Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses

BackgroundThere is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT.MethodsAndrogen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays.ResultsWe observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70^s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT.ConclusionMET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.     

Population Dynamics,Reproductive Biology and Productivity of Streblospio shrubsolii (Polychaeta: Spionidae) in Different Sediments at Low Salinities in a Mediterranean Lagoon (Monolimni Lagoon,Northern Aegean)

Monthly samples of Streblospio shrubsolii were collected from February 1998 to February 1999 at both parts of Monolimni Lagoon (0.3 psu < Sal. < 6 psu). Streblospio shrubsolii displayed a life cycle of about one year. Reproductive activity occurred from February to October. The worms showed a mean of 14 or 16 gametogenic segments. Reproductive activity, growth and density increased during spring despite the low salinities (∼0.3 psu). Streblospio shrubsolii showed faster growth, larger body size during autumn–winter, more reproductive peaks, a relatively higher mean annual density, mean anual biomass (B) and annual production (P) at the innermost part of the lagoon, in organically richer very fine sand, than those at the outer part in fine sand. Mean annual density was 1,320 individuals m^–2 at the outer part and 1,745 individuals m^–2 at the innermost. Production calculated by Hynes' s method gave a B of 0.20 g DW m^–2 y^–1 and P of 0.45 g DW m^–2 y^–1 at the outer part; the respective values at the innermost part were 0.29 g DW m^–2 y^–1 and 0.61 g DW m^–2 y^–1. (© 2005 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Discussion on Spatial and Time Averaging Restrictions Within the Electromagnetic Exposure Safety Framework in the Frequency Range Above 6 GHz for Pulsed and Localized Exposures

Both the current and newly proposed safety guidelines for local human exposure to millimeter-wave frequencies aim at restricting the maximum local temperature increase in the skin to prevent tissue damage. In this study, we show that the application of the current and proposed limits for pulsed fields can lead to a temperature increase of 10°C for short pulses and frequencies between 6 and 30 GHz. We also show that the proposed averaging area of 4 cm², that is greatly reduced compared with the current limits, does not prevent high-temperature increases in the case of narrow beams. A realistic Gaussian beam profile with a 1 mm radius can result in a temperature increase about 10 times higher than the 0.4°C increase the same averaged power density would produce for a plane wave. In the case of pulsed narrow beams, the values for the time and spatial-averaged power density allowed by the proposed new guidelines could result in extreme temperature increases. Bioelectromagnetics. 2020;41:164–168. © 2019 Bioelectromagnetics Society.     

Investment risk in bioenergy crops

Perennial, cellulosic bioenergy crops represent a risky investment. The potential for adoption of these crops depends not only on mean net returns, but also on the associated probability distributions and on the risk preferences of farmers. Using 6‐year observed crop yield data from highly productive and marginally productive sites in the southern Great Lakes region and assuming risk neutrality, we calculate expected breakeven biomass yields and prices compared to corn (Zea mays L.) as a benchmark. Next we develop Monte Carlo budget simulations based on stochastic crop prices and yields. The crop yield simulations decompose yield risk into three components: crop establishment survival, time to maturity, and mature yield variability. Results reveal that corn with harvest of grain and 38% of stover (as cellulosic bioenergy feedstock) is both the most profitable and the least risky investment option. It dominates all perennial systems considered across a wide range of farmer risk preferences. Although not currently attractive for profit‐oriented farmers who are risk neutral or risk averse, perennial bioenergy crops have a higher potential to successfully compete with corn under marginal crop production conditions.     

Autoinhibition Mechanism of the Ubiquitin-Conjugating Enzyme UBE2S by Autoubiquitination

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Review: Gastric cancer—Clinical aspects

Gastric cancer (GC) was responsible for over 1 000 000 new cases in 2018 and an estimated 783 000 deaths, making it still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Divergent trends for GC incidence were observed in the USA. Incidence rates, particularly for non‐cardia GC, were stable or increasing among persons aged <50 years. In an analysis of data from a public hospital database in Hong Kong, treatment of Helicobacter pylori infection was associated with a lower risk of GC, particularly in older subjects who received treatment ≥10 years before. Based on the results of a 16‐year endoscopy‐based follow‐up eradication trial, patients with incomplete‐type intestinal metaplasia (IM) should receive endoscopic surveillance upon H. pylori eradication therapy. Updated guidelines on the endoscopic surveillance of preneoplastic conditions of the stomach (MAPS II) have been published. In the RAINFALL trial, the addition of ramucirumab to a backbone chemotherapy as a first‐line regimen failed to improve overall survival (OS) of patients with metastatic disease. Also, pembrolizumab did not prolong OS when compared to paclitaxel in the second‐line treatment of patients with advanced GC or esophagogastric junction (EGJ) cancer. Trifluridine/tipiracil improved OS by 2.1 months in the third or further treatment line of patients with advanced GC. In a systematic investigation conducted on Chinese patients with GC, CLDN18‐ARHGAP26/6 fusion was associated with signet‐ring cell content and was prognostic for a worse outcome and predictive for no benefit from oxaliplatin/fluoropyrimidine‐based chemotherapy. Organoid cultures represent an appealing model that may be applied for therapy response testing in the near future.     

Evaluation of a DC pulsed magnetic tracking system in neurosurgical navigation: technique, accuracies, and influencing factors]

Navigation systems are useful instruments in cranial neurosurgery. For specification of position, so-called sensor-based navigation techniques use: (a) a signal emitter that generates a defined electromagnetic field in the area of the operation site; and (b) small sensors that detect the position of various operating instruments in the electromagnetic field. For a long time, owing to a lack of clinical data and long-term studies, electromagnetic systems have been regarded as error-prone and imprecise. With the development of a pulsed direct current (DC) technique, precision levels can now be reached that are comparable with those of established optical and mechanical measuring procedures. However, it must be noted that the influence on the measuring accuracy within the operating field increases with increasing susceptibility of the various metals used in the operating theatre (titanium相似文献   

Effects of congested match periods on acceleration and deceleration profiles in professional soccer

The aim of the present study was to analyse the influence of congested periods of matches on the acceleration (Acc) and deceleration (Dec) profiles of elite soccer players. Twenty-three elite male professional soccer players participated in the study across 31 official matches. Assessed periods included: (i) congested periods (three to four days between games), and (ii) non-congested periods (more than four days between games). Physical activity during matches was recorded during games using a 10Hz global positioning system device, coupled with a 100 Hz accelerometer, and was analysed according to the periods. Maximal Acc- (73.2 ± 20.3 vs. 84.918.5 m), high Acc- (244.0 ± 49.5 vs. 267.0 ± 37.8 m), maximal Dec- (139.0 ± 44.8 vs. 152.039.3 m) and the total decelerating- distance (5132 ± 690 vs. 5245 ± 552 m) were lower in congested than in non-congested periods (p < 0.05, effect size 0.31–0.70). Neither a main effect of playing position nor a period*playing position interaction on Acc and Dec were observed (p > 0.05). It was concluded that Acc and Dec match activities were significantly affected during congested periods compared to non-congested highlighting a possible fatigue accumulation being responsible for the observed decrement in physical activity. Monitoring Acc and Dec metrics throughout particular periods of congested fixtures amongst professional soccer teams is advised and may be a way to assess physical and fatigue status.