CD44 variant expression and estrogen receptor status in breast cancer

To understand the relationship between CD44 gene expressionand an established variable associated with aggressive behaviourin human breast cancer, we have studied apanel of 6 breast cell lines and 40breast tumors selected primarily on the basis ofestrogen receptor (ER) status. CD44s (standard form) mRNAwas assessed by semi-quantitative RT-PCR, and CD44 variantsincorporating exon v7 or v10 were studied byRT-PCR and Southern blot. While CD44 expression wasnot influenced by estrogen in ER+ve MCF-7 cells,CD44s expression was slightly higher (up to 2fold) in ER–ve cells but there was amarked decrease in the range of CD44 variantsincorporating exons v7 or v10. In microdissected tumors,the levels of CD44s showed no correlation withER status but the pattern of expression oflarger forms of CD44 incorporating variant exons v7and v10 was significantly different (p=0.005and p=0.015, respectively) between ER+ve andER–ve tumors, reflecting the pattern seen in thecell lines. These findings suggest that the profileof CD44 expression in breast cancer may reflectcellular differentiation as indicated by the ER phenotype.The influence of these differences in CD44 expressionon the increased metastatic potential of ER negativebreast cancer remains to be determined.     

The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma.

PURPOSE: Renal cell carcinoma (RCC) is the most common malignancy of the kidney composed of specific tumor types. The sporadic conventional RCCs are, in contrast to the other RCC types, characterized by a high rate of von Hippel-Lindau (VHL) mutations and hypermethylation. The majority of these tumors lack functional VHL protein (pVHL) that leads to increased hypoxia-inducible factor 1alpha (HIF-1alpha) expression. The pVHL is the physiologic regulator of the activity of HIF-1alpha by targeting it to the proteasome for degradation under normoxia. Both pVHL and HIF-1alpha target other genes that are important for cancer survival and proliferation. Expression of HIF-1alpha has been linked to poor prognosis in different malignancies, although few studies have been done on the relation between HIF-1alpha and clinical variables in RCC. EXPERIMENTAL DESIGN: HIF-1alpha protein expression was analyzed in tumor tissue from 92 patients with RCC. HIF-1alpha was quantified by Western blot relative to a positive control. RESULTS: The HIF-1alpha protein was expressed as two bands which strongly correlated (r = 0.906, P < 0.001); therefore, they were added and the sum evaluated against clinicopathologic variables. There was no association between HIF-1alpha and gender, stage, grade, tumor size, or vein invasion. Conventional RCCs had significantly higher HIF-1alpha expression compared with papillary and chromophobe RCCs and kidney cortex. In conventional RCC, HIF-1alpha was an independent prognostic factor. CONCLUSION: HIF-1alpha levels varied significantly between the different RCC types. In conventional RCC, HIF-1alpha was an independent prognostic factor. These data indicate that HIF-1alpha is involved in tumorogenesis and progression of RCC. Evaluation of other HIF target gene products and correlation to angiogenesis seems warranted.     

Parathyroid hormone-related protein and serum calcium in patients with renal cell carcinoma.

OBJECTIVE: To evaluate serum parathyroid hormone-related protein (PTHrP) in relation to serum calcium and clinical outcome of patients with renal cell carcinoma. METHODS: Sera from 243 patients with renal cell carcinoma were collected prior to therapy. Serum PTHrP was analyzed using an immunoradiometric assay. Tumour stage, nuclear grade, corrected serum calcium, and survival were assessed. RESULTS: Serum PTHrP was detectable in 37/243 sera (15%) and hypercalcaemia (> or =2.60 mmol/l) in 32/220 (15%). A positive correlation between serum PTHrP and serum calcium was found (r = 0.326; p < 0.01). Following subdivision of the material, based on storage time, the frequency of detectable serum PTHrP seemed to decrease with time. Serum calcium, but not serum PTHrP, was correlated to tumour stage (p < 0.001). Survival was similar for patients with detectable and undetectable PTHrP, but those with hypercalcaemia had a significantly shorter survival time compared to those with normal serum calcium (p < 0.001). A multivariate analysis showed that tumour stage and serum calcium were independent prognostic factors, but not grade or PTHrP. CONCLUSIONS: A positive relation of serum PTHrP to serum calcium was demonstrated in patients with renal cell carcinoma. Hypercalcaemia but not serum PTHrP predicted a worse prognosis.     

DNA methylation changes measured in pre‐diagnostic peripheral blood samples are associated with smoking and lung cancer risk

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre‐diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case‐control study nested within the EPIC‐Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case‐control pairs). We validated the top signals in 429 case‐control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p‐value_pooled = 4 × 10^?17), cg03636183 in the F2RL3 gene (p‐value_pooled = 2 × 10 ^{? 13}), cg21566642 and cg05951221 in 2q37.1 (p‐value_pooled = 7 × 10^?16 and 1 × 10^?11 respectively), cg06126421 in 6p21.33 (p‐value_pooled = 2 × 10^?15) and cg23387569 in 12q14.1 (p‐value_pooled = 5 × 10^?7). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p‐values_{heterogeneity} ≤ 1.8 x10 ^{? 7}), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p‐values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack‐years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.     

Insulin-like growth factor-I and C-reactive protein during pregnancy and maternal risk of non-epithelial ovarian cancer: a nested case�Ccontrol study

Background

Insulin-like growth factor-I (IGF-I) and C-reactive protein (CRP) may be positively associated with the risk of epithelial ovarian cancer (EOC) but no previous studies have investigated their associations with non-epithelial ovarian cancers (NEOC).

Methods

A case?Ccontrol study was nested within the Finnish Maternity Cohort. Case subjects were 58 women diagnosed with sex cord-stromal tumors (SCST) and 30 with germ cell tumors (GCT) after recruitment. Control subjects (144 for SCST and 74 for GCT) were matched for age, parity, and date of blood donation of the index case.

Results

Doubling of IGF-I concentration was not related to maternal risk of either SCST (OR 0.97, 95% CI 0.58?C1.62) or GCT (OR 1.13, 95% CI 0.51?C2.51). Similarly, doubling of CRP concentrations was not related to maternal risk of either SCST (OR 1.10, 95% CI 0.85?C1.43) or GCT (OR 0.93, 95% CI 0.68?C1.28).

Conclusions

Pre-diagnostic IGF-I and CRP concentrations during the first trimester of pregnancy were not associated with increased risk of NEOC in the mother. Risk factors for NEOC may differ from those of EOC.     

Symptom panorama in upper secondary school students and symptoms related to iron deficiency Screening with laboratory tests,questionnaire and interventional treatment with iron

Objective - To study the trend in premature mortality (before 75 years of age) from ischaemic heart disease (IHD) in a Swedish primary health care district compared to communities of similar demographic situation and all Sweden. Design - Mortality from IHD in men and women was compared between the community of Habo and other Swedish communities of similar size and all Sweden for the period 1984-96. Setting - The community of Habo in Sweden with about 9600 inhabitants. Intervention - Intensified efforts by the local primary health care organisation, in co-operation with the community, in respect of primary and secondary cardiovascular prevention since the beginning of the 1980s. Results - Mortality from IHD has decreased significantly both in Habo and in Sweden during these years. The decrease has been more prominent in Habo than in Sweden as a whole and other Swedish communities of similar demographic situation. Conclusion - With increased and purposeful efforts in primary and secondary prevention, in co-operation between the community and primary health care, it is possible to substantially decrease mortality from IHD in the community.     

Comparison of Muscle Activity in Three Single-Joint,Hip Extension Exercises in Resistance-Trained Women

The aim of the study was to compare neuromuscular activation in the gluteus maximus, the biceps femoris and the erector spinae from the Romanian deadlift, the 45-degree Roman chair back extension and the seated machine back extension. Fifteen resistance-trained females performed three repetitions with 6-RM loading in all exercises in a randomized and counterbalanced order. The activation in the whole movement as well as its lower and upper parts were analyzed. The results showed that the Romanian deadlift and the Roman chair back extension activated the gluteus maximus more than the seated machine back extension (94-140%, p < 0.01). For the biceps femoris the Roman chair elicited higher activation compared to both the Romanian deadlift and the seated machine back extension (71-174%). Further, the Romanian deadlift activated the biceps femoris more compared to the seated machine back extension (61%, p < 0.01). The analyses of the different parts of the movement showed that the Roman chair produced higher levels of activation in the upper part for both the gluteus maximus and the biceps femoris, compared to the other exercises. There were no differences in activation of the erector spinae between the three exercises (p = 1.00). In conclusion, both the Roman deadlift and the Roman chair back extension would be preferable to the seated machine back extension in regards to gluteus maximus activation. The Roman chair was superior in activating the biceps femoris compared to the two other exercises. All three exercises are appropriate selections for activating the lower back muscles. For overall lower limb activation, the Roman chair was the best exercise.Key points

• In general, the Roman chair back extension lead to superior muscle activation compared to the Romanian deadlift and the seated machine back extension
• The seated machine back extension showed the lowest gluteus and hamstring activation
• All three exercises are appropriate selections for activating the lower back muscles
• The differences in muscle activation are most likely caused by biomechanical differences.

Key words: Gluteus maximus, biceps femoris, erector spinae, muscle activation     

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.