DNA crosslinking and biological activity of a hairpin polyamide–chlorambucil conjugate

A prototype of a novel class of DNA alkylating agents, which combines the DNA crosslinking moiety chlorambucil (Chl) with a sequence-selective hairpin pyrrole-imidazole polyamide ImPy-beta-ImPy-gamma-ImPy-beta-Dp (polyamide 1), was evaluated for its ability to damage DNA and induce biological responses. Polyamide 1-Chl conjugate (1-Chl) alkylates and interstrand crosslinks DNA in cell-free systems. The alkylation occurs predominantly at 5'-AGCTGCA-3' sequence, which represents the polyamide binding site. Conjugate-induced lesions were first detected on DNA treated for 1 h with 0.1 muM 1-Chl, indicating that the conjugate is at least 100-fold more potent than Chl. Prolonged incubation allowed for DNA damage detection even at 0.01 muM concentration. Treatment with 1-Chl decreased DNA template activity in simian virus 40 (SV40) in vitro replication assays. 1-Chl inhibited mammalian cell growth, genomic DNA replication and cell cycle progression, and arrested cells in the G(2)/M phase. Moreover, cellular effects were observed at 1-Chl concentrations similar to those needed for DNA damage in cell-free systems. Neither of the parent compounds, unconjugated Chl or polyamide 1, demonstrated any cellular activity in the same concentration range. The conjugate molecule 1-Chl possesses the sequence-selectivity of a polyamide and the enhanced DNA reactivity of Chl

Water Supply Planning: Middle Illinois Assessment of Water Resources for Water Supply-Final Report

Illinois Department of Natural Resourcespublished or submitted for publicationis peer reviewedOpe

Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers

Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC(50) values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction

Water supply planning: Kankakee watershed assessment of water resources for water supply

This report examines the impacts of current and future demands on water supplies for the Kankakee Watershed Water Supply Planning Subregion (WSPR) in northeastern Illinois, an area comprising most of Kankakee and Iroquois Counties and portions of Ford, Will, Vermilion, and Grundy Counties that intersects the Kankakee River watershed boundary. Initial water demand scenarios were developed for a three-county region (Ford, Iroquois, and Kankakee) out to 2060 for five major water sectors, including thermoelectric power generation, public supply, self-supplied domestic, self-supplied industrial and commercial (IC), and self-supplied irrigation, livestock, and environmental (ILE), and are described in a companion report (Meyer et al., 2019). Total water usage in 2010 was estimated to be 39 million gallons per day (mgd), with two sectors, public supply and ILE, accounting for more than 80 percent of the demand in the region. Most of the ILE demand was for crop irrigation. Self-supplied IC accounted for 13 percent and the domestic sector 6 percent of the usage. Significant water resources are available to meet demands in the Kankakee WSPR, including both groundwater and surface water. Two major aquifer systems occur in the region: (1) productive sand and gravel aquifers, primarily in the south where the Mahomet Aquifer is encountered; and (2) weathered Silurian-Devonian dolomite, which is the most productive aquifer system in the region. Both the dolomite and Mahomet Aquifers are overlain by clay over most of the watershed, limiting leakage from shallower sources. The deeper Cambrian-Ordovician sandstones are generally too saline in this area to use as a water supply, although they are heavily used just outside of the watershed boundary in Will, Kendall, and Grundy Counties. Although the aquifers are generally thought to be adequate to meet most expected future demands, there are some sensitive areas that should be monitored closely. The most important area appears to be southeastern Kankakee and northeastern Iroquois Counties, where demands for irrigation water are highest on account of sandy soils. These demands are met from the dolomite aquifers and have been shown to result in dewatering of the dolomite during the irrigation season.Water quality in the Silurian-Devonian dolomite aquifer system is generally good. At a few locations, nitrate and chloride concentrations are elevated, but at concentrations below their respective drinking water standards. Water moves relatively rapidly from land surface into the Silurian-Devonian dolomite aquifer where it is near land surface, especially in the northern half of the region; aquifer protection activities should be a priority in these areas. The primary surface water sources in the Kankakee WSPR are the Kankakee and Iroquois Rivers. Currently there are four entities withdrawing water from the Kankakee River in the planning region: Aqua Illinois-Kankakee Division, which supplies the city of Kankakee, the city of Wilmington, Exelon Dresden Station, and Exelon Braidwood Generation Station.Although the Kankakee River has reliable water for meeting current power generation and public water supply needs, the cooling water withdrawals from the river could be limited on account of protected minimum flows and water temperature criteria. Therefore, both Dresden and Braidwood plants have a considerable storage capacity in their cooling ponds to buffer the impact of the minimum flow restriction. With increasing water demand and potential climate change, the frequency and duration of the minimum flow restriction may be increased in the 2 future. Both power plants using the Kankakee River for cooling water may rely on storage water more frequently.Water demand from within the watershed is not expected to increase dramatically in the future. However, large portions of Will County are at risk to dewatering of the Cambrian-Ordovician sandstone aquifers. As a result, communities within these at-risk areas are seeking alternate water supplies in anticipation of these impacts. One possible option is the Kankakee River. As part of the process of exploring alternative supplies, both Joliet and Godley have requested withdrawing a large amount of water from the lower reach of the Kankakee River. The communities served by this water lie primarily outside of the watershed, so both withdrawal and consumptive use of Kankakee River water could increase substantially. Unlike within the watershed, water demand for these communities outside of the watershed is expected to increase. Another unknown is how water demand will be met in the future by industries along the Des Plaines River. Many of these industries also rely on the at-risk sandstone aquifers, so the long-term viability of their sandstone wells is contingent on decisions by communities.The major concern with increasing water demand on the Kankakee River is the minimum flow restriction and how to supplement the river water when it is not available during drought conditions, especially when the water is diverted out of the watershed, as the wastewater may not be returned to the river. Other backup supplies are of limited availability in areas of sandstone risk, as currently the sandstone aquifers are likely to be the only viable backup option; however, there are questions about its viability under increasing demand. Off-channel storages and/or abandoned storage pits could also be explored to provide additional backup supply.As a result, conjunctive water management that accounts for impacts on both river and groundwater supplies will be essential moving forward. Water users within the Kankakee River watershed should be cognizant of this potential future demand on the river. Available flow on the Kankakee River during low-flow periods may be contingent on whether the communities in Will County also tap into it as a water supply, so water planners currently using or anticipating growth in use of the Kankakee River water should stay informed on planning decisions outside of the region. Sandstone users considering using the Kankakee River as a backup supply are also currently working with the ISWS to evaluate the viability of the Kankakee River as a backup supply under low-flow scenarios on the Kankakee River. This is critically important because of the rapid response of the sandstone aquifer when demands change.Illinois Department of Natural Resourcespublished or submitted for publicationis peer reviewedOpe

Activation of DNA-PK by Ionizing Radiation Is Mediated by Protein Phosphatase 6

DNA-dependent protein kinase (DNA-PK) plays a critical role in DNA damage repair, especially in non-homologous end-joining repair of double-strand breaks such as those formed by ionizing radiation (IR) in the course of radiation therapy. Regulation of DNA-PK involves multisite phosphorylation but this is incompletely understood and little is known about protein phosphatases relative to DNA-PK. Mass spectrometry analysis revealed that DNA-PK interacts with the protein phosphatase-6 (PP6) SAPS subunit PP6R1. PP6 is a heterotrimeric enzyme that consists of a catalytic subunit, plus one of three PP6 SAPS regulatory subunits and one of three ankyrin repeat subunits. Endogenous PP6R1 co-immunoprecipitated DNA-PK, and IR enhanced the amount of complex and promoted its import into the nucleus. In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation. Knockdown of other phosphatases PP5 or PP1γ1 and subunits PP6R3 or ARS-A did not reduce IR activation of DNA-PK, demonstrating specificity for PP6R1. Finally, siRNA knockdown of PP6R1 or PP6 but not other phosphatases increased the sensitivity of glioblastoma cells to radiation-induced cell death to a level similar to DNA-PK deficient cells. Our data demonstrate that PP6 associates with and activates DNA-PK in response to ionizing radiation. Therefore, the PP6/PP6R1 phosphatase is a potential molecular target for radiation sensitization by chemical inhibition

Decision aids for respite service choices by carers of people with dementia: development and pilot RCT

<p>Abstract</p> <p>Background</p> <p>Decision aids are often used to assist individuals confronted with a diagnosis of a serious illness to make decisions about treatment options. However, they are rarely utilised to help those with chronic or age related conditions to make decisions about care services. Decision aids should also be useful for carers of people with decreased decisional capacity. These carers' choices must balance health outcomes for themselves and for salient others with relational and value-based concerns, while relying on information from health professionals. This paper reports on a study that both developed and pilot tested a decision aid aimed at assisting carers to make evaluative judgements of community services, particularly respite care.</p> <p>Methods</p> <p>A mixed method sequential study, involving qualitative development and a pilot randomised controlled trial, was conducted in Tasmania, Australia. We undertook 13 semi-structured interviews and three focus groups to inform the development of the decision aid. For the randomised control trial we randomly assigned 31 carers of people with dementia to either receive the service decision aid at the start or end of the study. The primary outcome was measured by comparing the difference in carer burden between the two groups three months after the intervention group received the decision aid. Pilot data was collected from carers using interviewer-administered questionnaires at the commencement of the project, two weeks and 12 weeks later.</p> <p>Results</p> <p>The qualitative data strongly suggest that the intervention provides carers with needed decision support. Most carers felt that the decision aid was useful. The trial data demonstrated that, using the mean change between baseline and three month follow-up, the intervention group had less increase in burden, a decrease in decisional conflict and increased knowledge compared to control group participants.</p> <p>Conclusions</p> <p>While these results must be interpreted with caution due to the small sample size, all intervention results trend in a direction that is beneficial for carers and their decisional ability. Mixed method data suggest the decision aid provides decisional support that carers do not otherwise receive. Decision aids may prove useful in a community health services context.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN32163031">ISRCTN32163031</a></p

Urban futures and the code for sustainable homes

Copyright © 2012 ICE Publishing Ltd. Permission is granted by ICE Publishing to print one copy for personal use. Any other use of these PDF files is subject to reprint fees.A 6?6 ha (66 000 m2) regeneration site, commonly referred to as Luneside East, is to be turned from a run down, economically under-achieving area of Lancaster, UK, into a new, distinctive, vibrant, sustainable quarter of the city. As a result several aspects of water planning for 350 new homes and 8000 m2 of workspace needed to be considered before any infrastructure investment was undertaken. This included assessment of the future capacity requirements (i.e. inflows and outflows) for water infrastructure (i.e. mains water supply, wastewater disposal, rainwater storage and stormwater disposal) much of which will be located underground. This paper looks at the implications of various water management strategies on the Luneside East site (e.g. water-efficient appliances, greywater recycling and rainwater harvesting) in line with current policy measures that focus on technology changes alone (e.g. the code for sustainable homes). Based on these findings this paper outlines some basic implications for technological resilience discussed in the context of four ‘world views’ – that is, the urban futures scenarios considered in this special issue. Conclusions are drawn as to how far this can take engineers, planners and developers in understanding and planning for resilient water infrastructure within a development like Luneside East

An international collaborative evaluation of central serous chorioretinopathy: different therapeutic approaches and review of literature. The European Vitreoretinal Society central serous chorioretinopathy study

Purpose: To study and compare the efficacy of different therapeutic options for the treatment of central serous chorioretinopathy (CSCR). Methods: This is a nonrandomized, international multicentre study on 1719 patients (1861 eyes) diagnosed with CSCR, from 63 centres (24 countries). Reported data included different methods of treatment and both results of diagnostic examinations [fluorescein angiography and/or optical coherent tomography (OCT)] and best-corrected visual acuity (BCVA) before and after therapy. The duration of observation had a mean of 11&nbsp;months but was extended in a minority of cases up to 7&nbsp;years. The aim of this study is to evaluate the efficacy of the different therapeutic options of CSCR in terms of both visual (BCVA) and anatomic (OCT) improvement. Results: One thousand seven hundred nineteen patients (1861 eyes) diagnosed with CSCR were included. Treatments performed were nonsteroidal anti-inflammatory eye drops, laser photocoagulation, micropulse diode laser photocoagulation, photodynamic therapy (PDT; Standard PDT, Reduced-dose PDT, Reduced-fluence PDT), intravitreal (IVT) antivascular endothelial growth factor injection (VEGF), observation and other treatments. The list of the OTHERS included both combinations of the main proposed treatments or a variety of other treatments such as eplerenone, spironolactone, acetazolamide, beta-blockers, anti-anxiety drugs, aspirin, folic acid, methotrexate, statins, vitis vinifera extract medication and pars plana vitrectomy. The majority of the patients were men with a prevalence of 77%. The odds ratio (OR) showed a partial or complete resolution of fluid on OCT with any treatment as compared with observation. In univariate analysis, the anatomical result (improvement in subretinal fluid using OCT at 1&nbsp;month) was favoured by age &lt;60&nbsp;years (p&nbsp;&lt;&nbsp;0.005), no previous observation (p&nbsp;&lt;&nbsp;0.0002), duration less than 3&nbsp;months (p&nbsp;&lt;&nbsp;0.0001), absence of CSCR in the fellow eye (p&nbsp;=&nbsp;0.04), leakage outside of the arcade (p&nbsp;=&nbsp;0.05) and fluid height &gt;500&nbsp;\u3bcm (p&nbsp;=&nbsp;0.03). The OR for obtaining partial or complete resolution showed that anti-VEGF and eyedrops were not statistically significant; whereas PDT (8.5), thermal laser (11.3) and micropulse laser (8.9) lead to better anatomical results with less variability. In univariate analysis, the functional result at 1&nbsp;month was favoured by first episode (p&nbsp;=&nbsp;0.04), height of subretinal fluid &gt;500&nbsp;\u3bcm (p&nbsp;&lt;&nbsp;0.0001) and short duration of observation (p&nbsp;=&nbsp;0.02). Finally, there was no statistically significant difference among the treatments at 12&nbsp;months. Conclusion: Spontaneous resolution has been described in a high percentage of patients. Laser (micropulse and thermal) and PDT seem to lead to significant early anatomical improvement; however, there is little change beyond the first month of treatment. The real visual benefit needs further clarification

The Role of Sexual and Reproductive Rights in Social Work Practice

The understanding and promotion of sexual and reproductive rights are essential in the social work profession, not only to improve the health status of affected populations but to advocate effectively for social justice and to respond to globalized realities. This article highlights the relevance of sexual and reproductive rights in the philosophical foundation and practice of social work, emphasizes the impact of reproductive health and rights on women's lives, and proposes a social work agenda that will embrace and promote sexual and reproductive rights. It uses policy statements from the International Federation of Social Workers as well as a human rights framework focused on sexual and reproductive rights that stems from the global feminist movement.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline