Protective effect of Petroselinum crispum methanolic extract against acrylamide-induced reproductive toxicity in male rats through NF-ĸB, kinesin, steroidogenesis pathways.

This study examined the protective effects of a Petroselinum crispum (P. crispum) methanolic extract on reproductive dysfunction induced by acrylamide in male rats. A total of 40 rats were divided into four groups (n=10). The control group received distilled water, the acrylamide group received 10 mg/kg of acrylamide, the P. crispum group received 100 mg/kg of P. crispum extract, and the combined group was pretreated with P. crispum for two weeks before co-administration of P. crispum and acrylamide. All administrations were administered orally using a gastric tube for eight weeks. Acrylamide decreased testosterone levels but did not affect levels of FSH or LH. It also increased testicular levels of (MDA) malondialdehyde and reduced activity of (SOD) superoxide dismutase and impairment of sperm parameters. Furthermore, the administration of acrylamide resulted in an elevation of tumor necrosis factor-alpha (TNF-α) levels and a reduction in the levels of steroidogenic acute regulatory protein (STAR) and cytochrome P450scc (P450scc). Acrylamide negatively affected the histopathological outcomes, Johnsen's score, the diameter of seminiferous tubules, and the thickness of the germinal epithelium. It also upregulated the expression of NF-ĸB P65 and downregulated the expression of kinesin motor protein. In contrast, treatment with P. crispum extract restored the levels of antioxidant enzymes, improved sperm parameters, and normalized the gene expression of TNF-α, IL-10, IL-6, iNOS, NF-ĸB, STAR, CYP17A1, 17ß-HSD and P450scc. It also recovered testicular histological parameters and immunoexpression of NF-ĸB P65 and kinesin altered by acrylamide. P. crispum showed protective effects against acrylamide-induced reproductive toxicity by suppressing oxidative damage and inflammatory pathways.

Ameliorative effect of Odontonema cuspidatum extract against testicular damage induced by sodium nitrite in rats.

Background: Sodium nitrite (NaNO2) is a chemical substance used to enhance taste, add color, and keep food products fit for consumption for a longer time. NaNO2 gives rise to a negative adverse effect on male reproductive function. Odontonema cuspidatum (OC) is a natural plant that possesses antioxidant capacity. Aim: Our research evaluates the potential beneficial effect of OC extract on the harmful effects caused by NaNO2 on the testicular tissue and sperm characteristics of male rats. Methods: Four groups with a total of forty rats: the control, the NaNO2-received group, the OC-administered group, and the fourth group received both NaNO2 and OC. All groups were administered daily for two months. Sperm characteristics, testicular antioxidant status, qRT-PCR, and histopathological changes were evaluated. Results: Coadministration of NaNO2 and OC, in comparison with NaNO2 alone, contributed to a notable enhancement in acrosomal integrity, decreasing sperm abnormalities and restoring serum testosterone levels. Moreover, such coadministration reduced the oxidative stress marker, malondialdehyde (MDA), and increased superoxide dismutase (SOD) in testicular tissue, lowering TNF-α gene expression, and increasing the expression of P450scc and StAR genes. In addition, the NaNO2 and OC combination decreased the testicular histopathological changes and the Caspase-3 and Proliferating cell nuclear antigen (PCNA) immunoexpression in seminiferous tubules compared with the NaNO2 group. Conclusion: The extract of OC exhibited the ability to decrease oxidative stress and ameliorate the detrimental effects caused by NaNO2.

The Effects of Bacterial Lipopolysaccharide (LPS) on Turkey Poults: Assessment of Biochemical Parameters and Histopathological Changes.

A lipopolysaccharide (LPS) is a large molecule and an outer membrane glycolipid found in Gram-negative bacteria, including Escherichia coli (E. coli). These molecules (LPS) target acute inflammatory responses and significant physiological changes. Importantly, E. coli is considered one of the most important bacterial causes of avian colibacillosis that affect domestic turkey industry. However, little information is available about the potential influence of LPS on the biochemical parameters and histopathological changes in turkey poults. Therefore, this study aimed to evaluate the influence of bacterial lipopolysaccharide (LPS) molecules on serum biomarkers and histopathological changes in turkey poults. The birds were randomly divided into five groups, as follows: group I did not receive any inoculation; group II was inoculated with sterile saline; and groups III, IV, and V were inoculated intraperitoneally with LPS at 0.01, 0.1, and 1 mg/kg of body weight (BW), respectively. The biochemical parameters and the histopathology of different organs were examined in all birds one day post-inoculation. Our results revealed hypolipidemia, hypoglycemia, a significant decrease in uric acid, and a significant increase in serum activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and creatine kinase (CK), as well as cardiac troponin T concentrations in treated groups. Moreover, there was a significant increase in α1-, ß-, and γ-globulin concentrations and a decrease in albumin and α2-globulin concentrations in group V. However, a significant increase in α2- and γ-globulin levels and a decrease in albumin levels were detected in groups III and IV. In addition, significant decreases in the albumin/globulin ratio were recorded in all LPS-treated groups. Hepatocellular and cardiac muscle necrosis, slight renal changes, and massive pulmonary inflammatory reactions were recorded. This study provides valuable information about serum biomarkers, protein fractions, and histopathological changes in turkey poults treated with LPS for further investigations of pathophysiological mechanisms in avian medicine along with biomedical research.

Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus.

Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of ß-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.

Date press cake replaces corn grains in the diet of lactating Egyptian buffaloes and Barki rams.

High prices of corn grains due to their shortage in some regions force researcher to explore nonconventional alternatives. Therefore, the present study aimed to evaluate the effect of replacing corn grains at 25% (dry matter (DM) basis) with date press cake (DPC) without/with exogenous enzymes at 2 L/ton feed in diets of Barki sheep (24 rams divided as 6 rams/treatment) and Egyptian buffaloes (16 buffaloes divided as 4 buffalo/treatment). Each experiment was conducted under 4 treatments regime: control diet containing only corn grains, T1 diet where the control diet supplemented with exogenous enzyme, T2 diet where the control diet contained DPC on corn replacement (25% DM basis), and T3 diet where the control diet contained DPC on corn replacement (25% DM basis) along with exogenous enzyme supplement. The control diet contained concentrate feed mixture, corn silage, and rice straw at 50:40:10, respectively. Data on nutrient intake, digestibility, and nitrogen balance in sheep, as well as on blood parameters, milk production, and composition in buffaloes, were analyzed using the PROC GLM/MIXED procedure of SAS. The sheep under T2 and T3 treatments demonstrated greater digestibility of dry matter, organic matter, and neutral detergent fibers, along with improved nitrogen balance. The milk yield and its constituents were improved in the buffaloes under T3 treatment followed by those buffaloes under T2 and T1 treatments. This investigation could conclude that replacing corn grains with DPC at 25% (DM basis) in ruminant diets had beneficial effects on nutrients digestibility and milk yield along with its composition.

Dosimetric impact of switching from AAA to Acuros dose-to-water and dose-to-medium for RapidArc plans of nasopharyngeal carcinomas.

PURPOSE: This work aims to evaluate the dosimetric consequences of replacing the Anisotropic Analytical Algorithm (AAA) by Acuros XB (AXB), dose-to-water (Dw) or dose-to-medium (Dm), for RapidArc plans of nasopharyngeal carcinomas (NPC). MATERIALS AND METHODS: Seventeen NPC plans created with AAA (v15.6) were recalculated with AXB (v15.6) Dw and Dm. The dose-volume parameters to the planning target volumes (PTV) and relevant organs at risk (OAR) were compared. The high dose PTV was divided into bone, air and tissue components and the comparison was performed for each of them. RESULTS: AXB Dw revealed no significant differences in the PTVs compared to AAA. Lower values were observed to spinal cord, brainstem, oral cavity and parotids (0.5% to 2.3%), and higher values to cochleas (up to 5.4%) and mandible (up to 6.7%). AXB Dm predicted lower values than AAA for all PTVs and OARs (2.0% to 6.1%). For the bone PTV subvolume, AXB Dw and Dm predicted respectively higher (2.4%) and lower (2.2% to 3.4%) values. No significant differences were noted in air. AXB predicted lower values than AAA in soft tissues (0.4% to 1.6%). The largest difference was found to the mandible V60Gy parameter, with median differences of 6.7% for AXB Dw and -6.0% for AXB Dm. CONCLUSION: Significant dose differences are expected when switching from AAA to AXB in NPC cases. The dose prescriptions and the tolerance limits for some OARs, especially those of high density, may need to be adjusted depending on the selected dose calculation algorithm and reporting mode.

Collision prediction for intracranial stereotactic radiosurgery planning: An easy-to-implement analytical solution.

PURPOSE: Gantry collision is a concern in linac-based stereotactic radiosurgery (SRS). Without collision screening, the planner may compromise optimal planning, unnecessary re-planning delays can occur, and incomplete treatments may be delivered. To address these concerns, we developed a software for collision prediction based on simple machine measurements. MATERIALS AND METHODS: Three types of collision were identified; gantry-couch mount, gantry-couch and gantry-patient. Trigonometric formulas to calculate the distance from each potential point of collision to the gantry rotation axis were generated. For each point, collision occurs when that distance is greater than the gantry head to gantry rotational axis distance. The colliding arc for each point is calculated. A computer code incorporating these formulas was generated. The inputs required are the couch coordinates relative to the isocenter, the patient dimensions, and the presence or absence of a circular SRS collimator. The software outputs the collision-free gantry angles, and for each point, the shortest distance to the gantry or the colliding sector when collision is identified. The software was tested for accuracy on a TrueBEAM® machine equipped with BrainLab® accessories for 80 virtual isocenter-couch angle configurations with and without a circular collimator and a parallelepiped phantom. RESULTS: The software predicted the absence of collision for 19 configurations. The mean absolute error between the measured and predicted gantry angle of collision for the remaining 61 cases was 0.86 (0.01-2.49). CONCLUSION: This tool accurately predicted collisions for linac-based intracranial SRS and is easy to implement in any radiotherapy facility.

Role of lncRNAs as prognostic markers of hepatic cancer and potential therapeutic targeting by S-adenosylmethionine via inhibiting PI3K/Akt signaling pathways.

Hepatic cancer (HCC) is a well-identified dilemma throughout the world, and hence, the molecular mechanisms and strategy for preventive protection against this malignancy are critical. S-adenosylmethionine (SAM) is a unique methyl granter in vast reactions, including DNA methylation, and secures the genome against hypomethylation, which is a hallmark of tumors. Consequently, SAM may control the rate of gene expression. The objective of this investigation was to evaluate the expression of long noncoding RNAs (lncRNAs) transcript involved in hepatic tumorigenesis, including additional coding CEBPA (ecCEBPA) and urothelial carcinoma related 1 (UCA1), antioxidant enzymes transcripts, and relevant signaling pathway in diethylnitrosamine (DEN)-prompted HCC along with their conceivable targeting by SAM at different stages of HCC in rats. Our outcomes revealed that SAM particularly when given at the starting phase downregulates ecCEBPA and UCA1 gene transcripts and ameliorate histopathological alterations in DEN-initiated HCC. Interestingly, SAM attenuates DEN-induced upregulation of PI3K/Akt protein expression. However, SAM upregulates the antioxidant enzymes mRNA transcripts and effectively diminishing DNA oxidation. The results of a DNA fragmentation assay further support the capacity of SAM to ameliorate DEN-induced hepatic malignancy. These results revealed the role of ecCEBPA and UCA1 in HCC and suggest that these lncRNAs may be helpful as prognostic and analytical biomarkers of HCC. Curiously, SAM readily targets the studied genes via inhibiting PI3K/Akt signaling pathway, which should make SAM an appealing agent for both chemoprevention and treatment of HCC.

Antibacterial activity of silver nanoparticles against field and reference strains of Mycobacterium tuberculosis, Mycobacterium bovis and multiple-drug-resistant tuberculosis strains.

Tuberculosis (TB) is an endemic disease in animals and humans in Egypt. This study aims to investigate the antimycobacterial activity of silver nanoparticles(AgNPs) by determining the minimal inhibitory concentration (MIC) of AgNPs, using the microplate Alamar blue assay. The AgNPs were chemically synthesised and their form and size were characterised by ultraviolet-visible absorption spectrophotometry, transmission electron microscopy and X-ray diffraction.The reference strains of Mycobacterium bovis and Mycobacterium tuberculosisH37Rv, and one multiple-drug-resistant (MDR) strain of M. tuberculosis were tested, as well as clinical isolates of M. bovis and M. tuberculosis. The AgNPs were tetrahydral with a few spherical particles and an average particle size of 50 nm. The mycobacterial strains were varied with MICs of AgNPs. Both reference strains of M. tuberculosis and M. bovis, in addition to the MDR strain of M. tuberculosis, were successfully inhibited by AgNPs at MICs of 1 ?g/ml, 4 ?g/ml and 16 ?g/ml, respectively, whereas clinical isolates of M. bovis and M. tuberculosis were inhibited at MIC values of 4-32 ?g/ml and 1-16 ?g/ml, respectively. The AgNPs showed an in vitro chemotherapeutic effect against Mycobacterium spp.Thus, they can be used to treat TB not only in humans but also in animals, and maybe useful in TB prevention and control strategies worldwide.

En Egypte, la tuberculose est une maladie endémique chez l'homme comme chez l'animal. Les auteurs présentent les résultats d'une étude conduite pour mesurer l'activité antibactérienne des nanoparticules d'argent (NPAg) en déterminant les valeurs de concentration minimale inhibitrice (CMI) des NPAg au moyen du test au bleu Alamar sur microplaques. Les NPAg ont été synthétisées par une méthode chimique et leur forme et taille ont été caractérisées par spectrophotométrie d'absorption dans l'ultra-violet, microscopie électronique à transmission et diffraction des rayons X. L'étude a cible les souches de référence de Mycobacterium bovis et de Mycobacterium tuberculosis H37Rv, ainsi qu'une souche multirésistante de M. tuberculosis et des isolats cliniques de M. bovis et M. tuberculosis. Les NPAg étaient à structure tétraédrique avec quelques particules sphériques ; la taille moyenne des particules etait de 50 nm.La CMI des NPAg variait en fonction des souches. L'inhibition des deux souches de reference de M. tuberculosis et M. bovis et de la souche multirésistante de M. tuberculosis était obtenue avec des CMI de NPAg de 1 ?g/ml, 4 ?g/ml et16 ?g/ml, respectivement, tandis que les isolats cliniques de M. bovis et de M. tuberculosis étaient inhibés en présence de NPAg à des CMI comprises entre 4 et 32 ?g/ml et 1­16 ?g/ml, respectivement. L'efficacité chimiothérapeutique des NPAg contre Mycobacterium spp. a été démontrée in vitro. Ces nanoparticules peuvent donc servir à traiter la tuberculose non seulement chez l'homme mais également chez les animaux et contribuer ainsi aux stratégies de prévention et de lutte contre la tuberculose dans le monde.

En Egipto, la tuberculosis es una enfermedad endemica que afecta a personas y animales. Los autores describen un estudio encaminado a analizar la actividad antimicobacteriana de las nanoparticulas de plata, determinando para ello la concentracion inhibitoria minima de nanoparticulas mediante el ensayo de microtitulacion en placa con azul Alamar. Tras sintetizar quimicamente las nanoparticulas de plata y caracterizar su forma y tamano por espectrometria de absorcion ultravioleta-visible, microscopia electronica de transmision y difraccion de rayos X, se sometieron a prueba las cepas de referencia de Mycobacterium bovis y Mycobacterium tuberculosis H37Rv, asi como una cepa multirresistente de M. tuberculosis y muestras de M. bovis y M. tuberculosis aisladas a partir de casos clinicos. Salvo unas pocas de forma esferica, las nanoparticulas de plataeran tetraedricas. Su tamano era en promedio de 50 nm. Tras someter las cepas de micobacterias a distintas concentraciones de nanoparticulas, se observo que estas inhibian el crecimiento de las cepas de referencia de M. tuberculosis y M. bovis y de la cepa multirresistente de M. tuberculosis a concentraciones minimas de 1 ?g/ml, 4 ?g/ml y 16 ?g/ml, respectivamente, mientras que las muestras clinicas de M. bovis y M. tuberculosis quedaban inhibidas por la presencia de nanoparticulas a valores de concentracion minima de 4­32 ?g/ml y 1­16 ?g/ml, respectivamente. Tambien se observo que, in vitro, las nanoparticulas de plata mostraban actividad farmacologica contra Mycobacterium spp. De ahi se sigue que pueden ser empleadas para tratar la tuberculosis no solo en personas, sino tambien en animales, y que pueden resultar utiles en todo el mundo para las estrategias de prevencion y control de la tuberculosis.

Response of primiparous and multiparous buffaloes to yeast culture supplementation during early and mid-lactation.

Strains of live Saccharomyces cerevisiae yeast have exhibited probiotic effects in ruminants. This study investigated the effects of the dietary yeast supplement, S. cerevisiae (Yea-Sacc1026), on primiparous (PP) and multiparous (MP) Egyptian buffaloes in early to mid-lactation. Lactating buffaloes were fed either a basal total mixed ration (TMR, control; 4 PP and 8 MP) or the basal TMR plus 10 g Yea-Sacc1026 per buffalo cow per day (yeast; 4 PP and 8 MP). The feeds were given from 15 days prepartum to 180 days postpartum. Feed intake, body weight, and milk yields (MY) were recorded, and milk and blood samples were collected for analyses. Feces were collected from days 45 to 47 during early lactation and from days 90 to 92 during mid-lactation to determine apparent digestibility of dry matter (DM), organic matter (OM), crude protein (CP) and crude fiber (CF). Energy corrected milk yield (ECM), feed conversion, and energy and nitrogen conversion efficiency were calculated. Yeast treated MP buffaloes consumed more DM (P ≤ 0.041) and CP than the untreated control group. Apparent digestibility of DM and OM were significantly greater at mid-lactation for treated versus control group (P = 0.001). Crude fiber digestibility was greater in MP than in PP buffaloes (P = 0.049), and yeast supplemented MP cows had a greater CF digestibility than control MP buffaloes at mid-lactation (P = 0.010). Total blood lipids decreased after yeast supplementation (P = 0.029). Milk yields, ECM, fat and protein yields increased for yeast treated MP buffaloes (P ≤ 0.039). The study concluded that the response to yeast supplementation in buffalo cows is parity dependent. Multiparous buffaloes respond to yeast supplementation with an increased DM intake and CF digestibility without significant weight gains, allowing a greater ECM yield with less fat mobilization. Supplementing buffaloes with yeast culture may increase milk production in early lactation and results in a more persistent milk production during mid-lactation. Feed conversion and energy and nitrogen conversion efficiency may be increased with the use of yeast supplementation in Egyptian buffaloes.

[Prognostic factors of hyperbaric oxygen therapy in hemorrhagic radiation cystitis]. / Facteurs pronostiques d'efficacite de l'oxygénothérapie hyperbare dans le cadre de la cystite radique hemorragique.

OBJECTIVE: To emphasize prognostic factors of hyperbaric oxygen therapy (HBOT) on hematuria at 3 and 12 months in the context of a radiation cystitis. MATERIAL AND METHODS: A cohort of 134 patients was treated from 2008 to 2013 in the hyperbaric medicine center of Toulouse University Hospital, France for radiation cystitis. Hematuria was ranked using the SOMA score. HBOT has been applied according to a standardized protocol of 20 renewable sessions, with pure oxygen to 2.5 ATA. The median number of sessions at 12 months was 50. RESULTS: HBOT had an efficacy of 83% at 3 months and 81% at 12 months. Twenty percent of patients had minor side effects. Compared to the pre-HBOT period, the number of hospitalizations decreased by 75% following treatment. The efficacy at 3 months was predictive of efficacy at 12 months (P<0.0001). There was an inverse correlation between the initial grade and efficacy at 3 months (P=0.026) and 12 months (P=0.001). A high WHO status diminished HBOT efficacy at 3 and 12 months (P=0.0014 and P<0.0001, respectively). An anticoagulant intake decreased the HBOT response at 12 months (P=0.002). Other parameters had no effects on efficacy. CONCLUSION: The efficacy at 3 months seems to be predictive of efficacy at 12 months. The initial hematuria grade is inversely correlated with efficacy at 3 and 12 months. It appears necessary to achieve at least 32 HBOT sessions. Moreover, a high WHO status and an anticoagulant intake seem to have a negative prognostic value. LEVEL OF EVIDENCE: 4.

[Urinary complications of pelvic exenterations for rectal cancer with urinary invasion]. / Complications urinaires des exentérations pelviennes pour cancer du rectum avec envahissement urinaire.

OBJECTIVE: Pelvic exenteration for rectal cancer is indicated in locally advanced rectal tumors or pelvic recurrence invading adjacent organs. The oncologic goal being a complete R0 resection. Our aim was to study the urinary complications resulting from pelvic exenterations with urinary reconstruction in order to obtain a complete local control of the disease. METHODS: Between April 2004 and June 2013, 42 patients who underwent pelvic exenteration for primary or recurrent rectal adenocarcinoma with urinary tract reconstruction were included. The urinary reconstruction was performed based on preoperative imaging and intraoperative findings. We studied early (within 30 postoperative days) and late urinary morbidity, as well as postoperative carcinologic control. RESULTS: Forty-two exenterations were performed for primary rectal cancer (n=15) or pelvic recurrence (n=27). R0 complete resection was achieved in 64% of patients. The resection was incomplete (R1) on the urinary tract in 9.5% of patients. The urinary reconstruction methods used were: 31 transileal ureterostomies after total exenteration (bricker procedure), 6 ureteral reimplantations on psoic bladder, 2 ureteroileoplasties, 2 partial cystectomies and one ureteral resection with simple ligation. The median follow-up was 20 months. The perioperative mortality was 2.3% (n=1) and postoperative overall morbidity was 64%. Early and late urinary morbidity was 23.8% and 21.4% respectively. Six patients developed major urinary complications (≥ Clavien IIIb). CONCLUSION: Pelvic exenteration with urinary resection resulted in our experience, in a local disease control of 64% (including a 90.5% for the urinary tract) at the price of an acceptable early specific morbidity and a low mortality that seems to justify an aggressive surgical approach.

Ultrastructure and distribution of the taste buds in the buccal cavity in relation to the food and feeding habit of a herbivorous fish: Oreochromis niloticus.

The buccal cavity of an herbivorous fish Oreochromis niloticus was investigated by means of scanning electron microscopy. The buccal cavity distinguished into the roof and the floor. Three different types of taste buds (type I, II and III) are distributed in the buccal cavity. The proximal part of the buccal cavity bears relatively high epidermal papillae in which type I TBs was found. The middle region of the buccal cavity is mostly occupied by low epidermal papillae containing type II TBs. Type III TBs which are present within the metabranchial buccal cavity; never rise above the normal level of the epithelium. The different types of TBs are useful for ensuring full utilization of the gustatory ability of the fish. It is postulated that the TBs serve different functions: TBs type I and II may act as chemoreceptors and mechanoreceptors. TBs type III acts predominantly as a chemoreceptors. TBs of each type show two kinds of receptor villi within their receptor areas: tall villi and small villi. The surface of the lining epithelial cells shows a delicate microridge system. These structures protect against physical abrasion potentially caused during food maneuvering and swallowing. Furthermore, protection of the epithelium from abrasion is enhanced with goblet cells secretion.

Prognostic significance of Dicer expression in ovarian cancer-link to global microRNA changes and oestrogen receptor expression.

MicroRNA (miRNA) deregulation is a hallmark of human cancer. However, the mechanisms underlying miRNA alteration and the specific role of proteins involved in miRNA processing remains to be elucidated. Dicer is a key enzyme in the miRNA processing pathway that is essential for the production of mature miRNAs from their precursors. We tested the hypothesis that Dicer has biological and clinical relevance in ovarian cancer, using a range of methods including in vitro manipulation of Dicer expression. We observed down-regulation of Dicer in a subgroup of ovarian carcinomas, and found that decreased Dicer expression correlates significantly with reduced patient survival in serous cancers and advanced disease stages. Moreover, microarray and functional analysis suggest that reduced Dicer expression is connected with a global down-regulation of the microRNAome and with gene expression changes, particularly reduced expression of oestrogen receptor (ER) mRNA and protein in tumour tissue and in cell culture. Our data suggest a common mechanism for miRNAs changes by alterations in the basic machinery controlling miRNA biogenesis, of which Dicer is a central enzyme. These alterations of miRNA processing are of prognostic value and may play a role in the molecular pathogenesis of ovarian carcinoma and, possibly, other tumours. Knowledge of these molecular pathways may help toward new targeted therapeutic approaches for ovarian cancer.

Expression of multidrug resistance-associated protein 1 in invasive ovarian carcinoma: implication for prognosis.

AIMS: Multidrug resistance is a major impediment in chemotherapeutic treatment of ovarian carcinoma patients. The aim of this study was to investigate the expression of multidrug resistance-associated protein 1 (MRP1) and to assess the possible associations with clinicopathological variables and patient outcome in primary ovarian carcinoma. METHODS AND RESULTS: Tumour specimens from 129 patients were obtained before chemotherapy and analysed by immunohistochemistry on tissue microarrays, and by real-time reverse transcriptase-polymerase chain reaction on RNA extracted from formalin-fixed paraffin-embedded tissue specimens using a new technique. Significantly increased MRP1 protein expression was observed in high-grade tumours (P = 0.005) and advanced International Federation of Gynaecology and Obstetrics stages (P = 0.036). On univariate Kaplan-Meier analysis, patients with higher expression of MRP1 protein had significantly decreased overall survival (P = 0.006). On multivariate Cox regression analysis, MRP1 protein expression retained its significance as an independent negative prognostic marker for overall survival (hazard ratio = 6.52, P = 0.003). Furthermore, MRP1 expression correlated with topoisomerase IIalpha expression both at mRNA and protein level (P < 0.001 and P = 0.023, respectively). CONCLUSION: In summary, in patients with primary ovarian cancer, overexpression of MRP1 is an adverse marker for patient outcome and cancer aggressiveness. Our data provide a translational basis for further clinical studies on the predictive value of MRP1 expression for response to chemotherapy.