Effects of photobiomodulation and caffeine treatment on acute kidney injury in a hypoxic ischemic neonatal rat model.

Hypoxic ischemic encephalopathy (HIE) occurs in 2-5/1000 births, with acute kidney injury (AKI) occurring in 40%. AKI increases morbidity and mortality. Caffeine, an adenosine receptor antagonist, and photobiomodulation (PBM), working on cytochrome c oxidase, are potential treatments for AKI. To examine effects of caffeine and PBM on AKI in rats, Day 7 pups underwent a HIE intervention (Modified Rice-Vannucci model) replicating pathology observed in humans. Caffeine was administered for 3 days and/or PBM for 5 days following HIE. Weights and urine for biomarkers (NGAL, albumin, KIM-1, osteopontin) were collected prior to HIE, daily post intervention and at sacrifice. Both treatments reduced kidney injury seen on electron microscopy, but not when combined. HIE elevated urinary NGAL and albumin on Days 1-3 post-HIE, before returning to control levels. This elevation was significantly reduced by PBM or caffeine. KIM-1 was significantly elevated for 7 days post-HIE and was reduced by both treatments. Osteopontin was not altered by HIE or the treatments. Treatments, individually but not in combination, improved HIE-induced reductions in the enzymatic activity of mitochondrial complexes II-III. PBM and caffeine also improved weight gain. PBM and caffeine reduces AKI diagnosed by urinary biomarkers and confirmed by EM findings.

Adaptations of an Effective Evidence-Based Pediatric Weight Management Intervention.

Current childhood obesity treatment programs do not address medically underserved populations or settings where all members of an interdisciplinary team may not exist-either within one organization or within the community. In this paper, we describe the use of a community-academic partnership to iteratively adapt Epstein's Traffic Light Diet (TLD), into Building Healthy Families (BHF), a community-placed evidence-based pediatric weight management intervention (PWMI) and evaluate its effectiveness in reducing BMI z scores. Nine cohorts of families completed BHF. Participants included children aged 6-12 years with obesity (M = 9.46, SD = 1.74). The Framework for Reporting Adaptations and Modifications-Expanded guided our classification of modifications across BHF cohorts. Using the FRAME reporting structure, the changes that were documented were (1) planned and occurred pre-implementation, (2) based on decisions from local stakeholders (e.g., school administrator, members of the implementation team), and (3) specific to changes in content and context-with a focus on implementation and potential for local scale-up. The nature of the adaptations included adding elements (whole of family approach), removing elements (calorie counting), and substituting elements (steps for minutes of physical activity). Across 9 cohorts, 84 families initiated the BHF program, 69 families successfully completed the 12-week program, and 45 families returned for 6-month follow-up assessments. Results indicated that the BMI z score in children was reduced by 0.31 ± 0.17 at 6 months across all cohorts. Reduction in BMI z score ranged from 0.41 in cohort 4 to 0.13 in cohort 5. Iterative adaptations to BHF were completed to improve the fit of BHF to the setting and participants and have contributed to a sustained community PWMI that adheres to the underlying principles and core elements of other evidence-based PWMIs. Monitoring adaptations and related changes to outcomes can play a role in long-term sustainability and effectiveness.

Endocytosed silver nanoparticles degrade in lysosomes to form secondary nanoparticle structures during expression of autophagy genes in osteogenic cells.

Silver nanoparticles (AgNPs) are increasingly used in combination with biomaterials, such as bone grafts, to provide antimicrobial properties. Our research focused on the cytotoxic and intracellular uptake mechanism of AgNPs on osteogenic cells, and the affected gene expression of osteoblasts exposed to AgNPs. Osteoblast cells were found to be relatively resistant to AgNP exposure, compared to osteoclasts, with a higher IC50 and fewer adverse morphological features. AgNPs were endocytosed within lysosomes, which resulted in the secondary internal formation of curved AgO nano-chains assemblies within the cytosol. Furthermore, osteoblasts demonstrated an oxidative stress response, with autophagic cell death mechanisms, as indicated from qRT2-PCR analysis, with sustained upregulation of the protective gene Heme Oxygenase 1 reaching 86-fold by 48 hours (10 µg/mL). The internalization and fate of AgNPs in osteogenic cells, and the resulting impact on gene expression over time provide further understanding of the nanotoxicity mechanism of AgNPs.

Women's mobility and transport in the peripheries of three African cities: Reflecting on early impacts of COVID-19.

This paper reflects on the mobility experiences of women in African cities in COVID-19, based on research conducted both prior to and following entry into the COVID-19 'moment'. It draws on material collected during an ongoing action research study aimed at addressing the everyday transport and mobility challenges faced by young women living in poor peripheral communities of three African cities - Abuja, Cape Town and Tunis. The project has the specific objective of supporting young women's improved access to employment opportunities through trialling various mobility/transport-related skills interventions (based on prior in-depth analysis of mobility constraints). With the onset of COVID-19 some readjustments to the research focus and planned interventions became necessary. The research teams, together with an NGO partner, are now working to chart how young women's everyday experiences of mobility and transport - both as transport users and as transport sector workers - are changing as processes of lockdown and their relaxation evolve. The paper covers the period from early 2019 through to March 2021, and offers reflections regarding 'lived experiences' of mobility practice pre-pandemic, during the pandemic, and the potential longer-term mobility-related impacts for women resident in low-income neighbourhoods in a post-COVID-19 era. This leads to consideration of key policy lessons. There is potential for prioritisation of Non-Motorised Transport interventions towards a green restart that would benefit women (for instance through promoting women's cycling), and for growing women's participation as transport operators, even perhaps the usage of drones to aid women's safer pedestrian travel. But such interventions will require far greater representation of women in COVID-19 and wider transport decision-making entities than has hitherto been the case.

Machine learning applied to atopic dermatitis transcriptome reveals distinct therapy-dependent modification of the keratinocyte immunophenotype.

BACKGROUND: Atopic dermatitis (AD) arises from a complex interaction between an impaired epidermal barrier, environmental exposures, and the infiltration of T helper (Th)1/Th2/Th17/Th22 T cells. Transcriptomic analysis has advanced our understanding of gene expression in cells and tissues. However, molecular quantitation of cytokine transcripts does not predict the importance of a specific pathway in AD or cellular responses to different inflammatory stimuli. OBJECTIVES: To understand changes in keratinocyte transcriptomic programmes in human cutaneous disease during development of inflammation and in response to treatment. METHODS: We performed in silico deconvolution of the whole-skin transcriptome. Using co-expression clustering and machine-learning tools, we resolved the gene expression of bulk skin (seven datasets, n = 406 samples), firstly, into keratinocyte phenotypes identified by unsupervised clustering and, secondly, into 19 cutaneous cell signatures of purified populations from publicly available datasets. RESULTS: We identify three unique transcriptomic programmes in keratinocytes - KC1, KC2 and KC17 - characteristic of immune signalling from disease-associated Th cells. We cross-validate those signatures across different skin inflammatory conditions and disease stages and demonstrate that the keratinocyte response during treatment is therapy dependent. Broad-spectrum treatment with ciclosporin ameliorated the KC17 response in AD lesions to a nonlesional immunophenotype, without altering KC2. Conversely, the specific anti-Th2 therapy, dupilumab, reversed the KC2 immunophenotype. CONCLUSIONS: Our analysis of transcriptomic signatures in cutaneous disease biopsies reveals the effect of keratinocyte programming in skin inflammation and suggests that the perturbation of a single axis of immune signal alone may be insufficient to resolve keratinocyte immunophenotype abnormalities.

Anti-biofilm activity of silver nanoparticle-containing glass ionomer cements.

OBJECTIVE: To develop a silver nanoparticle (AgNP) formulation for incorporation into glass ionomer cements (GICs) which minimises biofilm growth on restoration surfaces. METHODS: GICs, Fuji IX, Ketac Molar, and Riva Selfcure were modified with 6, 10 and 24 µg per GIC capsule of α-lipoic acid-capped AgNPs. Monoculture biofilms of Streptococcus mutans were cultured (72 h) on GIC specimens (n = 3) and biofilm accumulation was quantified using a viability stain with confocal laser scanning microscopy. Compression strength and flexural strength (CS & FS) were measured according to ISO 9917-1:2007 (n = 8, n = 25). GIC colour was measured at 0, 1, and 14 days following AgNP incorporation using a digital spectrophotometer. Silver release from AgNP-modified GIC specimens was monitored at 1, 3, 7 and 14 days using inductively coupled plasma-mass spectrometry. RESULTS: AgNP-modified Fuji IX demonstrated the greatest reduction in biofilm accumulation, with 10 µg Ag/capsule inhibiting biofilm formation by 99%. Ketac Molar and Riva Selfcure required 24 µg Ag/capsule to achieve 78% biofilm reduction. AgNP-modified GICs demonstrated significantly higher CS and FS than sintered silver-containing GICs, and possessed equivalent or higher strength values when compared to unmodified GICs. The colour shades of AgNP-modified GICs were more comparable to VITA shades of non-modified GICs than were sintered silver-containing GICs. The silver (≥99.6%) remained within the GIC for at least two weeks following incorporation. SIGNIFICANCE: AgNP-modified GICs exhibited significant antibiofilm activity and retained mechanical properties equivalent or superior to non-modified GICs. AgNP-modified GICs could reduce bacterial colonisation on and around restorations thereby reducing restoration failure caused by secondary caries.

Cross-Canada differences in early-stage breast cancer treatment and acute-care use.

Background: Chemotherapy has improved outcomes in early-stage breast cancer, but treatment practices vary, and use of acute care is common. We conducted a pan-Canadian study to describe treatment differences and the incidence of emergency department visits (edvs), edvs leading to hospitalization (edvhs), and direct hospitalizations (hs) during adjuvant chemotherapy. Methods: The cohort consisted of women diagnosed with early-stage breast cancer (stages i-iii) during 2007-2012 in British Columbia, Manitoba, Ontario, or Nova Scotia who underwent curative surgery. Parallel provincial analyses were undertaken using linked clinical, registry, and administrative databases. The incidences of edvs, edvhs, and hs in the 6 months after treatment initiation were examined for patients treated with adjuvant chemotherapy. Results: The cohort consisted of 50,224 patients. The proportion of patients who received chemotherapy varied by province, with Ontario having the highest proportion (46.4%), and Nova Scotia, the lowest proportion (38.0%). Age, stage, receptor status, comorbidities, and geographic location were associated with receipt of chemotherapy in all provinces. Ontario had the highest proportion of patients experiencing an edv (36.1%), but the lowest proportion experiencing h (6.4%). Conversely, British Columbia had the lowest proportion of patients experiencing an edv (16.0%), but the highest proportion experiencing h (26.7%). The proportion of patients having an edvh was similar across provinces (13.9%-16.8%). Geographic location was associated with edvs, edvhs, and hs in all provinces. Conclusions: Intra- and inter-provincial differences in the use of chemotherapy and acute care were observed. Understanding variations in care can help to identify gaps and opportunities for improvement and shared learnings.

The metastasis suppressor, NDRG1, differentially modulates the endoplasmic reticulum stress response.

The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), is a stress response protein that is involved in the inhibition of multiple oncogenic signaling pathways. Initial studies have linked NDRG1 and the endoplasmic reticulum (ER) stress response. Considering this, we extensively examined the mechanism by which NDRG1 regulates the ER stress response in pancreatic and colon cancer cells. We also examined the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which induces NDRG1 expression and causes ER stress. The expression of NDRG1 was demonstrated to regulate the three main arms of the ER stress response by: (1) increasing the expression of three major ER chaperones, binding immunoglobulin protein (BiP), calreticulin, and calnexin; (2) suppressing the protein kinase, RNA-activated (PKR)-like ER kinase (PERK); (3) inhibiting the inositol-requiring kinase 1α (IRE1α) arm; and (4) increasing the cleavage of activating transcription factor 6 (ATF6). An important finding was that NDRG1 enhances the anti-proliferative and anti-migratory activity of Dp44mT. This increased efficacy could be related to the following effects in the presence of Dp44mT and NDRG1, namely: markedly increased activation of the PERK target, eukaryotic translation initiation factor 2α (eIF2α); the maintenance of activating transcription factor 4 (ATF4) expression; high cytosolic Ca+2 that increases the sensitivity of cells to apoptosis via activation of the calmodulin-dependent kinase II (CaMKII) signaling cascade; and increased pro-apoptotic C/EBP-homologous protein (CHOP) expression. Collectively, this investigation dissects the molecular mechanisms through which NDRG1 manipulates the ER stress response and its ability to potentiate the activity of the potent anti-cancer agent, Dp44mT.

Clinical development of targeted and immune based anti-cancer therapies.

Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to their specificity, these new therapies are expected to have better efficacy and limited adverse side effects when compared with other treatment options, including hormonal and cytotoxic therapies. In this review, we explore the clinical development, successes and challenges facing targeted anti-cancer therapies, including both small molecule inhibitors and antibody targeted therapies. Herein, we introduce targeted therapies to epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), BRAF, and the inhibitors of the T-cell mediated immune response, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1)/ PD-1 ligand (PD-1 L).