Treatment with aromatase inhibitors stimulates the expression of Epidermal growth factor receptor-1 and neuregulin 1 in ER positive \ HER-2neu non-amplified primary breast cancers

This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jsbmb.2016.06.011While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n = 64) and three months (n = 85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P ≤ 0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P = 0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P ≤ 0.001 and P = 0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P = 0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations.The study was supported by the Norwegian Cancer Society (https://kreftforeningen.no), The Western Norway Regional Health Authority (http://www.helse-bergen.no/forskning/samarbeidsorganet), Odd Fellow Medisinsk Vitenskapelig Forskningsfond (oddfellow.no) and Martin Flatners legat

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers.

While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations.The study was supported by the Norwegian Cancer Society (https://kreftforeningen.no), The Western Norway Regional Health Authority (http://www.helse-bergen.no/forskning/samarbeidsorganet), Odd Fellow Medisinsk Vitenskapelig Forskningsfond (oddfellow.no) and Martin Flatners legat.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jsbmb.2016.06.01

Atheroembolization and potential air embolization during aortic declamping in open repair of a pararenal aortic aneurysm: A case report

Introduction: When ischemic events ascribable to microembolization occur during open repair of proximal abdominal aortic aneurysms, a likely origin of atheroembolism is not always found. Presentation of case: A 78-year old man with enlargement of the entire aorta underwent open repair for a pararenal abdominal aortic aneurysm using supraceliac aortic clamping for 20 min. Then the graft was clamped, the supraceliac clamp was removed, and the distal and right renal anastomoses were also completed. The patient was stable throughout the operation with only transient drop in blood pressure on reperfusion. Postoperatively the patient developed ischemia, attributable to microembolization, in legs, small intestine, gall bladder and kidneys. He underwent fasciotomy, small bowel and gall bladder resections. Intestinal absorptive function did not recover adequately and he died after 4 months. Microscopic examination of hundreds of intestinal, juxtaintestinal mesenteric, and gall bladder arteries showed a few ones containing cholesterol emboli. Discussion: It is unsure whether a few occluded small arteries out of several hundred could have caused the ischemic injury alone. There had been only moderate backbleeding from aortic branches above the proximal anastomosis while it was sutured. Inadvertently, remaining air in the graft, aorta, and aortic branches may have been whipped into the pulsating blood, resulting in air microbubbles, when the aortic clamp was removed. Conclusion: Although both atheromatous particles and air microbubbles are well-known causes of iatrogenic microembolization, the importance of air microembolization in open repair of pararenal aortic aneurysms is not known and need to be studied

Wear particles and ions from cemented and uncemented titanium-based hip prostheses-A histological and chemical analysis of retrieval material

Wear debris-induced inflammation is considered to be the main cause for periprosthetic osteolysis in total hip replacements (THR). The objective of this retrieval study was to examine the tissue reactions and exposure to metal ions and wear particles in periprosthetic tissues and blood samples from patients with titanium (Ti)-based hip prostheses that were revised due to wear, osteolysis, and/or aseptic loosening. Semiquantitative, histological tissue evaluations in 30 THR-patients revealed numerous wear debris-loaded macrophages, inflammatory cells, and necrosis in both groups. Particle load was highest in tissues adjacent to loosened cemented Ti stems that contained mainly submicron zirconium (Zr) dioxide particles. Particles containing pure Ti and Ti alloy elements were most abundant in tissues near retrieved uncemented cups. Polyethylene particles were also detected, but accounted only for a small portion of the total particle number. The blood concentrations of Ti and Zr were highly elevated in cases with high abrasive wear and osteolysis. Our findings indicate that wear particles of different chemical composition induced similar inflammatory responses, which suggests that particle size and load might be more important than the wear particle composition in periprosthetic inflammation and osteolysis

Fatal injury as a function of rurality - a tale of two Norwegian counties

Background: Many studies indicate rural location as a separate risk for dying from injuries. For decades, Finnmark, the northernmost and most rural county in Norway, has topped the injury mortality statistics in Norway. The present study is an exploration of the impact of rurality, using a point-by-point comparison to another Norwegian county. Methods: We identified all fatalities following injury occurring in Finnmark between 2000 and 2004, and in Hordaland, a mixed rural/urban county in western Norway between 2003 and 2004 using data from the Norwegian Cause of Death Registry. Intoxications and low-energy trauma in patients aged over 64 years were excluded. To assess the effect of a rural locale, Hordaland was divided into a rural and an urban group for comparison. In addition, data from Statistics Norway were analysed. Results: Finnmark reported 207 deaths and Hordaland 217 deaths. Finnmark had an injury death rate of 33.1 per 100,000 inhabitants. Urban Hordaland had 18.8 deaths per 100,000 and rural Hordaland 23.7 deaths per 100,000. In Finnmark, more victims were male and were younger than in the other areas. Finnmark and rural Hordaland both had more fatal traffic accidents than urban Hordaland, but fewer non-fatal traffic accidents. Conclusions: This study illustrates the disadvantages of the most rural trauma victims and suggests an urban-rural continuum. Rural victims seem to be younger, die mainly at the site of injury, and from road traffic accident injuries. In addition to injury prevention, the extent and possible impact of lay people’s first aid response should be explored

High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function

Purpose: PTEN is an important tumor suppressor in breast cancer. Here, we examined the prognostic and predictive value of PTEN and PTEN pseudogene (PTENP1) gene expression in patients with locally advanced breast cancer given neoadjuvant chemotherapy. Methods: The association between pretreatment PTEN and PTENP1 gene expression, response to neoadjuvant chemotherapy, and recurrence-free and disease-specific survival was assessed in 364 patients with locally advanced breast cancer given doxorubicin, 5-fluorouracil/mitomycin, or epirubicin versus paclitaxel in three phase II prospective studies. Further, protein expression of PTEN or phosphorylated Akt, S6 kinase, and 4EBP1 was assessed in a subgroup of 187 tumors. Results: Neither PTEN nor PTENP1 gene expression level predicted response to any of the chemotherapy regimens tested (n = 317). Among patients without distant metastases (n = 282), a high pretreatment PTEN mRNA level was associated with inferior relapse-free (RFS; p = 0.001) and disease-specific survival (DSS; p = 0.003). Notably, this association was limited to patients harboring TP53 wild-type tumors (RFS; p = 0.003, DSS; p = 0.009). PTEN mRNA correlated significantly with PTENP1 mRNA levels (r s = 0.456, p < 0.0001) and PTEN protein staining (r s = 0.163, p = 0.036). However, no correlation between PTEN, phosphorylated Akt, S6 kinase or 4EBP1 protein staining, and survival was recorded. Similarly, no correlation between PTENP1 gene expression and survival outcome was observed. Conclusion: High intratumoral PTEN gene expression was associated with poor prognosis in patients with locally advanced breast cancers harboring wild-type TP53

Molecular pathogenesis of polymerase gamma-related neurodegeneration

Objective: Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using postmortem tissue from a large number of patients. Methods: Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls was studied employing a combination of histopathology, immunohistochemistry, and molecular studies of microdissected neurons. Results: The primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I–deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and that showed massive neuronal loss. Interpretation: POLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to 2 distinct but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears to be related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy

Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease

Increased somatic mitochondrial DNA (mtDNA) mutagenesis causes premature aging in mice, and mtDNA damage accumulates in the human brain with aging and neurodegenerative disorders such as Parkinson disease (PD). Here, we study the complete spectrum of mtDNA changes, including deletions, copy-number variation and point mutations, in single neurons from the dopaminergic substantia nigra and other brain areas of individuals with Parkinson disease and neurologically healthy controls. We show that in dopaminergic substantia nigra neurons of healthy individuals, mtDNA copy number increases with age, maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. This upregulation fails to occur in individuals with Parkinson disease, however, resulting in depletion of the wild-type mtDNA population. By contrast, neuronal mtDNA point mutational load is not increased in Parkinson disease. Our findings suggest that dysregulation of mtDNA homeostasis is a key process in the pathogenesis of neuronal loss in Parkinson disease.publishedVersio