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- Fibulin-5 is up-regulated by hypoxia in endothelial cells through a hypoxia-inducible factor-1 (HIF-1α)-dependent mechanism. [Journal Article, Research Support, Non-U.S. Gov't]
- J Biol Chem 2011 Mar 4; 286(9):7093-103.
Hypoxia modulates gene expression and affects multiple aspects of endothelial cell biology. Fibulin-5 (FBLN5) is an extracellular matrix protein essential for elastic fiber assembly and vasculogenesis that participates in vascular remodeling and controls endothelial cell adhesion, motility, and proliferation. In this context, we aimed to analyze FBLN5 regulation by hypoxia in endothelial cells. Hypoxia (1% O(2)) increased FBLN5 mRNA levels in endothelial cells in a time-dependent manner. Maximal induction (∼2.5-fold) was achieved after 24 h of hypoxia. This effect paralleled an increase in both intracellular and extracellular FBLN5 protein levels. The increase in FBLN5 mRNA levels observed in hypoxic cells was blocked by inhibitors of the PI3K/Akt/mTOR pathway (LY294002 and rapamycin) and mimicked by dimethyl oxal glycine, which prevents proline hydroxylase-mediated degradation of HIF-1α. Silencing of HIF-1α completely prevented hypoxia-induced FBLN5 up-regulation. Accordingly, both hypoxia and HIF-1α overexpression increased FBLN5 transcriptional activity. Serial promoter deletion and mutagenesis studies revealed the involvement of a putative hypoxia response element (HRE) located at -78 bp. In fact, EMSA and ChIP assays demonstrated increased HIF-1 binding to this site in hypoxic cells. Interestingly, the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia increased in FBLN5 knockdown cells, suggesting that hypoxia-induced FBLN5 expression contributes to preserve cell survival. These results provide evidence that HIF-1 signaling underlies the increase of FBLN5 expression elicited by hypoxia in endothelial cells and suggest that FBLN5 induction could be involved in the adaptive survival response of endothelial cells to hypoxia.
- Vinasse added to the concentrate for fattening lambs: intake, animal performance, and carcass and meat characteristics. [Journal Article, Research Support, Non-U.S. Gov't]
- J Anim Sci 2011 Apr; 89(4):1153-62.
Twenty-four Merino lambs (mean BW 15.4 ± 0.13 kg, 6 to 7 wk old) were used to study the effects of the addition of 0 (control), 100 (V10), and 200 (V20) g of vinasse per kilgram of concentrate on intake, animal performance, biochemical blood profile, and carcass and meat characteristics. Lambs were assigned to 1 of 3 experimental diets and fed barley straw and the corresponding concentrate ad libitum. When the animals reached 25 kg of BW, a sample of blood was taken and the lambs were slaughtered. Feed intake, growth rate, biochemical blood profile, and carcass and meat characteristics were assessed. Lambs that received the concentrates with vinasse showed a reduced concentrate intake (linear contrast, P = 0.029) and ADG (linear contrast, P = 0.004) and an increased length of fattening period (linear contrast, P = 0.002) as well as feed:gain ratio (linear contrast P = 0.011). Vinasse enhanced ruminal pH (orthogonal contrast control vs. V10 + V20; P = 0.007). Plasma glucose concentrations declined in lambs fed vinasse (linear contrast, P = 0.003), whereas plasma urea concentration increased in animals fed vinasse (linear contrast, P = 0.036). The plasma concentrations of creatinine, triglycerides, and lactate and the enzyme profile studied (alkaline phosphate, alanine transaminase, glutamate oxal-acetate transaminase, γ-glutamyl transpeptidase, and lactate dehydrogenase) were not modified in response to vinasse inclusion. Lambs in the vinasse groups had less Na(+) and nitrate and greater K(+) and nitrite plasma concentrations (linear contrasts, P < 0.05). None of the carcass characteristics studied was affected by vinasse (P > 0.10). Meat chemical composition and characteristics were unaffected (P > 0.10), but shear force was greater for lambs that received vinasse (orthogonal contrast, control vs. V10 + V20, P = 0.007). The addition of 100 or 200 g vinasse/kg of concentrate for fattening lambs reduced feed intake and growth rate and increased the feed:gain ratio and meat toughness without affecting any other carcass and meat characteristics.
- Allopregnanolone prevents and suppresses oxaliplatin-evoked painful neuropathy: multi-parametric assessment and direct evidence. [Journal Article, Research Support, Non-U.S. Gov't]
- Pain 2011 Jan; 152(1):170-81.
Oxaliplatin (OXAL) is a platinum-based drug used for the treatment of colorectal, lung, breast and ovarian cancers. OXAL does not cause renal or hematologic toxicity. However, OXAL induces neuropathic pain which hampers the chemotherapy success. Attempts with neuroprotective agents including anticonvulsivants and antidepressants were made to prevent OXAL-induced painful neuropathy but the clinical data are controversial and the tested neuroprotectors are able to evoke themselves undesirable effects. Here, we demonstrated that the natural neurosteroid allopregnanolone (3α,5α-THP), known to be devoid of toxic side-effects in humans and experimental models, prevented and suppressed OXAL-induced painful neuropathic symptoms. Indeed, 3α,5α-THP repaired OXAL-evoked neurochemical and functional alterations in peripheral nerves and intra-epidermal nerve fibers (IENF). Behavioral analyses showed that prophylactic or corrective 3α,5α-THP treatment (4mg/kg/2days) respectively prevented or abolished OXAL-induced cold allodynia, mechanical allodynia and hyperalgesia by reversing to normal decreased thermal and mechanical pain thresholds of OXAL-treated rats. Electrophysiological investigations revealed that 3α,5α-THP restored control values of sciatic nerve conduction velocity and action potential peak amplitude drastically reduced by OXAL-treatment. Furthermore, immunohistochemistry and confocal microscopic quantifications demonstrated that 3α,5α-THP repaired OXAL-induced neurochemical/cellular alterations by restoring IENF control density and normal level of neurofilament 200kDa that was strongly repressed by OXAL in dorsal root ganglion neurons and sciatic nerve axons. OXAL showed no toxicity for the non-compact myelin protein 2',3'-cyclic-nucleotide-3'-phosphodiesterase whose expression level was similarly increased by 3α,5α-THP in controls and OXAL-treated rat nerves. Together, these results may be interesting for the development of natural or safe neurosteroid-based neuroprotective strategy against anticancer drug-evoked painful neuropathy.
- Oxaliplatin-mediated inhibition of survivin increases sensitivity of head and neck squamous cell carcinoma cell lines to paclitaxel. [Comparative Study, Journal Article]
- Curr Cancer Drug Targets 2010 Nov; 10(7):660-9.
The present study deals with the evaluation of the efficacy of oxaliplatin and paclitaxel combination as a potential strategy in controlling HNSCC cell proliferation and the assessment of correlation between occurrence of apoptosis and changes in expression of survivin (IAP). The panel cell lines included two HNSCC cell lines (Cal27 and NT8e) and one normal cell line (293) with differential level of survivin expression in accordance with chemosensitivity. The cytotoxicity and effect of drugs on apoptosis was determined, separately and in combination. Combined treatment of cells with paclitaxel and oxaliplatin resulted in significantly higher cytotoxicity as compared to individual single drug treatment. Cytotoxicity was prominent in paclitaxel to oxaliplatin (pacl-oxal) sequence treatment with an approximate two-fold increase in apoptosis as compared to oxaliplatin to paclitaxel (oxal-pacl) sequence treatment. Paclitaxel treatment also caused increased survivin expression showing reduced apoptosis at low concentration. Oxaliplatin, when combined with paclitaxel, decreased the survivin level with increased cell death. Inhibition of survivin by a small interfering RNA (siRNA) method also increased the sensitivity of the cancer cell lines to paclitaxel whereas over-expression of survivin in the transfected 293-cell line provided resistance. In conclusion, the interaction between drugs was synergistic and schedule-dependent. Survivin played a critical role in paclitaxel resistance through the suppression of apoptosis, and a significant induction of apoptosis was observed when oxaliplatin was combined with paclitaxel at least in part by the down-regulation of survivin.
- Evaluation of soil characteristics potentially affecting arsenic concentration in paddy rice (Oryza sativa L.). [Journal Article, Research Support, Non-U.S. Gov't]
- Environ Pollut 2009 Oct; 157(10):2617-21.
Paddy rice may contribute considerably to the human intake of As. The knowledge of soil characteristics affecting the As content of the rice plant enables the development of agricultural measures for controlling As uptake. During field surveys in 2004 and 2006, plant samples from 68 fields (Italy, Po-area) revealed markedly differing As concentration in polished rice. The soil factors total As(aqua regia), pH, grain size fractions, total C, plant available P(CAL), poorly crystalline Fe(oxal.) and plant available Si(Na-acetate) content that potentially affect As content of rice were determined. A multiple linear regression analysis showed a significant positive influence of the total As(aqua regia) and plant available P(CAL) content and a negative influence of the poorly crystalline Fe(oxal.) content of the soil on the As content in polished rice and rice straw. Si concentration in rice straw varied widely and was negatively related to As content in straw and polished rice.
- The mechanism of the actions of oxaliplatin on ion currents and action potentials in differentiated NG108-15 neuronal cells. [Journal Article, Research Support, Non-U.S. Gov't]
- Neurotoxicology 2009 Jul; 30(4):677-85.
Oxaliplatin (OXAL) is a platinum-based chemotherapeutic agent which is effective against advanced or metastatic gastrointestinal cancer. However, the mechanisms responsible for the development of the neuropathy induced by this agent remain unclear. In this study, we attempted to evaluate the possible effects of OXAL on ion currents and action potentials (APs) in NG108-15 cells differentiated with dibutyryl cyclic-AMP. Application of OXAL decreased the peak amplitude of voltage-gated Na(+) current (I(Na)) with no change in the overall current-voltage relations of the currents. This agent also produced a concentration-dependent slowing of I(Na) inactivation. A further application of ranolazine reversed OXAL-induced slowing of I(Na) inactivation. Unlike ranolazine or riluzole, OXAL had no effect on persistent I(Na) elicited by long ramp pulses. OXAL (100 microM) also had little or no effect on the peak amplitude of L-type Ca(2+) currents in NG108-15 cells, while it suppressed delayed-rectifier K(+) current. In current-clamp recordings, OXAL alone reduced the amplitude of APs; however, it did not alter the duration of APs. However, after application of tefluthrin, OXAL did increase the duration of APs. Moreover, OXAL decreased the peak amplitude of I(Na) with a concomitant reduction of current inactivation in HEK293T cells expressing SCN5A. The effects of OXAL on ion currents presented here may contribute to its neurotoxic actions in vivo.
- Phase I trial of adjuvant hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone plus systemic oxaliplatin, 5-fluorouracil and leucovorin in patients with resected liver metastases from colorectal cancer. [Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't]
- Ann Oncol 2009 Jul; 20(7):1236-41.
The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5-fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone (Dex) in the adjuvant setting after hepatic resection.Thirty-five patients with resected liver metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU.The initial dose of HAI FUDR was fixed at 0.12 mg/kg x pump volume divided by pump flow rate plus Dex infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85 to 100 mg/m2 and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m2. The LV dose was fixed at 400 mg/m). Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4-year survival and progression-free survival were 88% and 50%, respectively.Adjuvant therapy after liver resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m2 and 5-FU by continuous infusion at 2000 g/m2 with LV at 400 mg/m2 is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.
- Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. [Comparative Study, Journal Article]
- J Am Coll Surg 2008 Jan; 206(1):96-106.
Although commonly used in combination with irinotecan or oxaliplatin (iri/oxal) for treatment of colorectal liver metastases before extirpation, the effects of preoperative bevacizumab on surgical outcomes are not established. The objective of this retrospective study was to determine if addition of bevacizumab to iri/oxal preoperative chemotherapy increases morbidity after hepatic resection.We compared demographics, clinicopathologic data, treatments, and postoperative outcomes between patients given preoperative iri/oxal with and without bevacizumab and patients who underwent hepatic resection within and after 8 weeks from the last dose of bevacizumab.From 1996 to 2006, 96 patients were treated with preoperative iri/oxal; 39 (40.6%) received concurrent bevacizumab. Preoperative bevacizumab treatment was associated with less blood loss (median 425 mL versus 600 mL, p=0.01) and lower RBC transfusion rates (43.9% versus 23.1%, p=0.06) after partial hepatectomy on univariable analysis. Only age>or=70 years (hazard ratio=8.52, 95% CI [2.00 to 36.45]) and concurrent extrahepatic procedures (hazard ratio=4.12, 95% CI [1.49 to 11.39]) independently predicted RBC transfusion and overall complications, respectively. There were no differences in overall (43.6% versus 38.6%), severe (28.2% versus 24.6%), hepatic (17.9% versus 26.3%), wound (10.3% versus 7%), or thromboembolic or bleeding (2.6% versus 5.3%) complications (all p > 0.05). For patients treated with iri/oxal and bevacizumab, overall complications were more common when resection was performed within 8 weeks after the last bevacizumab dose (62.5% versus 30.4%), but this difference was not statistically significant (p=0.06).If discontinued at least 8 weeks before hepatic resection, addition of bevacizumab to preoperative iri/oxal does not increase morbidity after hepatic resection.
- Automated determination of blood metabolic acidosis, total acid phosphatase, angiotensin converting enzyme, fructosamine and urinary oxalate and citrate on the ABX Pentra 400. [Comparative Study, Evaluation Studies, Journal Article]
- Clin Lab 2007; 53(7-8):461-7.
We have adapted automated assays for quantification of pyruvate (PYR), acetoacetate (AA), and betahydroxybutyrate (BOHB) in plasma, total acid phosphatase (TAP), angiotensin converting enzyme (ACE) and fructosamine (FRUCT) in serum, and oxalate (OXAL) and citrate (CIT) in urine that can be performed on the ABX Pentra 400. The aim of this study was to evaluate the analytical performances of these parameters and to compare data obtained in patient samples with those obtained with the Cobas Mira. Within-run and between-run imprecisions ranged from 0.55 to 14.2 and 0.37 to 11.8%, respectively. Correlations with the Cobas Mira showed r2 coefficients ranging from 0.816 to 0.983 and linear regression slopes from 0.706 to 1.087. The ABX Pentra 400 provides precise and accurate measurement for a wide variety of analytes including PYR, AA, BOHB, TAP, ACE, FRUCT in blood samples and OXAL, CIT in urine.
- Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. [Clinical Trial, Clinical Trial, Phase I, Journal Article]
- J Clin Oncol 2005 Aug 1; 23(22):4888-96.
To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer.Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days.The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection.Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.