner s optimism seemed to protect also the patient from elevated levels of anxiety. The role of the partner was also highlighted in the couples anger-expression styles. The patients and partners tendency to inhibit anger was associated with decreased partner support and worse patient quality of life. Finally, in the present study we found substantial gender differences. For the patients, partner support was more significant for the women than for the men. Furthermore, for the female patients, the husband s tendency to openly express anger (anger-out) had a negative impact on their psychological quality of life, whereas the wives high anger-out seemed to predict good psychological quality of life in the men. Also, in this study the female partners reported higher levels of anxiety and depression as compared to the male partners. The results of the present study extend the previous literature on positive psychological resources and psychological wellbeing among cancer couples. Furthermore, these findings support the theory on SOC and optimism as health-promoting factors. However, the construct of SOC seems to include other important elements besides optimism. The findings of this study are applicable in designing new rehabilitation programmes for cancer patients and their partners.

Exercise and psychosocial interventions in breast cancer survivors: Preliminary results of a randomized controlled trial

Physical and psychological decline is common in the post-treatment breast cancer population, yet the efficacy of concurrent interventions to meet both physical- psychosocial needs in this population has not been extensively examined. PURPOSE: This study explores the effects of a combined exercise and psychosocial intervention model on selected physiological-psychological parameters in post-treated breast cancer. METHODS: Forty-one breast cancer survivors were randomly assigned to one of four groups for an 8-week intervention: exercise only [EX, n=13] (aerobic and resistance training), psychosocial therapy only [PS, n=11] (biofeedback), combined EX and PS [EX+PS, n=11], or to control conditions [CO, n=6]. Mean delta score (post-intervention - baseline) were calculated for each of the following: body weight, % body fat (skin folds), predicted VO2max (Modified Bruce Protocol), overall dynamic muscular endurance [OME] (RMCRI protocol), static balance (Single leg stance test), dynamic balance (360° turn and 4-square step test), fatigue (Revised Piper Scale), and quality of life (FACT-B). A one-way ANOVA was used to analyze the preliminary results of this on-going randomized trial. RESULTS: Overall, there were significant differences in the delta scores for predicted VO2max, OME, and dynamic balance among the 4 groups (p<0.05). The EX+PS group showed a significant improvement in VO2max compared with the PS group (4.2 ± 3.8 vs. -0.9 ± 4.2 mL/kg/min; p<0.05). Both the EX+PS and EX groups showed significant improvements in OME compared with the PS and CO groups (44.5 ± 23.5 and 43.4 ± 22.1 vs. -3.9 ± 15.2 and 2.7 ± 13.7 repetitions; p<0.05). All 3 intervention groups showed significant improvements in dynamic balance compared with the CO group (-0.8 ± 0.6, -0.6 ± 0.8, and -0.6 ±1.0 vs. 0.6 ± 0.6 seconds; p<0.05). Overall, changes in fatigue tended towards significance among the 4 groups (p = 0.08), with decreased fatigue in the intervention groups and increased fatigue in the CO group. CONCLUSIONS: Our preliminary findings suggest that EX and PS seem to produce greater positive changes in the outcome measures than CO. However, at this point no definite conclusions can be made on the additive effects of combining the EX and PS interventions.

Higher intensity exercise helps cancer survivors remain motivated

Purpose The aim of the present study was to determine if exercise intensity impacts upon the psychosocial responses of breast and prostate cancer survivors to a rehabilitation program. Methods Eighty-seven prostate and 72 breast cancer survivors participated in an 8-week exercise and supportive group psychotherapy intervention (n=84) or control (n=75) group. Intervention participants were randomized to low-to-moderate intensity exercise (LIG; n=44; 60–65 % VO2peak, 50–65 % one repetition maximum (1RM)) or moderate-to-high intensity exercise (HIG; n=40; 75–80 % VO2peak, 65–80 % 1RM) while controls continued usual care. Before and after the 8 weeks, all participants completed the Functional Assessment of Cancer Therapy-Breast or -Prostate to assess quality of life (QOL) and Behavioural Regulations of Exercise Version 2 for exercise motivation. Intervention participants also completed a follow-up assessment 4 months post-intervention. Results All three groups improved in QOL from baseline to post-intervention, with no significant differences. From postintervention to follow-up, the LIG and HIG similarly maintained QOL scores. Between baseline and post-intervention, both intervention arms improved their motivation to exercise compared to the controls (p=0.004). At the 4-month followup, the HIG had maintained their overall exercise motivation (p<0.001) and both domains of intrinsic motivation (identified regulation, p=0.047; intrinsic regulation, p=0.007); however, the LIG had regressed. Conclusions The structured intervention was successful at improving autonomous exercise motivation, regardless of exercise intensity. However, only those participants who had exercised at a higher intensity sustained their improvement. Intervention participation did not improve QOL more than controls. Implications for Cancer Survivors Higher-intensity exercise is more likely to result in more sustainable increases in motivation to exercise among cancer survivors.

Lung cancer risk of airborne particles for Italian population

Airborne particles, including both ultrafine and supermicrometric particles, contain various carcinogens. Exposure and risk-assessment studies regularly use particle mass concentration as dosimetry parameter, therefore neglecting the potential impact of ultrafine particles due to their negligible mass compared to supermicrometric particles. The main purpose of this study was the characterization of lung cancer risk due to exposure to polycyclic aromatic hydrocarbons and some heavy metals associated with particle inhalation by Italian non-smoking people. A risk-assessment scheme, modified from an existing risk model, was applied to estimate the cancer risk contribution from both ultrafine and supermicrometric particles. Exposure assessment was carried out on the basis of particle number distributions measured in 25 smoke-free microenvironments in Italy. The predicted lung cancer risk was then compared to the cancer incidence rate in Italy to assess the number of lung cancer cases attributed to airborne particle inhalation, which represents one of the main causes of lung cancer, apart from smoking. Ultrafine particles are associated with a much higher risk than supermicrometric particles, and the modified risk-assessment scheme provided a more accurate estimate than the conventional scheme. Great attention has to be paid to indoor microenvironments and, in particular, to cooking and eating times, which represent the major contributors to lung cancer incidence in the Italian population. The modified risk assessment scheme can serve as a tool for assessing environmental quality, as well as setting up exposure standards for particulate matter.