Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy

BACKGROUND: Combined treatments of mycophenolate mofetil (MMF) and losartan (LSRT) have synergistic effects on various renal diseases through their hemodynamic and anti-inflammatory effects. This study investigated whether MMF treatment is effective in inhibiting inflammatory processes in chronic cyclosporine A (CsA) nephrotoxicity, and whether combined treatment using MMF and LSRT affords superior protection compared with the respective monotherapies. METHODS: Rats on a low-salt diet were given vehicle (VH group, olive oil, 1 mg/kg per day), CsA (15 mg/kg per day), CsA and LSRT (CsA+LSRT group, 100 mg/L per day), CsA and MMF (CsA+MMF group; 40 mg/kg per day), or CsA, LSRT and MMF (CsA+LSRT MMF group). Control groups received each drug without CsA treatment. Renal function, histologic parameters (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and mediators of CsA-induced nephrotoxicity (angiotensin-II, osteopontin, and transforming growth factor [TGF]-beta1) were studied. RESULTS: The CsA-treated rats showed decreased renal function and increased histologic parameters compared with the VH-treated rats. The CsA+MMF treatment significantly improved renal function and histopathologic parameters compared with the CsA group, and combined treatment with MMF and LSRT further improved those parameters compared with the CsA+LSRT and CsA+MMF groups. At a molecular level, increased expression of angiotensin II protein, osteopontin, and TGF-beta1 mRNAs in the CsA group were significantly decreased with MMF, and further decrease was observed with the combined treatment using MMF and LSRT. CONCLUSIONS: MMF treatment decreases CsA-induced nephrotoxicity, and combined treatment with LSRT has a synergistic effect in preventing chronic CsA nephrotoxicity.     

hOGG1 Ser326Cys polymorphism and breast cancer risk among Asian women

To evaluate the potential association between breast cancer risk and Ser ³²⁶ Cys polymorphism of hOGG1 gene, encoding for an enzyme involved in the base excision repair of 8-hydroxyguanine, hospital based case-control studies were conducted in two Asian populations consisting of 475 breast cancer cases (271 Korean and 204 Japanese) and 500 controls (314 Korean and 186 Japanese). PCR-based methods were employed for the genotyping analyses and the statistical evaluations were performed by unconditional logistic regression model. The frequency of hOGG1 Ser/Ser, Ser/Cys, and Cys/Cys genotypes were 22.5, 48.7, and 28.8% in all cases, and 23.7, 52.1, and 24.1% in the controls. No statistically significant associations between the genotypes and breast cancer risk were observed, neither when the ethnic groups were examined separately nor when the total study population was included. Neither did stratification by menopausal status reveal any association between hOGG1 genotypes and breast cancer. Our novel findings therefore suggest that hOGG1 Ser ³²⁶ Cys polymorphism is unlikely to play a modifying role in individual susceptibility to breast cancer among Asian women.     

Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma

SAP-1 (stomach cancer-associated protein tyrosine phosphatase-1) is a transmembrane-type protein tyrosine phosphatase that has been implicated as a negative regulator of integrin-mediated signaling. The potential role of this enzyme in hepatocarcinogenesis has now been investigated by examining its expression in 32 surgically excised human hepatocellular carcinoma (HCC) specimens. Both immunohistochemical and immunoblot analyses revealed that normal liver tissue, as well as tissue affected by chronic hepatitis or cirrhosis, contained substantial amounts of SAP-1. The expression level of SAP-1 in 75% of well-differentiated HCCs was similar to or higher than that observed in the surrounding noncancerous tissue. In contrast, the abundance of SAP-1 in 85.7% of moderately differentiated HCCs and in all poorly differentiated HCCs was greatly reduced compared with that in the adjacent tissue. Indeed, SAP-1 was almost undetectable in 83.3% of poorly differentiated HCCs. Furthermore, expression of recombinant SAP-1 in two highly motile human HCC cell lines resulted in a change in morphology and a marked reduction in both migratory activity and growth rate. In conclusion, these results indicate that SAP-1 expression is downregulated during the dedifferentiation of human HCC, and that this downregulation may play a causal role in disease progression.     

Doxorubicin-based chemotherapy for diffuse large B-cell lymphoma in elderly patients: comparison of treatment outcomes between young and elderly patients and the significance of doxorubicin dosage

BACKGROUND: Although many studies of elderly patients with non-Hodgkin lymphoma have focused on the dose intensity of chemotherapy, few studies have restricted the histologic inclusion criteria such that only patients with diffuse large B-cell lymphoma (DLCL) are considered. In the current study, treatment outcomes for elderly patients (age > or = 60 years) were analyzed, with emphasis on the dose intensity of doxorubicin. METHODS: Between 1994 and 2000, 195 patients with DLCL were treated initially with doxorubicin-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, vincristine, bleomycin, doxorubicin, procarbazine, and prednisone). Of these patients, 70 were aged 60 years or older. RESULTS: Elderly patients had poorer treatment outcomes than did young patients (5-year survival, 30% vs. 57%; P < 0.001); however, elderly patients who received doxorubicin at dose intensities > or = 10 mg/m2 per week (n = 25) had outcomes (5-year survival, 52%) that were comparable to those of young patients. Among prognostic factors, only International Prognostic Index score (P = 0.022) and dose intensity of doxorubicin (P = 0.039) were found to have significant effects on the overall survival of elderly patients. When the reasons for doxorubicin dose reduction in 45 elderly patients who ultimately received doxorubicin at dose intensities < 10 mg/m2 per week were analyzed, it was found that 20 patients received reduced doses from the start of treatment because of their old age alone; these dose reductions in the 20 cases resulted in poorer treatment outcomes. CONCLUSIONS: Elderly patients with DLCL who received doxorubicin at dose intensities > or = 10 mg/m2 per week had treatment outcomes that were comparable to those of young patients; however, physician bias associated with patient age was found to be related to unnecessary dose reductions. Efforts to maintain doxorubicin dose intensities > or = 10 mg/m2 per week and more objective standards for the selection of elderly patients capable of tolerating doxorubicin-based regimens are required.     

Effect of lifetime lactation on breast cancer risk: a Korean women's cohort study

The objective of our study was to examine the effect of lifetime lactation on breast cancer risk among premenopausal women. The data were from a prospective cohort study with a follow-up period of 6 years in Korea (1995-2000). The cohort was composed of 110,604 premenopausal parous Korean women, aged 20 years and older, who received health insurance from the Korea Medical Insurance Corporation and who had medical evaluations in 1992 and 1994. Multivariate Cox proportional hazard models were tested, controlling for age, age at menarche, number of children, age at first pregnancy, oral contraceptive use, smoking, exercise and obesity. At baseline, 57,440 (51.9%) reported breastfeeding and 4,584 (4.1%) reported breastfeeding more than 24 months. From 1995-2000, 360 incident cases of breast cancer (61.8/100,000 person-years) occurred. Compared to parous women who had no history of lactation, a period of lactation of 13-24 months decreased the risk of breast cancer (RR, 0.7; 95% CI, 0.5-1.1), and this risk was decreased even further for those who breastfed for more than 24 months (RR, 0.6; 95% CI, 0.3-1.0). There was a clear trend of decreasing breast cancer risk with the duration of lactation (p for trend <0.001). In conclusion, our study of a large Korean cohort provides additional empirical evidence to current theoretical conjecture that lactation decreases the risk of breast cancer among premenopausal women.     

Rational design of an indolebutanoic acid derivative as a novel aldose reductase inhibitor based on docking and 3D QSAR studies of phenethylamine derivatives

A series of 45 phenethylamine derivatives were synthesized and evaluated for their inhibitory activity against pig kidney aldose reductase (ALR2, EC 1.1.1.21). Their IC(50) values ranged from 400 microM to 24 microM. The binding modes of compounds at the active site of ALR2 were examined using flexible docking. The results indicated that phenethylamine derivatives nicely fit into the active pocket of ALR2 by forming various hydrogen bonding and hydrophobic interactions. 3D-QSAR analysis was also conducted using FlexX-docked alignment of the compounds. The best prediction was obtained by CoMSIA combined with hydrophobic and hydrogen bond donor/acceptor field (q(2) = 0.557, r(2) = 0.934). A new derivative, 4-oxo-4-(4-hydroxyindole)butanoic acid, was designed, taking into account the CoMSIA field and the binding mode derived by FlexX docking. This rationally designed compound exhibits an ALR2 inhibition with an IC(50) value of 7.4 microM, which compares favorably to that of a well-known ALR2 inhibitor, tolrestat (IC(50) = 16 microM) and represents a potency approximately 240-fold higher than that of an original phenethylamine lead compound, YUA001.     

The effect of extremely low frequency electromagnetic fields (ELF-EMF) on the frequency of micronuclei and sister chromatid exchange in human lymphocytes induced by benzo(a)pyrene

The interaction of extremely low frequency electromagnetic fields (ELF-EMF) on the frequency of micronuclei (MN) and sister chromatid exchange (SCE) induced by benzo(a)pyrene (BP) in human lymphocytes was examined. A 60 Hz ELF-EMF of 0.8 mT field strength was applied either alone or with the tumor initiator, BP for 24 h. The frequencies of MN and SCE induced by BP increased in a dose-dependent manner. The co-exposure of cells to BP and 0.8 mT ELF-EMF for 24 h, followed by BP exposure for 48 h led to significant increases in the frequencies of MN and SCE compared to BP treatment for 72 h alone (P<0.05), but no significant difference was observed between field exposed and sham exposed control cells. The obtained results suggest that low density ELF-EMF could act as an enhancer of the initiation process of BP rather than as an initiator of mutagenic effects in human lymphocytes.     

A High-Throughput Combinatorial Approach for the Discovery of a Cremophor EL-Free Paclitaxel Formulation

Purpose. The purpose of this work was to replace Cremophor-EL in the commercial paclitaxel intravenous formulation, Taxol®, using a novel high-throughput combinatorial formulation approach. Methods. Full factorial combinations of 12 generally regarded as safe excipients at three different concentrations were screened using an automated liquid dispenser. The hit formulations were further optimized to give the final optimized formulation TPI-1. TPI-1 was then tested in rats to compare its pharmacokinetic profile to Taxol®. Results. Of the 9,880 combinations tested in the initial screen, 19 were identified as hit combinations. These were further optimized to give the final formulation TPI-1. When tested in rats, TPI-1 was well tolerated at both the low and high doses of 5 mg/kg and 10 mg/kg, whereas Taxol® killed all the rats at the high dose. TPI-1 experienced slower elimination compared to Taxol®. Similar to Taxol®, TPI-1 also exhibited nonlinear pharmacokinetics. Conclusions. This study demonstrated the power of a high-throughput combinatorial approach for alternative paclitaxel formulations. We believe that this approach can be applied to drug formulation in general and it can improve the speed and efficiency of drug formulation design.     

Umbilical arteritis and phlebitis mark different stages of the fetal inflammatory response

OBJECTIVE: Funisitis, the inflammation of the umbilical cord determined by histologic examination of the placenta, is evidence of a fetal inflammatory response. The inflammatory process may involve the umbilical vein (phlebitis) and one or both umbilical arteries (arteritis) and extend into the Wharton's jelly. This study was conducted to examine whether the pattern of inflammation of the umbilical cord correlates with a biochemical marker of systemic fetal inflammation (umbilical cord plasma interleukin-6) and an adverse neonatal outcome. STUDY DESIGN: This cohort study included 636 cases of preterm delivery (<36 weeks) with or without inflammation of the umbilical cord. Umbilical cord blood was collected at the time of delivery. The aim of pathologic examination was to characterize the extent of umbilical cord inflammation and the involvement of the vein (phlebitis), the involvement of one or both arteries (arteritis), and the presence of inflammation of the Wharton's jelly. Umbilical cord plasma interleukin-6 concentrations were assayed by a sensitive and specific immunoassay. RESULTS: Neonates with umbilical arteritis had a significantly higher median concentration of cord plasma interleukin-6 (median, 111 pg/mL; range, 0.1-19,230 pg/mL) than those without umbilical arteritis (median, 22.5 pg/mL; range, 0.9-511.6 pg/mL; P <.05). Also, severe neonatal morbidity occurred more frequently in infants with arteritis than in those without arteritis (74% vs 50%; P <.05). And finally, the most severe form of inflammation, which involves both arteries, vein, and Wharton's jelly, was associated with the highest median concentration of plasma interleukin-6 observed in this study (median, 182.6 pg/mL; range, 0.1-7,400 pg/mL), whereas inflammation limited to the vein (phlebitis) was associated with a lower concentration of cord plasma interleukin-6 (median, 29.1 pg/mL; range, 0.9-511.6 pg/mL; P <.05). CONCLUSION: Neonates whose placenta demonstrates umbilical arteritis have higher concentrations of umbilical cord plasma interleukin-6 and higher rates of adverse outcome than those without umbilical arteritis.