Seeing Community for the Trees: The Links among Contact with Natural Environments, Community Cohesion, and Crime

Individuals may be losing touch with nature as their contact with it decreases worldwide. Although the consequences for people's personal well-being outcomes are becoming well documented, there is almost no research examining the social correlates of contact with nature. This article used a large nationally representative sample to link objective (percent greenspace) and subjective measurements of contact with nature, community cohesion, and local crime incidence. The perceived quality, views, and amount of time spent in nature were linked to more community cohesion, and in turn, the perception of cohesive communities enhanced individual well-being outcomes and contributions back to society through higher workplace productivity and environmentally responsible behaviors. Our findings also indicated that local nature was linked to lower crime both directly and indirectly through its effects on community cohesion

Graphic loans: East Asia and beyond

The national languages of East Asia (Chinese, Japanese, Korean and Vietnamese) have made extensive use of a type of linguistic borrowing sometimes referred to as a 'graphic loan'. Such loans have no place in the conventional classification of loans based on Haugen (1950) or Weinreich (1953), and research on loan word theory and phonology generally overlooks them. The classic East Asian phenomenon is discussed and a framework is proposed to describe its mechanism. It is argued that graphic loans are more than just 'spelling pronunciations', because they are a systematic and widespread process, independent of but not inferior to phonological borrowing. The framework is then expanded to cover a range of other cases of borrowing between languages to show that graphic loans are not a uniquely East Asian phenomenon, and therefore need to be considered as a major category of loan

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

MicroRNAs and potential targets in osteosarcoma: review

Osteosarcoma is the most common bone cancer in children and young adults. Surgery and multi-agent chemotherapy are the standard treatment regimens for this disease. New therapies are being investigated to improve overall survival in patients. Molecular targets that actively modulate cell processes such as cell-cycle control, cell proliferation, metabolism and apoptosis, have been studied, but it remains a challenge to develop novel, effective targeted therapies to treat this heterogeneous and complex disease. MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating cell processes including growth, development and disease. miRNAs function as oncogenes or tumor suppressors to regulate gene and protein expression. Several studies have demonstrated the involvement of miRNAs in the pathogenesis of osteosarcoma with the potential for development in disease diagnostics and therapeutics. In this review, we discuss the current knowledge on the role of miRNAs and their target genes and evaluate their potential use as therapeutic agents in osteosarcoma. We also summarize the efficacy of inhibition of oncogenic miRNAs or expression of tumor suppressor miRNAs in preclinical models of osteosarcoma. Recent progress on systemic delivery as well as current applications for miRNAs as therapeutic agents has seen the advancement of miR-34a in clinical trials for adult patients with non-resectable primary liver cancer or metastatic cancer with liver involvement. We suggest a global approach to the understanding of the pathogenesis of osteosarcoma may identify candidate miRNAs as promising biomarkers for this rare disease

Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways.

Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS

Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways

<div><p>Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited <i>in vitro</i> in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS.</p></div

Summary of EWS cellular response to ST and vorinostat drug combinations.

<p>The figure depicts EWS cellular response following DNA damage (DNA double-strand breaks and ROS production) and HDAC inhibition. ST promotes DNA damage and vorinostat inhibits HDACs leading to activation of p53, inhibition of CD1, cleavage of caspase-3 and induction of apoptosis. A secondary drug response involves activation of STAT3, mediated by Src, and activation of AKT and MAPK mediated in part through ALK and IGF-1R. V/ST combination facilitates greater cell proliferation (Survival) and ST/V and STV combinations facilitate greater cell death (Apoptosis). Abbreviations: HDAC—Histone deacetylase; ROS—reactive oxygen species, CD1 –cyclin D1, STAT3 –signal transducer and activator of transcription 3; MAPK—mitogen-activated protein kinase, ALK—anaplastic lymphoma kinase; IGF-1R –insulin-like growth factor 1 receptor. Red arrows represent drug inhibition; Solid gray arrows represent constitutive signaling pathways; Solid blunt lines represent inhibition of signals; Dotted gray lines represent activation of signaling pathways in response to drug treatments.</p

STAT3, AKT and MAPK inhibition in EWS cell lines following exposure to ST and vorinostat, MK-2206 and AZD3463.

<p><b>(A)</b> Immunoblot analysis of lysates of A4573 and TC32 cells following exposure to media only (Control, C); ST/V and V/ST with (+) or without (-) 5.0 μM MK-2206 using antibodies against AKT, p-AKT (S473), HDAC1, histone 2B (H2B) and ac-H2B (K5). GAPDH was loading control. <b>(B)</b> Immunoblot analysis of A4573 and TC32 cells following exposure to single (ST and V) and combination (ST/V, V/ST and STV) drug treatments, using an antibody against MGMT. <b>(C)</b> A4573 cells and <b>(D)</b> TC32 cells were incubated with media only (Control, C); ST/V and V/ST with (+) or without (-) 20 nM AZD3463 and viable cells were measured at 48 h by the MTT assay. Data represents mean absorbance (±SE), n = 6. Asterisks denote significant differences between (+) versus (-) 20 nM AZD3463, **p< 0.01 <b>(E)</b> Immunoblot analysis of lysates of A4573 and TC32 cells following exposure to media only (Control, C); ST/V and V/ST with (+) or without (-) 20 nM AZD3463 using antibodies against ALK, IGF-1R, STAT3 (Y705), p-STAT3, AKT, p-AKT (S473), MAPK, p-MAPK (p42/44).</p