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"Lowe, Johnny"
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The haunted cabin mystery
\"Henry, Jesse, Violet, and Benny Alden take a trip down the Mississippi River and stay in a haunted cabin! At least it seems haunted--there are spooky phone calls, flickering lights, and strange shadows. Is there a ghost in the cabin? Join the Boxcar Children in their graphic novel adventure as they solve the mystery of the haunted cabin!\"--Page 4 of cover.
Book
Bio-activating ultrafine grain titanium: RNA sequencing reveals enhanced mechano-activation of osteoconduction on nanostructured substrates
Titanium is essentially absent from biological systems yet reliably integrates into bone. To achieve osseointegration, titanium must activate biological processes without entering cells, defining it as a bio-activating material. Nanostructuring bulk titanium reduces grain size, increases strength, and improves other quantifiable physical properties, including cytocompatibility. The biological processes activated by increasing grain boundary availability were detected with total RNA-sequencing in mouse pre-osteoblasts grown for 72 hours on nanometrically smooth substrates of either coarse grain or nanostructured ultrafine grain titanium. The average grain boundary length under cells on the conventional coarse grain substrates is 273.0 μm, compared to 70,881.5 μm for cells adhered to the nanostructured ultrafine grain substrates; a 260-fold difference. Cells on both substrates exhibit similar expression profiles for genes whose products are critical for mechanosensation and transduction of cues that trigger osteoconduction. Biological process Gene Ontology term enrichment analysis of differentially expressed genes reveals that cell cycle, chromatin modification, telomere maintenance, and RNA metabolism processes are upregulated on ultrafine grain titanium. Processes related to immune response, including apoptosis, are downregulated. Tumor-suppressor genes are upregulated while tumor-promoting genes are downregulated. Upregulation of genes involved in chromatin remodeling and downregulation of genes under the control of the peripheral circadian clock implicate both processes in the transduction of mechanosensory information. Non-coding RNAs may also play a role in the response. Merging transcriptomics with well-established mechanobiology principles generates a unified model to explain the bio-activating properties of titanium. The modulation of processes is accomplished through chromatin remodeling in which the nucleus responds like a rheostat to grain boundary concentration. This convergence of biological and materials science reveals a pathway toward understanding the biotic-abiotic interface and will inform the development of effective bio-activating and bio-inactivating materials.
Journal Article
Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study
Background
Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM.
Methods
Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS).
Results
The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (
n
= 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44–47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed.
Conclusion
Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).
Journal Article
The UGT2A1/UGT2A2 locus is associated with COVID-19-related loss of smell or taste
Using online surveys, we collected data regarding COVID-19-related loss of smell or taste from 69,841 individuals. We performed a multi-ancestry genome-wide association study and identified a genome-wide significant locus in the vicinity of the
UGT2A1
and
UGT2A2
genes. Both genes are expressed in the olfactory epithelium and play a role in metabolizing odorants. These findings provide a genetic link to the biological mechanisms underlying COVID-19-related loss of smell or taste.
Multi-ancestry genome-wide analyses identify variants near
UGT2A1
and
UGT2A2
associated with COVID-19-related loss of smell or taste. Both genes are expressed in the olfactory epithelium and play a role in metabolizing odorants.
Journal Article
Potential Usefulness of Losartan as an Antifibrotic Agent and Adjunct to Platelet-Rich Plasma Therapy to Improve Muscle Healing and Cartilage Repair and Prevent Adhesion Formation
Postoperative tissue fibrosis represents a major complication in orthopedics. Transforming growth factor beta 1 is a key molecule in the development of postoperative fibrosis. High concentrations of transforming growth factor beta 1 have also been implicated in various diseases. Agents that counteract the actions of transforming growth factor beta 1 have been investigated as potential antifibrotic medications and as adjunct treatment to platelet-rich plasma injections (increased amounts of transforming growth factor beta 1) to improve their effectiveness and/or safety profile. Losartan blocks transforming growth factor beta 1 action and has attracted special interest in orthopedic research that focuses on how to reduce the risk of postoperative fibrosis. [ Orthopedics . 2018; 41(5):e591–e597.]
Journal Article
Influences of donor and host age on human muscle-derived stem cell-mediated bone regeneration
Background
Human muscle-derived stem cells (hMDSCs) have been shown to regenerate bone efficiently when they were transduced with Lenti-viral bone morphogenetic protein 2 (LBMP2). However, whether the age of hMDSCs and the animal host affect the bone regeneration capacity of hMDSCs and mechanism are unknown which prompted the current study.
Methods
We isolated three gender-matched young and old populations of skeletal muscle stem cells, and tested the influence of cells’ age on in vitro osteogenic differentiation using pellet culture before and after Lenti-BMP2/green fluorescent protein (GFP) transduction. We further investigated effects of the age of hMDSCs and animal host on hMDSC-mediated bone regeneration in a critical-size calvarial bone defect model in vivo. Micro-computer tomography (CT), histology, and immunohistochemistry were used to evaluate osteogenic differentiation and mineralization in vitro and bone regeneration in vivo. Western blot, quantitative polymerase chain reaction (PCR), and oxidative stress assay were performed to detect the effects of age of hMDSCs on cell survival and osteogenic-related genes. Serum insulin-like growth factor 1 (IGF1) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured with an enzyme-linked immunosorbent assay (ELISA).
Results
We found LBMP2/GFP transduction significantly enhanced osteogenic differentiation of hMDSCs in vitro, regardless of donor age. We also found old were as efficient as young LBMP2/GFP-transduced hMDSCs for regenerating functional bone in young and old mice. These findings correlated with lower phosphorylated p38MAPK expression and similar expression levels of cell survival genes and osteogenic-related genes in old hMDSCs relative to young hMDSCs. Old cells exhibited equivalent resistance to oxidative stress. However, both young and old donor cells regenerated less bone in old than young hosts. Impaired bone regeneration in older hosts was associated with high bone remodeling due to higher serum levels of
RANKL
and lower level of IGF-1.
Conclusion
hMDSC-mediated bone regeneration was not impaired by donor age when hMDSCs were transduced with LBMP2/GFP, but the age of the host adversely affected hMDSC-mediated bone regeneration. Regardless of donor and host age, hMDSCs formed functional bone, suggesting a promising cell resource for bone regeneration.
Journal Article
Problematizing profit and profitability: discussions
Purpose The purpose of this paper is to report the outcome of an interdisciplinary discussion on the concepts of profit and profitability and various ways in which we could potentially problematize these concepts. It is our hope that a much greater attention or reconsideration of the problematization of profit and related accounting numbers will be fostered in part by the exchanges we include here. Design/methodology/approach This paper adopts an interdisciplinary discussion approach and brings into conversation ideas and views of several scholars on problematizing profit and profitability in various contexts and explores potential implications of such problematization. Findings Profit and profitability measures make invisible the collective endeavour of people who work hard (backstage) to achieve a desired profit level for a division and/or an organization. Profit tends to preclude the social process of debate around contradictions among the ends and means of collective activity. An inherent message that we can discern from our contributors is the typical failure of managers to appreciate the value of critical theory and interpretive research for them. Practitioners and positivist researchers seem to be so influenced by neo-liberal economic ideas that organizations are distrusted and at times reviled in their attachment to profit. Research limitations/implications Problematizing opens-up the potential for interesting and significant theoretical insights. A much greater pragmatic and theoretical reconsideration of profit and profitability will be fostered by the exchanges we include here. Originality/value In setting out a future research agenda, this paper fosters theoretical and methodological pluralism in the research community focussing on problematizing profit and profitability in various settings. The discussion perspectives offered in this paper provides not only a basis for further research in this critical area of discourse and regulation on the role and status of profit and profitability but also emancipatory potential for practitioners (to be reflective of their practices and their undesired consequences of such practices) whose overarching focus is on these accounting numbers.
Journal Article