The effects of phenoxodiol on the cell cycle of prostate cancer cell lines

Background: Prostate cancer is associated with a poor survival rate. The ability of cancer cells to evade apoptosis and exhibit limitless replication potential allows for progression of cancer from a benign to a metastatic phenotype. The aim of this study was to investigate in vitro the effect of the isoflavone phenoxodiol on the expression of cell cycle genes. Methods: Three prostate cancer cell lines-LNCaP, DU145, and PC3 were cultured in vitro, and then treated with phenoxodiol (10 μM and 30 μM) for 24 and 48 h. The expression of cell cycle genes p21WAF1, c-Myc, Cyclin-D1, and Ki-67 was investigated by Real Time PCR. Results: Here we report that phenoxodiol induces cell cycle arrest in the G1/S phase of the cell cycle, with the resultant arrest due to the upregulation of p21WAF1 in all the cell lines in response to treatment, indicating that activation of p21WAF1 and subsequent cell arrest was occurring via a p53 independent manner, with induction of cytotoxicity independent of caspase activation. We found that c-Myc and Cyclin-D1 expression was not consistently altered across all cell lines but Ki-67 signalling expression was decreased in line with the cell cycle arrest. Conclusions: Phenoxodiol demonstrates an ability in prostate cancer cells to induce significant cytotoxicity in cells by interacting with p21WAF1 and inducing cell cycle arrest irrespective of p53 status or caspase pathway interactions. These data indicate that phenoxodiol would be effective as a potential future treatment modality for both hormone sensitive and hormone refractory prostate cancer

Efficient control of atmospheric sulfate production based on three formation regimes

The formation of sulfate (SO₄²⁻) in the atmosphere is linked chemically to its direct precursor, sulfur dioxide (SO₂), through several key oxidation paths for which nitrogen oxides or NO_x (NO and NO₂) play essential roles. Here we present a coherent description of the dependence of SO₄²⁻ formation on SO₂ and NO_x under haze-fog conditions, in which fog events are accompanied by high aerosol loadings and fog-water pH in the range of 4.7–6.9. Three SO₄²⁻ formation regimes emerge as defined by the role played by NO_x. In the low-NO_x regime, NO_x act as catalyst for HO_x, which is a major oxidant for SO₂, whereas in the high-NO_x regime, NO₂ is a sink for HO_x. Moreover, at highly elevated NO_x levels, a so-called NO₂-oxidant regime exists in which aqueous NO₂ serves as the dominant oxidant of SO₂. This regime also exists under clean fog conditions but is less prominent. Sensitivity calculations using an emission-driven box model show that the reduction of SO₄²⁻ is comparably sensitive to the reduction of SO₂ and NO_x emissions in the NO₂-oxidant regime, suggesting a co-reduction strategy. Formation of SO₄²⁻ is relatively insensitive to NO_x reduction in the low-NO_x regime, whereas reduction of NO_x actually leads to increased SO₄²⁻ production in the intermediate high-NO_x regime

Acute Beneficial Hemodynamic Effects of a Novel 3D-Echocardiographic Optimization Protocol in Cardiac Resynchronization Therapy

Post-implantation therapies to optimize cardiac resynchronization therapy (CRT) focus on adjustments of the atrio-ventricular (AV) delay and ventricular-to-ventricular (VV) interval. However, there is little consensus on how to achieve best resynchronization with these parameters. The aim of this study was to examine a novel combination of doppler echocardiography (DE) and three-dimensional echocardiography (3DE) for individualized optimization of device based AV delays and VV intervals compared to empiric programming.25 recipients of CRT (male: 56%, mean age: 67 years) were included in this study. Ejection fraction (EF), the primary outcome parameter, and left ventricular (LV) dimensions were evaluated by 3DE before CRT (baseline), after AV delay optimization while pacing the ventricles simultaneously (empiric VV interval programming) and after individualized VV interval optimization. For AV delay optimization aortic velocity time integral (AoVTI) was examined in eight different AV delays, and the AV delay with the highest AoVTI was programmed. For individualized VV interval optimization 3DE full-volume datasets of the left ventricle were obtained and analyzed to derive a systolic dyssynchrony index (SDI), calculated from the dispersion of time to minimal regional volume for all 16 LV segments. Consecutively, SDI was evaluated in six different VV intervals (including LV or right ventricular preactivation), and the VV interval with the lowest SDI was programmed (individualized optimization).EF increased from baseline 23±7% to 30±8 (p<0.001) after AV delay optimization and to 32±8% (p<0.05) after individualized optimization with an associated decrease of end-systolic volume from a baseline of 138±60 ml to 115±42 ml (p<0.001). Moreover, individualized optimization significantly reduced SDI from a baseline of 14.3±5.5% to 6.1±2.6% (p<0.001).Compared with empiric programming of biventricular pacemakers, individualized echocardiographic optimization with the integration of 3-dimensional indices into the optimization protocol acutely improved LV systolic function and decreased ESV and can be used to select the optimal AV delay and VV interval in CRT

Adjuvant therapy following oesophagectomy for adenocarcinoma in patients with a positive resection margin.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy is contentious. In UK practice, surgical resection margin status is often used to classify patients for receiving adjuvant treatment. The aim of this study was to assess the survival benefit of adjuvant therapy in patients with positive (R1) resection margins. METHODS: Two prospectively collected UK institutional databases were combined to identify eligible patients. Adjusted Cox regression analyses were used to compare overall and recurrence-free survival according to adjuvant treatment. Recurrence patterns were assessed as a secondary outcome. Propensity score-matched analysis was also performed. RESULTS: Of 616 patients included in the combined database, 242 patients who had an R1 resection were included in the study. Of these, 112 patients (46·3 per cent) received adjuvant chemoradiotherapy, 46 (19·0 per cent) were treated with adjuvant chemotherapy and 84 (34·7 per cent) had no adjuvant treatment. In adjusted analysis, adjuvant chemoradiotherapy improved recurrence-free survival (hazard ratio (HR) 0·59, 95 per cent c.i. 0·38 to 0·94; P = 0·026), with a benefit in terms of both local (HR 0·48, 0·24 to 0·99; P = 0·047) and systemic (HR 0·56, 0·33 to 0·94; P = 0·027) recurrence. In analyses stratified by tumour response to neoadjuvant chemotherapy, non-responders (Mandard tumour regression grade 4-5) treated with adjuvant chemoradiotherapy had an overall survival benefit (HR 0·61, 0·38 to 0·97; P = 0·037). In propensity score-matched analysis, an overall survival benefit (HR 0·62, 0·39 to 0·98; P = 0·042) and recurrence-free survival benefit (HR 0·51, 0·30 to 0·87; P = 0·004) were observed for adjuvant chemoradiotherapy versus no adjuvant treatment. CONCLUSION: Adjuvant therapy may improve overall survival and recurrence-free survival after margin-positive resection. This pattern seems most pronounced with adjuvant chemoradiotherapy in non-responders to neoadjuvant chemotherapy

Microbial carbon use efficiency: accounting for population, community, and ecosystem-scale controls over the fate of metabolized organic matter

Microbial carbon use efficiency (CUE) is a critical regulator of soil organic matter dynamics and terrestrial carbon fluxes, with strong implications for soil biogeochemistry models. While ecologists increasingly appreciate the importance of CUE, its core concepts remain ambiguous: terminology is inconsistent and confusing, methods capture variable temporal and spatial scales, and the significance of many fundamental drivers remains inconclusive. Here we outline the processes underlying microbial efficiency and propose a conceptual framework that structures the definition of CUE according to increasingly broad temporal and spatial drivers where (1) CUEP reflects population-scale carbon use efficiency of microbes governed by species-specific metabolic and thermodynamic constraints, (2) CUEC defines community-scale microbial efficiency as gross biomass production per unit substrate taken up over short time scales, largely excluding recycling of microbial necromass and exudates, and (3) CUEE reflects the ecosystem-scale efficiency of net microbial biomass production (growth) per unit substrate taken up as iterative breakdown and recycling of microbial products occurs. CUEE integrates all internal and extracellular constraints on CUE and hence embodies an ecosystem perspective that fully captures all drivers of microbial biomass synthesis and decay. These three definitions are distinct yet complementary, capturing the capacity for carbon storage in microbial biomass across different ecological scales. By unifying the existing concepts and terminology underlying microbial efficiency, our framework enhances data interpretation and theoretical advances