Modulation by hydroxytyrosol of oxidative stress and antitumor activities of paclitaxel in breast cancer.

PURPOSE: The main objective of this study was to test the therapeutic potential of hydroxytyrosol and its combination with paclitaxel in breast cancer on oxidative stress status. METHODS: Impact on proliferation rates of different chemotherapy administration patterns was assayed in MCF-7 and MDA-MB-231 breast cancer cell lines. Breast tumor-bearing rats were randomly assigned to Control, Hydroxytyrosol, Paclitaxel and Paclitaxel plus hydroxytyrosol groups, for 6 weeks. Tumor volume, cell proliferation and several systemic oxidative stress parameters were measured. Anti-proliferative activity in vitro experiments was correlated with in vivo experiments. RESULTS: Combination group did significantly reduce tumor volume when compared with paclitaxel alone. Additionally, the combination improved the antioxidant status without compromising the antitumor activity of standard chemotherapy. CONCLUSION: These findings reveal for the first time that hydroxytyrosol is an active partner in combined therapies with paclitaxel against breast cancer. Combination with hydroxytyrosol would also ensure a less oxidative impact of chemotherapeutic drugs that could potentially improve patient wellness.

Male breast cancer: correlation between immunohistochemical subtyping and PAM50 intrinsic subtypes, and the subsequent clinical outcomes.

Male breast cancer is a rare disease that is still poorly understood. It is mainly classified by immunohistochemistry as a luminal disease. In this study, we assess for the first time the correlation between molecular subtypes based on a validated six-marker immunohistochemical panel and PAM50 signature in male breast cancer, and the subsequent clinical outcome of these different subtypes. We collected 67 surgical specimens of invasive male breast cancer from four different Spanish pathology laboratories. Immunohistochemical staining for the six-marker panel was performed on tissue microarrays. PAM50 subtypes were determined in a research-use-only nCounter Analysis System. We explored the association of immunohistochemical and PAM50 subtypes. Overall survival and disease-free survival were analyzed in the different subtypes of each classification. The distribution of tumor molecular subtypes according PAM50 was: 60% luminal B, 30% luminal A and 10% human epidermal growth factor receptor 2 (Her2) enriched. Only one Her2-enriched tumor was also positive by immunohistochemistry and was treated with trastuzumab. None of the tumors were basal-like. Using immunohistochemical surrogates, 51% of the tumors were luminal B, 44% luminal A, 4% triple-negative and 1% Her2-positive. The clinicopathological characteristics did not differ significantly between immunohistochemical and PAM50 subtypes. We found a significant worse overall survival in Her2-enriched compared with luminal tumors. Male breast cancer seems to be mainly a genomic luminal disease with a predominance of the luminal B subtype. In addition, we found a proportion of patients with Her2-negative by immunohistochemistry but Her2-enriched profile by PAM50 tumors with a worse outcome compared with luminal subtypes that may benefit from anti-Her2 therapies.

Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.

Sunflower Oil but Not Fish Oil Resembles Positive Effects of Virgin Olive Oil on Aged Pancreas after Life-Long Coenzyme Q Addition.

An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. In this context, it has been reported that different pancreatic compartments from rats were affected according to the fat composition consumed. Since there is a close relationship between mitochondria, oxidative stress and aging, an experimental approach has been developed to gain more insight into this process in the pancreas. A low dosage of coenzyme Q was administered life-long in rats in order to try to prevent pancreatic aging-related alterations associated to some dietary fat sources. According to that, three groups of rats were fed normocaloric diets containing Coenzyme Q (CoQ) for two years, where virgin olive, sunflower, or fish oil was included as unique fat source. Pancreatic samples for microscopy and blood samples were collected at the moment of euthanasia. The main finding is that CoQ supplementation gives different results according to fat used in diet. When sunflower oil was the main fat in the diet, CoQ supplementation seems to improve endocrine pancreas structure and in particular ß-cell mass resembling positive effects of virgin olive oil. Conversely, CoQ intake does not seem to improve the structural alterations of exocrine compartment previously observed in fish oil fed rats. Therefore CoQ may improve pancreatic alterations associated to the chronic intake of some dietary fat sources.

Impact of diet on breast cancer risk: a review of experimental and observational studies.

Breast cancer, which presents the highest global incidence of all female cancers, is caused by the interaction of genetic and environmental factors. Among the latter, diet has attracted considerable attention, as it is a modifiable risk factor and thus offers an opportunity to design preventive strategies. Nevertheless, only alcohol consumption has been unequivocally related to increased breast cancer risk. Despite the failure of observational studies in human populations to clearly define the nature of the relationship between specific nutrient exposures and breast cancer risk, in vivo and in vitro studies strongly suggest its existence. Moreover, studies at the molecular level have identified the putative action mechanism by which the nutritional constituents of specific foodstuffs may exert protective or enhancing effects with respect to breast cancer risk. The inadequate experimental design of some observational studies, or the occurrence of measurement errors and/or recall bias during data collection, or insufficient follow-up and subject characterization, may underlie these controversies. By improving the methods used to study the relationship between diet and breast cancer risk, and by applying new technologies linked to novel approaches such as "nutrigenomics," it might be possible to derive effective recommendations for breast cancer prevention and thus improve anti-cancer treatment.

Dietary antioxidants and lifespan: Relevance of environmental conditions, diet, and genotype of experimental models.

The rise of life expectancy in current societies is not accompanied, to date, by a similar increase in healthspan, which represents a great socio-economic problem. It has been suggested that aging can be manipulated and then, the onset of all age-associated chronic disorders can be delayed because these pathologies share age as primary underlying risk factor. One of the most extended ideas is that aging is consequence of the accumulation of molecular damage. According to the oxidative damage theory, antioxidants should slow down aging, extending lifespan and healthspan. The present review analyzes studies evaluating the effect of dietary antioxidants on lifespan of different aging models and discusses the evidence on favor of their antioxidant activity as anti-aging mechanisms. Moreover, possible causes for differences between the reported results are evaluated.

Differences reported in the lifespan and aging of male Wistar rats maintained on diets containing fat with different fatty acid profiles (virgin olive, sunflower or fish oils) are not reflected by histopathological lesions found at death in central nervous and endocrine systems.

The present study was designed to examine if dietary fat sources that have shown differences in lifespan and if some aging-related aspects can modulate the range of histopathologic changes in central nervous and endocrine systems that occur during the lifespan of Wistar rats. Moreover, it was attempted to gain insight into the relationship between longevity and the development of the different pathological changes, as well as possible interaction with diet. In order to achieve this, male Wistar rats were randomly assigned to three experimental groups fed semisynthetic and isoenergetic diets from weaning until death with different dietary fat sources, namely virgin olive, sunflower, or fish oil. An individual follow-up until death of each animal was performed. Incidence, severity, and burden of specific or group (i.e., neoplastic or non-neoplastic proliferative and non-proliferative) of lesions was calculated along with individual's disease and individual organ lesion burden. Most of the histopathological lesions found have been described in previous studies. Neoplasms, and in particular pituitary adenomas followed by brain tumors, were the most prevalent lesions found in the rats and the main cause of death involving both systems. Incidence of brain lesions was associated with age-at-death. Assayed dietary fats did not present differential effects on pathological changes occurring in endocrine and central nervous systems throughout rat lifespan.

Hypoxia-Inducible Factor-1 Alpha Expression Is Predictive of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy.

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). METHODS: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on anthracyclines and taxanes. For expression of HIF-1α, EGFR, pAKT and pMAPK, tumor samples were analyzed by immunohistochemistry in tissues microarrays. Standard statistical methods (Pearson chi-square test, Fisher exact test, Kruskal-Wallis test, Mann-Whitney test and Kaplan-Meier method) were used to study the association of HIF-1α with tumor response, survival and other clinicopathologic variables/biomarkers. RESULTS: HIF-1α expression was positive in 35 (39.7%) cases and was significantly associated to complete pathological response (pCR) (p = 0.014). HIF-1α expression was correlated positively with tumor grade (p = 0.015) and Ki-67 expression (p = 0.001) and negativity with progesterone receptors (PR) (p = 0.04) and luminal A phenotype expression (p = 0.005). No correlation was found between HIF-1α expression and EGFR, pAKT and pMAPK. In terms of survival, HIF-1α expression was associated with a significantly shorter disease-free survival (p = 0.013), being identified as an independent prognostic factor in multivariate analysis. CONCLUSIONS: Overexpression of HIF-1α is a predictor of pCR and shorter DFS; it would be valuable to confirm these results in prospective studies.

Longevity and Cause of Death in Male Wistar Rats Fed Lifelong Diets Based on Virgin Olive Oil, Sunflower Oil, or Fish Oil.

Extending life by delaying the aging process has been proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. This study investigated how different unsaturated dietary fats affect life span and cause of death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S), or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ10 reduced mortality associated with S diet, but CoQ10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ10 failed to increase the maximum life span potential of rats fed a V or F diet. No clear evidence showing that monounsaturated fatty acids, n-3 polyunsaturated fatty acids, or CoQ10 exerted the observed effects by modulating the rate of aging has been found.

A Diet Rich in Saturated Fat and Cholesterol Aggravates the Effect of Bacterial Lipopolysaccharide on Alveolar Bone Loss in a Rabbit Model of Periodontal Disease.

Increasing evidence connects periodontitis with a variety of systemic diseases, including metabolic syndrome, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). The proposal of this study was to evaluate the role of diets rich in saturated fat and cholesterol in some aspects of periodontal diseases in a lipopolysaccharide (LPS)-induced model of periodontal disease in rabbits and to assess the influence of a periodontal intervention on hyperlipidemia, atherosclerosis, and NAFLD progression to non-alcoholic steatohepatitis. Male rabbits were maintained on a commercial standard diet or a diet rich in saturated fat (3% lard w/w) and cholesterol (1.3% w/w) (HFD) for 40 days. Half of the rabbits on each diet were treated 2 days per week with intragingival injections of LPS from Porphyromonas gingivalis. Morphometric analyses revealed that LPS induced higher alveolar bone loss (ABL) around the first premolar in animals receiving standard diets, which was exacerbated by the HFD diet. A higher score of acinar inflammation in the liver and higher blood levels of triglycerides and phospholipids were found in HFD-fed rabbits receiving LPS. These results suggest that certain dietary habits can exacerbate some aspects of periodontitis and that bad periodontal health can contribute to dyslipidemia and promote NAFLD progression, but only under certain conditions.

Heart Histopathology and Mitochondrial Ultrastructure in Aged Rats Fed for 24 Months on Different Unsaturated Fats (Virgin Olive Oil, Sunflower Oil or Fish Oil) and Affected by Different Longevity.

Diet plays a decisive role in heart physiology, with lipids having especial importance in pathology prevention and development. This study aimed to investigate how dietary lipids varying in lipid profile (virgin olive oil, sunflower oil or fish oil) affected the heart of rats during aging. Heart histopathology, mitochondrial morphometry, and oxidative status were assessed. Typical histopathological features associated with aging, such as valvular lesions, endomyocardical hyperplasia, or papillary muscle calcification, were found at a low extent in all the experimental groups. The most relevant finding was that inflammation registered by fish oil group was lower compared to the other treatments. At the ultrastructural level, heart mitochondrial area, perimeter, and aspect ratio were higher in fish oil-fed rats than in those fed on sunflower oil. Concerning oxidative stress markers, there were differences only in coenzyme Q levels and catalase activity, lower in sunflower oil-fed animals compared with those fed on fish oil. In summary, dietary intake for a long period on dietary fats with different fatty acids profile led to differences in some aspects associated with the aging process at the heart. Fish oil seems to be the fat most protective of heart during aging.

Oxidative stress status in liver mitochondria and lymphocyte DNA damage of atherosclerotic rabbits supplemented with water soluble coenzyme Q10.

The effects of the administration of water soluble coenzyme Q10 (25 mg/kg per day) over 30 days, after 50 days feeding on a high-fat diet (3% lard + 1.3% cholesterol), were investigated in the plasma and liver mitochondria of rabbits. Results showed that this atherogenic diet enhanced lipid levels both in plasma and liver mitochondria, reduced plasma and mitochondrial concentrations of retinol and coenzyme Q10, led to higher DNA damage in peripheral blood lymphocytes and reactive oxygen species concentration in liver mitochondria. The treatment of animals with coenzyme Q10 reduced (to the healthy group levels) lipid concentration in liver mitochondria with no effect on plasma lipids, increased mitochondrial levels of alpha-tocopherol, restored mitochondrial coenzyme Q10 and improved alpha-tocopherol levels in plasma. Moreover, coenzyme Q10 supplementation reduced mitochondrial reactive oxygen species levels and decreased DNA damage in peripheral blood lymphocytes. The findings suggest that antioxidant therapy with coenzyme Q10 may be used in the treatment of liver pathologies associated to the intake of high-fat, atherogenic, diets.

Activating Transcription Factor 4 Modulates TGFß-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling.

Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFß1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFß and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature.Experimental Design: Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFß and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX).Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFß was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFß/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer.Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697-709. ©2018 AACR.

Age-Related Loss in Bone Mineral Density of Rats Fed Lifelong on a Fish Oil-Based Diet Is Avoided by Coenzyme Q10 Addition.

During aging, bone mass declines increasing osteoporosis and fracture risks. Oxidative stress has been related to this bone loss, making dietary compounds with antioxidant properties a promising weapon. Male Wistar rats were maintained for 6 or 24 months on diets with fish oil as unique fat source, supplemented or not with coenzyme Q10 (CoQ10), to evaluate the potential of adding this molecule to the n-3 polyunsaturated fatty acid (n-3 PUFA)-based diet for bone mineral density (BMD) preservation. BMD was evaluated in the femur. Serum osteocalcin, osteopontin, receptor activator of nuclear factor-κB ligand, ostroprotegerin, parathyroid hormone, urinary F2-isoprostanes, and lymphocytes DNA strand breaks were also measured. BMD was lower in aged rats fed a diet without CoQ10 respect than their younger counterparts, whereas older animals receiving CoQ10 showed the highest BMD. F2-isoprostanes and DNA strand breaks showed that oxidative stress was higher during aging. Supplementation with CoQ10 prevented oxidative damage to lipid and DNA, in young and old animals, respectively. Reduced oxidative stress associated to CoQ10 supplementation of this n-3 PUFA-rich diet might explain the higher BMD found in aged rats in this group of animals.

Coenzyme Q Protects Against Age-Related Alveolar Bone Loss Associated to n-6 Polyunsaturated Fatty Acid Rich-Diets by Modulating Mitochondrial Mechanisms.

An age-dependent model of the periodontium was reproduced to evaluate the effect of life-long feeding on a low coenzyme Q10 dosage in n-6, n-3 polyunsaturated fatty acid or monounsaturated fatty acid-based diets on periodontal tissues of young and old rats. Results shown that exacerbated age-related alveolar bone loss previously associated to n-6 polyunsaturated fatty acid diet was attenuated by coenzyme Q10 Gene expression analysis suggests that involved mechanisms might be related to a restored capacity of mitochondria to adapt to aging in gingival cells from rats fed on n-6 polyunsaturated fatty acid. In particular, this could be due to an age-related increase of the rate of mitochondrial biogenesis and a better oxidative and respiratory balance in these animals. From the nutritional and clinical point of view, it is noteworthy that supplementation with coenzyme Q10 could counteract the negative effects of n-6 polyunsaturated fatty acid on alveolar bone loss (a major feature of periodontitis) associated to age.

Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits.

OBJECTIVE: This study evaluates the effect of a Curcuma longa extract on the development of experimental atherosclerosis (fatty streak) in rabbits and its interaction with other plasmatic antioxidants. METHODS AND RESULTS: Two experimental groups of male New Zealand White rabbits, a control group and a curcuma-extract (CU) group, were fed an atherogenic diet. Additionally, the CU group received an oral curcuma hydroalcoholic extract. Six animals from each experimental group were killed after 10, 20, and 30 days. Compared with the CU group, the control group showed significantly higher plasma lipid peroxide at all experimental times (10, 20, and 30 days) and significantly lower alpha-tocopherol and coenzyme Q levels at 20 and 30 days. Histological results for the fatty streak lesions revealed damage in the thoracic and abdominal aorta that was significantly lower in the CU group than in the control group at 30 days. CONCLUSIONS: Supplementation with Curcuma longa reduces oxidative stress and attenuates the development of fatty streaks in rabbits fed a high cholesterol diet.

Monounsaturated and omega-3 but not omega-6 polyunsaturated fatty acids improve hepatic fibrosis in hypercholesterolemic rabbits.

OBJECTIVE: Although the influence of saturated fatty acids, monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), lipids, cholesterol levels, and other blood lipids has been established, few studies have examined the influence of these dietary lipids on the composition and histologic damage of organs in situations of hypercholesterolemia. Biliary lipids come from the liver, and this organ is essential in cholesterol homeostasis; thus, it may be helpful to evaluate the inter-relations among biliary, hepatic lipids, and hepatotoxic effects in situations of hypercholesterolemia with different dietary lipids. This study investigated whether administration of diets differing in fatty acid profiles (omega-3 PUFA, omega-6 PUFA, or MUFA) influence the content of biliary lipids, the lithogenic index of gallbladder bile, and the development of hepatic fibrosis in hypercholesterolemic rabbits. METHODS: Thirty rabbits were randomized to one of five groups. A control group received rabbit chow for 80 d. The remaining four groups received a 50-d diet that contained 3% lard and 13% cholesterol to provoke hypercholesterolemia. After this period, three groups were fed for another 30 d on a diet enriched with omega-6 PUFAs, MUFAs, and omega-3 PUFAs, respectively. Liver, bile, and plasma lipid compositions, lipid peroxidation in hepatic mitochondria, and histologic hepatic lesions were analyzed. RESULTS AND CONCLUSIONS: There was a beneficial effect of MUFA and omega-3 PUFA on hepatic fibrosis in hypercholesterolemic rabbits because both dietary fats led to recovery from hepatic lesions. However, because intake of omega-3 PUFA provoked lithogenic bile in rabbits, MUFA intake would be more advisable.

Oral administration of a turmeric extract inhibits erythrocyte and liver microsome membrane oxidation in rabbits fed with an atherogenic diet.

OBJECTIVES: The aim of this study was to evaluate the effects of an oral supplementation with a Curcuma longa ethanol and aqueous extract on the susceptibility to oxidation of cellular and subcellular membranes affected in the atherosclerotic process, such as erythrocyte membranes and liver microsomes, in rabbits fed with a high-fat diet. METHODS: Twenty-four male rabbits were randomly assigned to one of two groups: group T was treated with a turmeric hydroalcoholic extract (1.66 mg/kg of body weight) dissolved in a hydroalcoholic mixture vehicle (7:2), and group C (control): received a curcuma-free hydroalcoholic solution (7:2). All rabbits had access ad libitum to 150 g/d of an experimental diet rich in cholesterol and lard to provoke an atherosclerotic process. Erythrocyte membranes and liver microsomes were isolated, and the levels of hydroperoxides and thiobarbituric acid-reactive substances were measured after oxidation induction. RESULTS: The oxidation of erythrocyte membranes in group T was significantly lower than that in group C, mainly by 30 d (P < 0.05). Levels of hydroperoxides and thiobarbituric acid-reactive substances in liver microsomes also were significantly lower in group T than in group C (P < 0.05). CONCLUSIONS: The results of this study indicated that oral administration of a nutritional dose of C. longa extracts reduces the susceptibility to oxidation of erythrocyte and liver microsome membranes in vitro and may contribute to the prevention of effects caused by a diet high in fat and cholesterol in blood and liver during the development of atherosclerosis.

Comparative analysis of pancreatic changes in aged rats fed life long with sunflower, fish, or olive oils.

An adequate pancreatic structure is necessary for optimal organ function. Structural changes are critical in the development of age-related pancreatic disorders. We aimed to study the effect of oil consumption on pancreas histology in order to find aging-related signs. To this end, three groups of rats were fed an isocaloric diet for 2 years, where virgin olive, sunflower, or fish oil was included. Pancreatic samples for microscopy and blood samples were collected at the moment of sacrifice. As a result, the sunflower oil-fed rats presented higher ß-cell numbers and twice the insulin content than virgin olive oil-fed animals. In addition, rats fed with fish oil developed acinar fibrosis and macrophage infiltrates in peri-insular regions, compared with counterparts fed with virgin olive oil. Inflammation signs were less prominent in the sunflower group. The obtained data emphasize the importance of dietary fatty acids in determining pancreatic structure.

Transcriptional shift identifies a set of genes driving breast cancer chemoresistance.

BACKGROUND: Distant recurrences after antineoplastic treatment remain a serious problem for breast cancer clinical management, which threats patients' life. Systemic therapy is administered to eradicate cancer cells from the organism, both at the site of the primary tumor and at any other potential location. Despite this intervention, a significant proportion of breast cancer patients relapse even many years after their primary tumor has been successfully treated according to current clinical standards, evidencing the existence of a chemoresistant cell subpopulation originating from the primary tumor. METHODS/FINDINGS: To identify key molecules and signaling pathways which drive breast cancer chemoresistance we performed gene expression analysis before and after anthracycline and taxane-based chemotherapy and compared the results between different histopathological response groups (good-, mid- and bad-response), established according to the Miller & Payne grading system. Two cohorts of 33 and 73 breast cancer patients receiving neoadjuvant chemotherapy were recruited for whole-genome expression analysis and validation assay, respectively. Identified genes were subjected to a bioinformatic analysis in order to ascertain the molecular function of the proteins they encode and the signaling in which they participate. High throughput technologies identified 65 gene sequences which were over-expressed in all groups (P ≤ 0·05 Bonferroni test). Notably we found that, after chemotherapy, a significant proportion of these genes were over-expressed in the good responders group, making their tumors indistinguishable from those of the bad responders in their expression profile (P ≤ 0.05 Benjamini-Hochgerg`s method). CONCLUSIONS: These data identify a set of key molecular pathways selectively up-regulated in post-chemotherapy cancer cells, which may become appropriate targets for the development of future directed therapies against breast cancer.