BP Treatment Research Articles

Tissue-specific expression of hormonal carcinogenesis target genes in rats treated with polycyclic aromatic hydrocarbons

We have investigated the effect of polycyclic aromatic hydrocarbons (PAHs) on estrogen-metabolizing genes CYP1A1, CYP1B1, CYP19 and ERalpha and cyclin D1 genes, which control of cell division in estrogen-depended tissues. Treatment of rats with benzo(a)pyren (BP) or 3-methylcholantrene (MC) significantly up-regulated CYP1A1, CYP1B1 gene expression in liver, uterus and ovary, whereas alfa-naphthoflavone (alpha-NF) did not have any effect. The high level of aromatase gene (CYP19) expression was detected in ovary only. Treatment of rats with BP or MC significantly down-regulated expression of this gene (15- and 5,5-fold, respectively), whereas alpha-NF did not have any effect. BP produced an increase in ERalpha and cyclin D1 gene expression in rat liver. This effect was not seen with MC and alpha-NF. ERalpha and cyclin D1 mRNA levels were unchanged in uterus of rats after PAHs treatment. On the other hand, BP treatment caused an increase of the ERalpha and cyclin D1 mRNA levels (3,5- and 2,5-fold, respectively) in ovary, whereas MC and alpha-NF did not have any effects. Thus, our results give evidence for tissue-specific effects of PAHs on expression of genes, which participate in hormonal carcinogenesis. Moreover, the fact that BP and MC treatment affects the expression of estrogen-metabolizing genes and genes, which control of cell division, supports the view that PAHs may be one of the causes of endocrine disorder and consequent hormonal carcinogenesis.

Confidence and quality in managing CKD compared with other cardiovascular diseases and diabetes mellitus: a linked study of questionnaire and routine primary care data

BackgroundMuch of chronic disease is managed in primary care and chronic kidney disease (CKD) is a recent addition. We are conducting a cluster randomised study of quality improvement interventions in CKD (QICKD) - Clinical Trials Registration: ISRCTN56023731. CKD registers have a lower than expected prevalence and an initial focus group study suggested variable levels of confidence in managing CKD.Our objective is to compare practitioner confidence and achievement of quality indicators for CKD with hypertension and diabetes.MethodWe validated a new questionnaire to test confidence. We compared confidence with achievement of pay-for-performance indicators (P4P) and implementation of evidence-based guidance. We achieved a 74% (148/201) response rate.Results87% (n = 128) of respondents are confident in managing hypertension (HT) compared with 59% (n = 87) in managing HT in CKD (HT+CKD); and with 61% (n = 90) in HT, CKD and diabetes (CKD+HT+DM).85.2% (P4P) and 62.5% (National targets) of patients with hypertension are at target; in patients with HT and CKD 65.1% and 53.3%; in patients with HT, CKD and DM 67.8% and 29.6%.Confidence in managing proteinuria in CKD is low (42%, n = 62). 87% of respondents knew BP treatment thresholds in CKD, but only 53% when proteinuria is factored in. Male GPs, younger (< 35 yrs), and older (> 54 yrs) clinicians are more confident than females and 35 to 54 year olds in managing CKD.84% of patients with hypertension treated with angiotensin modulating drugs achieve achieved P4P targets compared to 67% of patients with CKD.ConclusionsPractitioners are less likely to achieve management targets where their confidence is low.

AKT Kinase Activity Is Required for Lithium to Modulate Mood-Related Behaviors in Mice

Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response-activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice-and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.

Inhibitory Effect of n‐Butylidenephthalide on Neointimal Hyperplasia in Balloon Injured Rat Carotid Artery

This investigation was designed to determine the inhibitory effects and mechanisms of n-butylidenephthalide (BP) from Angelica sinensis on smooth muscle cell (SMC) proliferation in vitro and in balloon injured rat carotid artery. Treatment of cultured rat aorta SMC-derived A7r5 cells with 25-100 μg/mL BP significantly inhibited the proliferation and arrested the cell cycle in G(0)/G(1) phase. BP induced the expression and migration of Nur77 from the nucleus to the cytoplasm. Among signal pathways, JNK and p38 MAPK were phosphorylated after BP treatment. In vivo, the neointimal area of common carotid artery 2 weeks after balloon injury reduced significantly in Sprague-Dawley rats treated with 150-300 mg/kg BP compared with the control. The proliferative activity indicated by immunohistochemical detection of Ki-67 positive cells in the neointima was significantly decreased in the 60-300 mg/kg BP treatment groups. The apoptotic activity indicated by cleaved caspase-3 positive cells and Nur77 positive cells in the neointima was significantly increased in rats treated with 60-300 mg/kg BP. This study demonstrated BP inhibited neointimal hyperplasia in balloon injured rat carotid artery due to its dual effects of proliferative inhibition and apoptotic induction on SMCs. Up-regulation of Nur77 gene may partly explain the antihyperplasia activity of BP on the neointima.

Acute Disruption of Bone Marrow Hematopoiesis by Benzo(a)pyrene Is Selectively Reversed by Aryl Hydrocarbon Receptor-Mediated Processes

Bone marrow (BM) hematopoietic cells are selectively sensitive to polycyclic aromatic hydrocarbons (PAH) in vivo. 7,12-Dimethylbenz(a)anthracene (DMBA), but not benzo(a)pyrene (BP), depletes BM hematopoietic cells in C57BL/6 mice. This difference is due to a BP-selective aryl hydrocarbon receptor (AhR)-mediated recovery. Colony-forming unit assays show suppression of lymphoid progenitors by each PAH within 6 h but a subsequent recovery, exclusively after BP treatment. Suppression of myeloid progenitors (6 h) occurs only for DMBA. Each progenitor responded equally to DMBA and BP in congenic mice expressing the PAH-resistant AhR (AhR(d)). AhR, therefore, mediates this BP recovery in each progenitor type. These PAH suppressions depend on Cyp1b1-mediated metabolism. Paradoxically, few genes responded to DMBA, whereas 12 times more responded to BP. Progenitor suppression by DMBA, therefore, occurs with minimal effects on the general BM population. Standard AhR-mediated stimulations (Cyp1a1, Cyp1b1, Ahrr) were similar for each PAH and for the specific agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin but were absent in AhR(d) mice. A group of 12 such AhR responses was sustained from 6 to 24 h. A second, larger set of BP responses (chemokines, cytokines, cyclooxygenase 2) differed in two respects; DMBA responses were low and BP responses declined extensively from 6 to 24 h. A third cluster exhibited BP-induced increases in protective genes (Nqo1, GST-mu) that appeared only after 12 h. Conversion of BP to quinones contributes oxidative signaling not seen with DMBA. We propose that genes in this second cluster, which share oxidative signaling and AhR activation, provide the AhR-dependent protection of hematopoietic progenitors seen for BP.

Effect of ultrasound and addition of bacterial product on hydrolysis of by-products from the meat-processing industry

The hydrolysis efficiency of ultrasound (US) and bacterial product (BP; Liquid Certizyme 5™) was studied as a pre-treatment for anaerobic digestion (AD) of four animal by-products (ABP) from the meat-processing industry (digestive tract content + drumsieve waste, dissolved air flotation (DAF) sludge, grease trap sludge and the mixture of these). The change in volatile solids (VS) based hydrolysis parameters was screened using different specific US energy (Es) inputs (1000–14,000 kJ/kg of total solids (TS)) and durations of BP treatment (3–48 h). The Es of 6000–8500 kJ/kg TS increased most extensively the soluble chemical oxygen demand (CODsol) and VS ratio, by 45–290%, and soluble nitrogen (Nsol) by 44–99%. Simultaneously, the average particle size (APS) decreased by 45–75%, from the original value. With BP, the highest increases in CODsol/VS (29–130%), Nsol (35–63%) and decline in APS (40–70%) depended on the raw material (digestive tract content + drumsieve waste: 3 and 24 h; DAF sludge: 3 and 6 h, mixture: 12 and 48 h). BP apparently was more effective at hydrolyzing smaller cellulose particles, while US appeared to enhance the degradation of grease-containing cells.

Optimising Bone Disease In Myeloma; Zoledronic Acid Plus Thalidomide Combinations Improves Survival and Bone Endpoints: Results of the MRC Myeloma IX Trial

AbstractAbstract 311 Introduction:MRC Myeloma IX (N = 1,960) included intensive and non-intensive pathways and 2 bisphosphonates (BPs; zoledronic acid [ZOL] and clodronate [CLO]) in patients (pts) with newly diagnosed multiple myeloma. The trial is unique in having investigated both overall survival (OS) and bone endpoints in the context of BP treatment and a thalidomide (Thal), alkylating agent, and steroid induction regimen; and maintenance Thal. We have shown that ZOL significantly reduces skeletal-related events (SREs) and improves OS independent of its effect on SREs, suggesting potential antimyeloma activity (Morgan et al. ASCO 2010, #8021). Early comparisons between antimyeloma regimens demonstrated superiority of Thal-containing regimens for induction (Morgan et al. ASH 2009, #352) and maintenance. Here we present important new data on interactions between BPs, Thal, and standard induction regimens used in terms of response, progression-free survival (PFS), OS, and on the bone endpoints included in SREs. Methods:The intensive pathway randomized pts to 4 to 6, 3-wk cycles of CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) or CTD (cyclophosphamide, Thal, dexamethasone) as induction therapy, followed by high-dose melphalan treatment and ASCT. The non-intensive pathway randomized pts to 4-wk cycles of melphalan and prednisolone (MP) or attenuated CTD (CTDa). Each treatment arm also was randomized to ZOL (4 mg IV q 3–4 wk, dose-adjusted based on renal function) or CLO (1600 mg/d) continued at least until disease progression. After induction, pts in both pathways were offered entry to a maintenance Thal or no maintenance randomization. Endpoints included PFS, OS, and response. SREs include fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions at disease progression. Time to first SRE was assessed using cumulative incidence function, and OS was estimated using the Kaplan-Meier method. Cox analysis was used to assess hazard ratio (HR) and associated 95% CI for SRE risk, adjusting for effects of treatment regimen, minimization factors, and SRE history at baseline (stratified by pathway). Diagnosis of bone lesions was not a study-entry requirement; BP use may be off-label outside the UK in some pts. Results:With a median follow-up of 3.7 yr and 1,960 evaluable pts, ZOL and Thal-containing regimens produced multiple treatment benefits. Overall, there was a trend for more pts with complete response (CR; P = .15), fewer early deaths (within 60 days of randomization; P = .06), and improved OS for ZOL vs CLO (P = .04). SRE risk was significantly reduced with ZOL vs CLO (HR = 0.74, P = .0004), and—for the first time—SRE risk also proved lower for CTDa vs MP (HR = 0.74, P = .021), but was similar for CTD vs CVAD (HR = 1.03; P = .80). In the intensive pathway (n = 1,111; median age 59 yr), CR or very-good-partial response (VGPR) was achieved after induction therapy by 43.2% of pts with CTD and 27.5% of pts with CVAD. Similar proportions of pts achieved CR/VGPR with ZOL and CLO (36.0% vs 34.7%). OS and PFS were slightly better for ZOL vs CLO (OS: HR = 0.84; 95% CI, 0.68–1.03; PFS: HR = 0.90; 95% CI, 0.78–1.05; P > .05 for both). In both the CVAD and CTD arms, fewer ZOL- vs CLO-treated pts had SREs (overall intensive: 27.9% vs 36.3%; log-rank P = .034). In the nonintensive pathway (n = 849; median age 73 yr), pts randomized to CTDa had a significantly higher CR rate (13.1% vs 2.4%; P < .0001) and CR/VGPR (30.0% vs 4.0%; P < .0001) vs MP. In each treatment arm, the ZOL group had higher rates of CR/VGPR vs CLO (MP: 6% vs 2%; CTDa: 34% vs 26%, respectively; P = .03 overall). ZOL significantly reduced risk of death by 17% vs CLO (HR = 0.83; P = .049). Time to first SRE was significantly longer for CTDa vs MP (P = .021) and ZOL vs CLO (log-rank P = .008). In modeling analyses we show that the impact of achieving a CR and of CTDa on SREs may not be independent, suggesting that the improved response is important in reducing bone disease. ZOL prolonged the median time to first SRE vs CLO in both the MP and CTDa arms. In the maintenance randomization (n = 820), ZOL significantly reduced SREs compared with CLO. Conclusions:We demonstrate that ZOL provided benefits beyond CLO, improving OS and response status, and preventing potentially debilitating SREs. Pts receiving regimens containing Thal and ZOL had the best clinical outcomes, being associated with better response, survival, and lower SRE risk. Disclosures:Morgan:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Pharmion: Research Funding; Chugai: Research Funding. Off Label Use: Diagnosis of bone lesions was not a study-entry requirement; Therefore bisphosphonate use may be off-label outside the UK in some patients. Davies:Celgene: Honoraria; Ortho Biotech: Honoraria; Novartis: Honoraria. Cook:Orthobiotec: Consultancy, Speakers Bureau. Jackson:Celgene: Honoraria; Janssen-Cilag: Honoraria.

BP Treatment Bar Lowered for African Americans

BP Treatment Bar Lowered for African Americans

Modulatory effects of curcumin and resveratrol on lung carcinogenesis in mice

The aim of the present study is to explore the chemopreventive potential of curcumin and resveratrol during promotional phase of benzo(a)pyrene (BP) induced lung carcinogenesis in mice. The mice were segregated into five groups which included normal control, BP-treated, BP+curcumin-treated, BP+resveratrol-treated and BP+curcumin+resveratrol-treated groups. The BP treatment resulted in a significant increase in the levels of lipid peroxidation (LPO). On the other hand, reduced glutathione (GSH) levels and the activities of superoxide dismutase (SOD) were found to be significantly decreased following BP treatment. Administration of curcumin to BP-treated mice decreased the levels of LPO significantly. Further, treatment of resveratrol to BP-treated mice significantly elevated the activities of SOD. Combined treatment of curcumin and resveratrol, kowever, showed significant improvement in LPO and GSH levels as well as in the activities of SOD. Histo-architectural studies showed well-differentiated signs of lung carcinogenesis following BP administration to mice. Although treatments with resveratrol and curcumin given separately to BP-treated mice showed appreciable improvement in the histo-architecture of the lung, combined treatment resulted in a noticeable improvement in the lung histo-architecture.

Periodontal Disease and Potent Bisphosphonates Induce Maxillary Osteonecrosis in the Rat

Statement of the Problem: Bisphosphonate related osteonecrosis of the jaws (BRONJ) is a devastating complication of BP therapy in bone cancer and osteoporosis patients. BRONJ is defined as exposed bone in the maxillofacial region that has persisted for more than 8 weeks in patients with current or previous BP treatment, without a history of radiation to the jaws. BRONJ causes severe pain, swelling, infection, fistulae, and jaw fracture, all of which significantly impact patients' quality of life. Despite the increasing number of cases since the first report in 2003, no validated treatment protocols exist. A rather puzzling, and still unanswered, question is why BP related osteonecrosis affects only the jaw. The oral cavity comprises a unique environment, where the oral mucosa, alveolar bone, periodontal organ, teeth, and muscles perform a series of complicated, specialized functions. Hypotheses attempting to explain the unique localization of BRONJ include altered bone remodeling, angiogenesis inhibition, constant microtrauma, and bacterial infection. However, the mechanisms of high jaw sensitivity to BP treatment remain unidentified. In the great majority of cases, BRONJ occurs after extraction of teeth deemed unrestorable due to the severity of dental disease, or around teeth with active periodontal or periapical disease. Although not always reported as the initiating factor, inflammation of the periodontal tissues is present in the majority of BRONJ cases. Interestingly, oral preventive measures decrease BRONJ incidence, further emphasizing the importance of dental disease in BRONJ pathophysiology.

Genetic basis for skeletal disease. Osteogenesis imperfecta

Osteogenesis imperfecta (OI) is characterized by its bone fragility. But the spectrum of the severity of the fragility is widely distributed. Recently, amino-bisphosphonate has been introduced into the treatment of the bone fragility of OI. Apparently, the treatment may reduce the frequency of the fractures in severe form of OI. However, its efficacy has not been supported by strong evidences, such as randomized controlled clinical trial. This section describes the pathophysiology and new pathogenetic mechanism of OI, and describes recent evidence for the efficacy of BP treatment in OI.

GH in combination with bisphosphonate treatment in osteogenesis imperfecta

To verify the effects of bisphosphonates (Bps) in combination with recombinant human GH (rGH) in pediatric osteogenesis imperfecta (OI) patients; we focused on possible improvement of bone mineral density (BMD), projected bone areas, growth velocity, and fractures risk. A randomized controlled 1-year clinical trial on 30 prepubertal children (M:F=14:16) affected by OI (type I, IV, and III) being treated with neridronate. Following an observational period of 12 months during ongoing neridronate treatment, the patients were randomly divided into two groups: 15 were treated for 12 months with rGH and neridronate (group Bp+rGH) and 15 continued neridronate alone (group Bp). We evaluated auxological parameters, number of fractures, bone age (BA), bone metabolic parameters, and bone mass measurements (at lumbar spine and radius by dual-energy X-ray absorptiometry). The mean variation in percentage of BMD (Delta%BMD)--at lumbar spine (L2-L4), at distal and ultradistal radius--and the projected area of lumbar spine increased significantly in group Bp+rGH (P<0.05). Growth velocity was significantly higher during rGH treatment in group Bp+rGH versus group Bp and versus pretreatment (P<0.05), with no difference in increase in BA or fracture risk rate. Patients with quantitative (-qt) collagen synthesis defects had a higher, although not significant, response to rGH in terms of growth velocity and BMD. In OI patients, the combined rGH-Bp treatment may give better results than Bp treatment alone, in terms of BMD, lumbar spine projected area and growth velocity, particularly in patients with quantitative defects.

An insight into the chemopreventive role of curcumin and quercetin during promotional phase of benzo(a)pyrene-induced lung carcinogenesis in mice

The aim of the present study was to gain insight into the combined chemopreventive potential of curcumin and quercetin during promotional phase of lung carcinogenesis in male Laka mice. The mice were segregated into five groups; normal control, benzo(a)pyrene (BP) treated, BP + curcumin treated, BP + quercetin treated, and BP + curcumin + quercetin treated. After 10 weeks of BP treatment a significant increase in lipid peroxidation (LPO) levels, a significant decrease in the glutathione (GSH) levels, as well as in the activities of superoxide dismutase (SOD) and well-differentiated histological signs of promotional phase were noted. Treatment with curcumin and quercetin when given separately as well as in combination restored LPO levels to within normal range. Quercetin alone supplementation and in combination with curcumin significantly elevated the levels of GSH as well as the activities of SOD in the BP-treated mice. Further, treatment with quercetin and curcumin given separately, as well as in combination, to the BP-treated mice showed protective effects in the lung morphology. In conclusion, results suggest that treatment with curcumin and quercetin alone and in combination provides beneficial effects against BP-induced lung alterations in mice.

30-year risk of myocardial infarction, stroke, or coronary death in childhood cancer survivors.

e19541 Background: Concerns that survivors face an increased burden from atherosclerosis have led to recommendations for early testing of traditional risk factors such as cholesterol and their aggressive treatment. These recommendations, however, provide no method for aggregating test results or estimating the cumulative risk from traditional risk factors. This may now be possible using the recently developed Framingham Heart Study's calculator (FHC) that predicts 30-yr risk of CVD (myocardial infarction [MI], stroke, or coronary death) in those over 20 yrs old. Methods: Risk factors were measured in a representative sample of 73 survivors and 17 siblings over 20 yrs old in an NCI prospective cohort study in Rochester, NY, from 1999-2004. Risk factors were aggregated using the FHC, a weighted combination of age, sex, total cholesterol, HDL-cholesterol, smoking, BP, diabetes, and hypertensive treatment. FHC estimates for survivors were compared to siblings after adjusting for age and sex. Results: Survivors were a mean 28 yrs of age and 17 yrs since diagnosis (dx); 49% received anthracyclines, 57% cardiac radiation, 38% cranial radiation, and 4% total body radiation, as part of multiagent therapy. Survivors had 52% (p = 0.22) increased risk vs. siblings. Among survivors from the Long-Term Survivors Study (LTSS), median age of 56 yrs and 48 yrs since dx, 17% reported coronary artery disease and 4% reported cerebral vascular disease. Among survivors from the Childhood Cancer Survivor Study (CCSS), 30 yrs since dx, 1.5% reported MI. Conclusions: The high risk of CVD predicted by the FHC using traditional risk factors and the comparability of this estimate to rates observed in the LTSS and CCSS suggest traditional risk factors account for much of the CVD in survivors, though cancer treatments such as radiation add additional independent risk not captured by the FHC. Our findings and variations in risk estimates confirm screening recommendations and suggest the easy to use and cost-free FHC may help identify survivors in need of further assessment. Mean (range) FHC risk estimate for survivors by age group and sex 20-29-yr-old females 20-29-yr-old males 30-39-yr-old females 30-39-yr-old males 2.1% (1-9%) 3.3% (1-12%) 2.9% (1-5%) 15.6% (5-35%) No significant financial relationships to disclose.

Growth Hormone in Combination with Bisphosphonate Treatment in Osteogenesis Imperfecta

Objective: To verify the effects of bisphosphonates (Bps) in combination with recombinant human growth hormone (rGH) in pediatric osteogenesis imperfecta (OI) patients; we focused on possible improvement of bone mineral density (BMD), projected bone areas, growth velocity and fractures risk. Design: A randomized controlled 1-year clinical trial on 30 pre-pubertal children (M:F=14:16) affected by OI (type I, IV, III) being treated with Neridronate (N). Methods: Following an observational period of 12 months during ongoing N treatment, the patients were randomly divided into two groups: 15 were treated for 12 months with rGH and N (Group Bp+rGH) and 15 continued N alone (Group Bp). We evaluated auxological parameters, number of fractures, bone age (BA), bone metabolic parameters and bone mass measurements (at lumbar spine and radius by DXA). Results: The mean variation in percentage of BMD (∆%BMD) at lumbar spine (L2-L4), at distal and ultra distal radiusand the projected area of lumbar spine increased significantly in Group Bp+rGH (p<0.05). Growth velocity was significantly higher during rGH treatment in group Bp+rGH vs group Bp and vs pre-treatment (p< 0.05), with no difference in increase in BA or fracture risk rate. Patients with quantitative collagen synthesis defects had a higher, although not significant, response to rGH in terms of growth velocity and BMD. Conclusions: In OI patients the combined rGH-Bp treatment may give better results than Bp treatment alone, in terms of BMD, lumbar spine projected area and growth velocity, particularly in patients with quantitative defects. Page 2 of 22

Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure

Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n = 255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n = 111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every 4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75% (IV BP-naive) and 80% (prior IV BP) after denosumab treatment and 71% (IV BP-naive) and 56% (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73%, IV BP 11%). SRE incidence was low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8%) than the IV BP group (17%). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers independently of prior BP treatment, even in patients who appear to respond poorly to BPs.

Extended O6-Methylguanine Methyltransferase Promoter Hypermethylation Following n-Butylidenephthalide Combined with 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) on Inhibition of Human Hepatocellular Carcinoma Cell Growth

Epigenetic alteration of DNA methylation plays an important role in the regulation of gene expression associated with chemosensitivity of human hepatocellular (HCC) carcinoma cells. With the aim of improving the chemotherapeutic efficacy for HCC, the effect of the naturally occurring compound n-butylidenephthalide (BP), which is isolated from a chloroform extract of Angelica sinensis, was investigated. In both HepG2 and J5 HCC cell lines, a synergistic antiproliferative effect was observed when a low dosage of BP was combined with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU is an alkylating agent, and it prompts us to examine one of DNA repair genes, O(6)-methylguanine methyltransferase (MGMT). It was evident from methylation-specific polymerase chain reaction (PCR) analysis that BP/BCNU combined treatment caused a time- and concentration-dependent enhancement of MGMT promoter methylation. Overexpression of MGMT could abolish BP-induced growth inhibition in the J5 tumor cell line as measured by colony formation assay. When BP was combined with BCNU and administered, it showed significant antitumor effects in both HepG2 and J5 xenograft tumors as compared with the use of only one of these drugs. The BCNU-induced apoptosis and inhibited MGMT protein expression in HCC cells, both in vitro and in vivo, resulting from the combination treatment of BP and BCNU suggest a potential clinical use of this compound for improving the prognosis for HCCs.

Valsartan-Aliskiren Combination Pill Approved for Treatment of High BP

Valsartan-Aliskiren Combination Pill Approved for Treatment of High BP

Disease-specific risk for an osteonecrosis of the jaw under bisphosphonate therapy

Osteonecrosis of the jaw (ONJ) presents a severe side-effect of intravenous bisphosphonate (i.v. BP) treatment; yet, the pathoethiological influence of the underlying disease which indicated that treatment remains unclear. We studied a large register of subjects who suffered an ONJ (n = 356) under i.v. BP therapy and characterized them according to underlying diseases and BP intake. By using claims data, we analysed indications in the general public in a cohort of new users of i.v. BPs (n = 1,075) in ambulatory care. For the years 2004-2006, both data sources were compared to indirectly assess the disease-specific risk for the development of an ONJ. We further assessed disease-specific survival after treatment initiation. Patients with multiple myeloma were found more often, in the ONJ register, than were treated in real life (males: 36.4% vs. 16.2%; females: 27.8% vs. 6.5%) while the proportions of patients with prostate or breast cancer were as expected, and malignancies with low survival rates were strongly underrepresented. No patients with osteoporosis were reported to the ONJ register despite accounting for 18.8% of all the treated females in the general public. The pattern of diagnoses that indicated i.v. BP treatment in patients who suffered an ONJ is different from what would be expected when looking at indications in the general public. Each underlying disease may, hence, have its own inherent risk to develop an ONJ due to varying life-expectancies and overall oncological treatment regimes including the interval and type of i.v. BP application.

SOIL SOLARIZATION ENHANCEMENT WITH HIGH TUNNELS IN SOUTHERN CALIFORNIA

Soil solarization can be an effective preplant soil treatment under high temperature and irradiance conditions, but its effectiveness is poor in coastal California due to cool, cloudy conditons. Previous reports indicate that use of polyethylene tunnels can enhance soil warming beyond that of standard soil solarization. From August 31 to October 4, 2007, we monitored soil temperatures as a function of three solarization treatments on non-fumigated strawberry beds in coastal southern California: 1) black polyethylene bed mulch (BP); 2) clear polyethylene bed mulch (CP, control); and 3) a high tunnel covered with clear polyethylene that enclosed beds covered with CP (CPT). Maximum soil temperatures (10 cm depth) were 45.4, 53 and 57.9°C for treatments 1-3, respectively. At 10 cm soil depth, accumulated temperature-hours ≥37°C were 82.5, 235, and 520.3 for treatments 1-3, respectively, while at soil depth of 30 cm, accumulated temperature-hours ≥372°C were 0, 51.5 and 525 for treatments 1-3, respectively. The tunnel cover was removed on October 4 and strawberry plants ('Ventana') were established in all plots. Weed populations were determined on November 15, and yield performance determined from December, 2007 until May 5. Results indicate complete weed control with use of CPT, and an abundance of various weed species in CP and BP plots. Yields to May 5 were lowest for BP treatment, intermediate for CP and CPT treatments, and greatest for an adjacent parcel treated with methyl bromide: chloropicrin.