Restoration of E-cadherin/beta-catenin expression in pancreatic cancer cells inhibits growth by induction of apoptosis

BACKGROUND: beta-Catenin is a component of the E-cadherin/catenin adhesion complex that maintains epithelial cell integrity. We have previously observed decreased beta-catenin expression in both human pancreatic cancer cell lines and primary tumors. To determine the significance of this finding with respect to pancreatic carcinogenesis, this study evaluated the effects of restoring expression of beta-catenin with and without E-cadherin in pancreatic cancer cells. METHODS: MiaPaca-2 cells were stably transfected with full-length cDNAs for beta-catenin, E-cadherin, or a mutated E-cadherin lacking the beta-catenin-binding domain. Doubly transfected cell clones containing beta-catenin and either E-cadherin or deleted E-cadherin were also selected. Assays for cell adhesion, cell cycle profile, motility, and apoptosis were performed. RESULTS: Cell clones expressing beta-catenin alone or beta-catenin and deleted E-cadherin did not differ significantly from the parental cell lines in any of the assays performed. In contrast, MiaPaca-2 cell clones expressing both beta-catenin and E-cadherin showed tight adhesion, decreased cell growth, and a significantly increased apoptotic index as compared to the parental line or singly transfected clones. CONCLUSIONS: MiaPaca-2 cells undergo apoptosis at a significantly increased rate after restoration of the E-cadherin/beta-catenin adhesion complex. This increase in apoptosis is dependent on the ability of E-cadherin to bind beta-catenin. Loss of beta-catenin expression may therefore provide pancreatic cancer cells with a growth advantage that contributes to tumor progression.     

Intensity of care in cancer patients in the last year of life: a retrospective data linkage study

Background Delivering high-quality palliative and end-of-life care for cancer patients poses major challenges for health services. We examine the intensity of cancer care in England in the last year of life.Methods We included cancer decedents aged 65+ who died between January 1, 2010 and December 31, 2017. We analysed healthcare utilisation and costs in the last 12 months of life including hospital-based activities and primary care.Results Healthcare utilisation and costs increased sharply in the last month of life. Hospital costs were the largest cost elements and decreased with age (0.78, 95% CI: 0.73–0.72, p < 0.005 for age group 90+ compared to age 65–69 and increased substantially with comorbidity burden (2.2, 95% CI: 2.09–2.26, p < 0.005 for those with 7+ comorbidities compared to those with 1–3 comorbidities). The costs were highest for haematological cancers (1.45, 95% CI: 1.38–1.52, p < 0.005) and those living in the London region (1.10, 95% CI: 1.02–1.19, p < 0.005).Conclusions Healthcare in the last year of life for advanced cancer patients is costly and offers unclear value to patients and the healthcare system. Further research is needed to understand distinct cancer populations’ pathways and experiences before recommendations can be made about the most appropriate models of care.Subject terms: Cancer, Cancer     

Stereoselective Synthesis and Anticancer Activity of 2,6-Disubstituted trans-3-Methylidenetetrahydropyran-4-ones

In this report, we present efficient and stereoselective syntheses of 2,6-disubstituted trans-3-methylidenetetrahydropyran-4-ones and 2-(4-methoxyphenyl)-5-methylidenetetrahydropyran-4-one that significantly broaden the spectrum of the available methylidenetetrahydropyran-4-ones with various substitution patterns. Target compounds were obtained using Horner–Wadsworth–Emmons methodology for the introduction of methylidene group onto the pyranone ring. 3-Diethoxyphosphoryltetrahydropyran-4-ones, which were key intermediates in this synthesis, were prepared by fully or highly stereoselective addition of Gilman or Grignard reagents to 3-diethoxyphosphoryldihydropyran-4-ones. Addition occurred preferentially by axial attack of the Michael donors on the dihydropyranone ring. Relative configurations and conformations of the obtained adducts were assigned using a detailed analysis of the NMR spectra. The obtained methylidenepyran-4-ones were evaluated for cytotoxic activity against two cancer cell lines (HL-60 and MCF-7). 2,6-Disubstituted 3-methylidenetetrahydropyran-4-ones with isopropyl and phenyl substituents in position 2 were more cytotoxic than analogs with n-butyl substituent. Two of the most cytotoxic analogs were then selected for further investigation on the HL-60 cell line. Both analogs induced morphological changes characteristic of apoptosis in cancer cells, significantly inhibited proliferation and induced apoptotic cell death. Both compounds also generated DNA damage, and one of the analogs arrested the cell cycle of HL-60 cells in the G2/M phase. In addition, both analogs were able to inhibit the activity of topoisomerase IIα. Based on these findings, the investigated analogs may be further optimized for the development of new and effective topoisomerase II inhibitors.     

The Use of Barley Malt as a Binder in Molding Sand Technology

The aim of this study was to attempt to use barley malt as a natural, organic binder in the technology of molding sand. TGA analysis of the binder was performed, during which temperatures of thermal decomposition of its components were determined. The results of TG/DTG analysis show that a loss of ~75% of mass of the MB binder is organic matter. Over 50% of this is starch. The results indicate the possibility of using a binder made of barley malt as a binding material for quartz sand grains. This fact was confirmed by tests carried out with use of SEM. During the observations, it was found that barley malt forms smooth bridges connecting individual grains of quartz sand. The typical properties of molding sands with barley malt were also determined, compared to sands containing commonly used binders. At the same time, the influence of the content of this binder on flowability, permeability, strength properties, and wear resistance was assessed. It has been found that increasing the binder content in molding mass results in an increase in strength and wear resistance, as opposed to flowability and permeability. Test castings were also made. It was found that the addition of a binder made of barley malt has a positive effect on the surface quality of castings. This was confirmed by roughness measurements of the test castings. At the same time, a tendency to excessive gas evolution during pouring was shown, with higher contents of this binder. Moreover, greater amounts of barley malt in the molding sand (MB 5%) as compared to the lower content (MB 2%) increased the thickness of the burnt layer of the sand by 25%. This is due to the exothermic reaction when more binder is burnt. It is extremely important from the point of view of the regeneration of molding sand.     

The effect of hydrological connectivity on water beetles fauna in water bodies within the floodplain of a lowland river (Neman river, Belarus)

The middle course of the Neman River is the habitat of 120 water beetle species. Water beetles were most abundant in the Neman River, its major tributaries and oxbow lakes. They consisted of four synecological groups: rheobiontic and rheophilic organisms, type ??a?? and ??b?? stagnobionts. The diverse types of aquatic environments constitute faunal centers which, in addition to the specific and dominant Coleopteran populations, also feature migrational elements. The presence of close relations between the fauna of different environments indicates that they form a single, faunistically integrated hydrological system.     

Towards the automatic computational assessment of enlarged perivascular spaces on brain magnetic resonance images: A systematic review

Enlarged perivascular spaces (EPVS), visible in brain MRI, are an important marker of small vessel disease and neuroinflammation. We systematically evaluated the literature up to June 2012 on possible methods for their computational assessment and analyzed confounds with lacunes and small white matter hyperintensities. We found six studies that assessed/identified EPVS computationally by seven different methods, and four studies that described techniques to automatically segment similar structures and are potentially suitable for EPVS segmentation. T2‐weighted MRI was the only sequence that identified all EPVS, but FLAIR and T1‐weighted images were useful in their differentiation. Inconsistency within the literature regarding their diameter and terminology, and overlap in shape, intensity, location, and size with lacunes, conspires against their differentiation and the accuracy and reproducibility of any computational segmentation technique. The most promising approach will need to combine various MR sequences and consider all these features for accurate EPVS determination. J. Magn. Reson. Imaging 2013;38:774–785. © 2013 Wiley Periodicals, Inc.     

The Leeds assessment scale of handicap: its operationalisation,reliability, validity and responsiveness in in-patient rehabilitation

Purpose : This paper describes the application of the handicap dimension of the International Classification of Impairments, Disabilities and Handicaps. Method : A method of assessing four of the six roles (or areas of expected competency) was developed and applied to an inpatient population, aged 16 to 65 years, receiving specialist rehabilitation following neurological damage. Handicap assessment was a collaborative process by a multidisciplinary team. Difficulties were experienced in measuring inter-rate reliability in the busy, clinical setting. Results : We conclude that handicap assessment in an in-patient rehabilitation unit which uses a multidisciplinary approach to treating patients with complex physical, sensory and cognitive problems is both feasible and useful. Conclusion : The developed scale, The Leeds Assessment Scale of Handicap, provides a valid and valuable summary of human disadvantage, complementing the common disability assessments.     

论中医和希腊医学哲学理论的异同

中国和希腊,看似遥远的两个国家在古代哲学思想方面却近乎一致。古人一直在探寻自然现象的本质问题,并一直在试图回答这些系统联系的基础。在诸多问题中,他们最感兴趣的是天体运动,健康与疾病的相互关系,以及物质运动的原理。通过探究两种不同文化背景基础哲学理论的异同。     

Transurethral prostate resection,noncontact laser therapy or conservative management in men with symptoms of benign prostatic enlargement? An economic evaluation

PURPOSE: We evaluated the cost-effectiveness of noncontact laser therapy compared with transurethral prostate resection and conservative treatment in men with symptoms associated with benign prostatic enlargement. MATERIALS AND METHODS: A total of 340 men with uncomplicated lower urinary tract symptoms participated in a large multicenter pragmatic randomized trial called the CLasP (Conservative management, Laser therapy, transurethral resection of the Prostate) study. Costs to the United Kingdom National Health Service and patients were determined from the time of randomization to the 7.5-month followup. Incremental cost-effectiveness ratios using conservative management as the base case were calculated for certain trial outcomes, including International Prostate Symptom Score (I-PSS), I-PSS quality of life score, maximum urinary flow, post-void residual urine volume, quality adjusted life-years and a composite measure of success based on I-PSS and maximum urinary flow. One-way sensitivity analysis of the basic costs and incremental cost-effectiveness ratios were done from the NHS viewpoint. RESULTS: Mean costs per patient were greatest for noncontact laser therapy and least for conservative management. The incremental cost-effectiveness ratios showed that transurethral prostate resection was more cost-effective than noncontact laser treatment for all primary trial outcomes. The incremental cost-effectiveness ratios of transurethral prostate resection compared with conservative management were pound 81 per unit decrease in the I-PSS score and pound 1,338 per additional successful case per 100 patients. Sensitivity analysis showed that the initial results were robust. CONCLUSIONS: Noncontact laser was the mostly costly treatment option. Transurethral prostate resection was more cost-effective than noncontact laser therapy in terms of symptomatic improvement. In men wishing to delay treatment conservative treatment appears to provide a cost-effective alternative in the short term.