A controlled study of risk factors for disease and current problems in long-term testicular cancer survivors

Introduction  

To compare risk factors for disease and current problems in long-term testicular cancer survivors (TCSs) and age-matched population-based controls (NORMs).     

Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

Introduction

Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.

Methods

We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.

Results

Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.

Conclusion

Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.     

Identification of factors regulating thiopurine methyltransferase activity in a Norwegian population

Summary Red blood cell (RBC) thiopurine methyltransferase (TPMT), an inactivating pathway of 6-mercaptopurine, is controlled by genetic polymorphism and is subject to ethnic variation. RBC TPMT is a good predictor of clinical outcome in children with acute lymphoblastic leukemia. RBC TPMT activity was determined in 226 patients, 176 of them living in northern Norway (of which 123 were Saami (Lapps)). Demographic variables, use of drugs and presence of chronic diseases were evaluated as possible predictors of RBC TPMT activity by a multiple regression model.Men had higher RBC TPMT activity compared to women. Living in the northernmost county of Norway was associated with increased RBC TPMT activity irrespective of ethnicity. The use of diuretics was associated with increased RBC TPMT activity.The gender difference in RBC TPMT activity may indicate a need to treat male subjects more aggressively with thiopurine drugs compared to female subjects.This study was supported by the Erna and Olav Aakre Foundation for Cancer Research and the Norwegian Cancer Society     

Effect of plant neutrophil elastase inhibitor on leucocyte migration, adhesion and cytokine release in inflammatory conditions

BACKGROUND AND PURPOSE

The serine and cysteine peptidase inhibitor, BbCI, isolated from Bauhinia bauhinioides seeds, is similar to the classical plant Kunitz inhibitor, STI, but lacks disulphide bridges and methionine residues. BbCI blocks activity of the serine peptidases, elastase (K_iapp 5.3 nM) and cathepsin G (K_iapp 160.0 nM), and the cysteine peptidase cathepsin L (K_iapp 0.2 nM). These three peptidases play important roles in the inflammatory process.

EXPERIMENTAL APPROACH

We measured the effects of BbCI on paw oedema and on leucocyte accumulation in pleurisy, both induced by carrageenan. Leucocyte–endothelial cell interactions in scrotal microvasculature in Wistar rats were investigated using intravital microscopy. Cytokine levels in pleural exudate and serum were measured by elisa.

KEY RESULTS

Pretreatment of the animals with BbCI (2.5 mg·kg⁻¹), 30 min before carrageenan-induced inflammation, effectively reduced paw oedema and bradykinin release, neutrophil migration into the pleural cavity. The number of rolling, adhered and migrated leucocytes at the spermatic fascia microcirculation following carrageenan injection into the scrotum were reduced by BbCI pretreatment. Furthermore, levels of the rat chemokine cytokine-induced neutrophil chemo-attractant-1 were significantly reduced in both pleural exudates and serum from animals pretreated with BbCI. Levels of interleukin-1β or tumour necrosis factor-α, however, did not change.

CONCLUSIONS AND IMPLICATIONS

Taken together, our data suggest that the anti-inflammatory properties of BbCI may be useful in investigations of other pathological processes in which human neutrophil elastase, cathepsin G and cathepsin L play important roles.     

The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors

Background and purpose:

K⁺ channels play a role in the proliferation of cancer cells. We have investigated the effects of specific K⁺ channel inhibitors on basal and oestrogen-stimulated proliferation of breast cancer cells.

Experimental approach:

Using the mammary adenocarcinoma cell line MCF-7 we assayed cell proliferation by radiolabelled thymidine incorporation in the absence or presence of various K⁺ channel inhibitors with or without 17β-oestradiol.

Key results:

Inhibitors of K_v10.1 and K_Ca3.1 K⁺ channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of K_Ca3.1 channels increased or decreased cell proliferation depending on the concentration. At intermediate concentrations (3–10 µM) TRAM-34 increased cell proliferation, whereas at higher concentrations (20–100 µM) TRAM-34 decreased cell proliferation. The enhancement of cell proliferation caused by TRAM-34 was blocked by the oestrogen receptor antagonists ICI182,780 and tamoxifen. TRAM-34 also increased progesterone receptor mRNA expression, decreased oestrogen receptor-α mRNA expression and reduced the binding of radiolabelled oestrogen to MCF-7 oestrogen receptor, in each case mimicking the effects of 17β-oestradiol.

Conclusions and implications:

Our results demonstrate that K⁺ channels K_v10.1 and K_Ca3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting K_Ca3.1, directly interacts with the oestrogen receptor and mimics the effects of 17β-oestradiol on MCF-7 cell proliferation and gene modulation. Our finding that TRAM-34 is able to activate the oestrogen receptor suggests a novel action of this supposedly specific K⁺ channel inhibitor and raises concerns of interpretation in its use.     

Aspects of posttraumatic stress disorder in long-term testicular cancer survivors: cross-sectional and longitudinal findings

Purpose

The purpose of this research is to study the prevalence of posttraumatic stress disorder (PTSD) and variables associated with PTSD in Norwegian long-term testicular cancer survivors (TCSs) both cross-sectionally and longitudinally.

Methods

At a mean of 11 years after diagnosis, 1418 TCSs responded to a mailed questionnaire, and at a mean of 19 years after diagnosis, 1046 of them responded again to a modified questionnaire. Posttraumatic symptoms related to testicular cancer were self-rated with the Impact of Event Scale (IES) at the 11-year study only. An IES total score ≥35 defined Full PTSD, and a score 26–34 identified Partial PTSD, and the combination of Full and Partial PTSD defined Probable PTSD.

Results

At the 11-year study, 4.5 % had Full PTSD, 6.4 % had Partial PTSD, and 10.9 % Probable had PTSD. At both studies, socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxic adverse effects were significantly associated with Probable PTSD in bivariate analyses. Probable anxiety disorder, poor self-rated health, and neurotoxicity remained significant with Probable PTSD in multivariate analyses at the 11-year study. In bivariate analyses, probable PTSD at that time significantly predicted socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxicity among participants of the 19-year study, but only probable anxiety disorder remained significant in multivariable analysis.

Conclusions

In spite of excellent prognosis, 10.9 % of long-term testicular cancer survivors had Probable PTSD at a mean of 11 years after diagnosis. Probable PTSD was significantly associated with a broad range of problems both at that time and was predictive of considerable problems at a mean of 19 year postdiagnosis.

Implications for cancer survivors

Among long-term testicular cancer survivors, 10.9 % have Probable PTSD with many associated problems, and therefore health personnel should explore stress symptoms at follow-up since efficient treatments are available.

     

Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (∼30%) and slow onset of action (2–4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3–5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression.