Publications by authors named "Mark Jackson"

332 Publications

Biological effects of inhaled crude oil vapor. II. Pulmonary effects.

Toxicol Appl Pharmacol 2022 Sep 5;450:116154. Epub 2022 Jul 5.

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, United States of America.

Workers involved in oil exploration and production in the upstream petroleum industry are exposed to crude oil vapor (COV). COV levels in the proximity of workers during production tank gauging and opening of thief hatches can exceed regulatory standards, and several deaths have occurred after opening thief hatches. There is a paucity of information regarding the effects of COV inhalation in the lung. To address these knowledge gaps, the present hazard identification study was undertaken to investigate the effects of an acute, single inhalation exposure (6 h) or a 28 d sub-chronic exposure (6 h/d × 4 d/wk × 4 wks) to COV (300 ppm; Macondo well surrogate oil) on ventilatory and non-ventilatory functions of the lung in a rat model 1 and 28 d after acute exposure, and 1, 28 and 90 d following sub-chronic exposure. Basal airway resistance was increased 90 d post-sub-chronic exposure, but reactivity to methacholine (MCh) was unaffected. In the isolated, perfused trachea preparation the inhibitory effect of the airway epithelium on reactivity to MCh was increased at 90 d post-exposure. Efferent cholinergic nerve activity regulating airway smooth muscle was unaffected by COV exposure. Acute exposure did not affect basal airway epithelial ion transport, but 28 d after sub-chronic exposure alterations in active (Na and Cl¯) and passive ion transport occurred. COV treatment did not affect lung vascular permeability. The findings indicate that acute and sub-chronic COV inhalation does not appreciably affect ventilatory properties of the rat, but transient changes in airway epithelium occur.
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http://dx.doi.org/10.1016/j.taap.2022.116154DOI Listing
September 2022

British medical bulletin article: resourcing of palliative and end of life care in the UK during the Covid-19 pandemic.

Authors:
Mark Jackson

Br Med Bull 2022 07;142(1):44-51

Policy & Public Affairs Manager for England, Marie Curie, England.

Introduction: Covid-19 led to a sustained increase in deaths in all four United Kingdom nations, placing strain on the UK's palliative and end-of-life care sector and raising concerns about the long-term sustainability of the sector's funding and resourcing model in the face of rising demand for these services in the coming decades.

Sources Of Data: Published research, Marie Curie, King's College London Cicely Saunders Institute, Hull York Medical School, University of Hull, University of Cambridge, National Statistics, PubMed, DOI.

Areas Of Agreement: Care for people at the end of their lives is a core part of the UK's health and care system with demand set to increase significantly as the UK's population ages.

Areas Of Controversy: The UK's funding model for palliative and end-of-life care, with most care delivered by charitable sector providers and reliant on charitable donations, may be unsustainable in the face of increasing demand.

Growing Points: The Covid-19 pandemic led to rapid service innovation in palliative and end-of-life care, and providers should assess which of and how these innovations can be retained after the pandemic.

Areas Timely For Developing Research: Although there has been a rapid growth in knowledge during Covid-19, gaps still remain including: the reasons underlying shifts to deaths at home and the implications for family carers; the education needs of the wider healthcare workforce in palliative care; the impact of specialist palliative care services on the wider health system, including hospital admissions and place of death; and inequalities in the experiences of dying, death and bereavement during Covid-19 among groups such as those from lower socioeconomic groups and BAME communities.
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http://dx.doi.org/10.1093/bmb/ldac013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270992PMC
July 2022

Biological effects of inhaled crude oil vapor V. Altered biogenic amine neurotransmitters and neural protein expression.

Toxicol Appl Pharmacol 2022 Aug 21;449:116137. Epub 2022 Jun 21.

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, United States of America.

Workers in the oil and gas industry are at risk for exposure to a number of physical and chemical hazards at the workplace. Chemical hazard risks include inhalation of crude oil or its volatile components. While several studies have investigated the neurotoxic effects of volatile hydrocarbons, in general, there is a paucity of studies assessing the neurotoxicity of crude oil vapor (COV). Consequent to the 2010 Deepwater Horizon (DWH) oil spill, there is growing concern about the short- and long-term health effects of exposure to COV. NIOSH surveys suggested that the DWH oil spill cleanup workers experienced neurological symptoms, including depression and mood disorders, but the health effects apart from oil dispersants were difficult to discern. To investigate the potential neurological risks of COV, male Sprague-Dawley rats were exposed by whole-body inhalation to COV (300 ppm; Macondo surrogate crude oil) following an acute (6 h/d × 1 d) or sub-chronic (6 h/d × 4 d/wk. × 4 wks) exposure regimen. At 1, 28 or 90 d post-exposure, norepinephrine (NE), epinephrine (EPI), dopamine (DA) and serotonin (5-HT) were evaluated as neurotransmitter imbalances are associated with psychosocial-, motor- and cognitive- disorders. Sub-chronic COV exposure caused significant reductions in NE, EPI and DA in the dopaminergic brain regions, striatum (STR) and midbrain (MB), and a large increase in 5-HT in the STR. Further, sub-chronic exposure to COV caused upregulation of synaptic and Parkinson's disease-related proteins in the STR and MB. Whether such effects will lead to neurodegenerative outcomes remain to be investigated.
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http://dx.doi.org/10.1016/j.taap.2022.116137DOI Listing
August 2022

Return to play in paediatric & adolescent patients following anterior cruciate ligament reconstruction.

Knee 2022 Jun 18;37:87-94. Epub 2022 Jun 18.

Sports Surgery Clinic, Santry, Dublin, Ireland.

Background: There is an increased risk of anterior cruciate ligament (ACL) rupture and subsequent ACL reconstruction in patients <18 years old due to their high levels of sporting participation.

Purpose: The purpose of this study was to assess the rate and timing of return to play (RTP) in paediatric and adolescent patients following ACL reconstruction, and to compare the outcomes between those undergoing ACL reconstruction with bone patella tendon bone autograft (BTB) and hamstring tendon (HT) autograft.

Study Design: Level of Evidence: Level III; Retrospective Comparative Cohort Study.

Methods: The institutional ACL registry was screened for patients <18 that had undergone a primary ACL reconstruction. Outcomes were analysed for patients undergoing either a BTB or HT autograft for rate and timing of return to play, functional outcomes and subsequent knee injuries. Statistical analysis was performed using SPSS.

Results: 358 (BTB; 253, HT; 105) patients were followed up for 24-months (95% follow up). 86 athletes (27 BTB; 59 HT) were aged 13-15 years old with no significant difference in RTP rate or timing between graft types, however, there was a difference in ipsilateral re-ruptures (10.2% HT vs 0% BTB p = 0.03). 272 athletes (226 BTB; 46 HT) were aged 16-18 years old with no significant difference in RTP rate or timing between graft types, or ipsilateral re-ruptures (8.7% HT vs 2.7% BTB p = 0.07). Concurrent ligament, meniscal or chondral injuries found at the time was treated as necessary.

Conclusion: Paediatric and adolescent patients undergoing ACL reconstruction with either BTB or HT had high rates of return to play. This was seen in both subgroups with 13-15-year-olds mostly receiving a HT graft repair and 16-18-year-olds mainly receiving a BTB repair. A moderate re-rupture rate was seen at 24-months. However longer follow up is needed to truly see the long-term impact of such an injury at such a young age.
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http://dx.doi.org/10.1016/j.knee.2022.05.013DOI Listing
June 2022

Rational domestication of a plant-based recombinant expression system expands its biosynthetic range.

J Exp Bot 2022 Jun 20. Epub 2022 Jun 20.

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia.

Plant molecular farming aims to provide a green, flexible, and rapid alternative to conventional recombinant expression systems, capable of producing complex biologics such as enzymes, vaccines, and antibodies. Historically, the recombinant expression of therapeutic peptides in plants has proven difficult, largely due to their small size and instability. However, some plant species harbour the capacity for peptide backbone cyclization, a feature inherent in stable therapeutic peptides. One obstacle to realizing the potential of plant-based therapeutic peptide production is the proteolysis of the precursor before it is matured into its final stabilized form. Here we demonstrate the rational domestication of Nicotiana benthamiana within two generations to endow this plant molecular farming host with an expanded repertoire of peptide sequence space. The in planta production of molecules including an insecticidal peptide, a prostate cancer therapeutic lead and an orally active analgesic are demonstrated.
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http://dx.doi.org/10.1093/jxb/erac273DOI Listing
June 2022

Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics.

Cell Death Differ 2022 Apr 26. Epub 2022 Apr 26.

Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.

Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. High anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics.
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http://dx.doi.org/10.1038/s41418-022-01001-3DOI Listing
April 2022

Validation-Based Insertional Mutagenesis (VBIM), A Powerful Forward Genetic Screening Strategy.

Curr Protoc 2022 Mar;2(3):e394

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Forward genetics begins with a biological phenotype and attempts to identify genetic changes that influence that phenotype. These changes can be induced in a selected group of genes, for instance, by using libraries of cDNAs, shRNAs, CRISPR guide RNAs, or genetic suppressor elements (GSEs), or randomly throughout the genome using chemical or insertional mutagens, with each approach creating distinct genetic changes. The Validation-Based Insertional Mutagenesis (VBIM) strategy utilizes modified lentiviruses as insertional mutagens, placing strong promoters throughout the genome. Generating libraries with millions of cells carrying one or a few VBIM promoter insertions is straightforward, allowing selection of cells in which overexpression of VBIM-driven RNAs or proteins promote the phenotype of interest. VBIM-driven RNAs may encode full-length proteins, truncated proteins (which may have wild-type, constitutive, or dominant-negative activity), or antisense RNAs that can disrupt gene expression. The diversity in VBIM-driven changes allows for the identification of both gain-of-function and loss-of-function mutations in a single screen. Additionally, VBIM can target any genomic locus, regardless of whether it is expressed in the cells under study or known to have a biological function, allowing for true whole-genome screens without the complication and cost of constructing, maintaining, and delivering a comprehensive library. Here, we review the VBIM strategy and discuss examples in which VBIM has been successfully used in diverse screens to identify novel genes or novel functions for known genes. In addition, we discuss considerations for transitioning the VBIM strategy to in vivo screens. We hope that other laboratories will be encouraged to use the VBIM strategy to identify genes that influence their phenotypes of interest. © 2022 Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/cpz1.394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969887PMC
March 2022

A comprehensive review on metallic implant biomaterials and their subtractive manufacturing.

Int J Adv Manuf Technol 2022 23;120(3-4):1473-1530. Epub 2022 Feb 23.

Department of Mechanical Engineering, Vaugh Institute of Agricultural Engineering and Technology, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007 India.

There is a tremendous increase in the demand for converting biomaterials into high-quality industrially manufactured human body parts, also known as medical implants. Drug delivery systems, bone plates, screws, cranial, and dental devices are the popular examples of these implants - the potential alternatives for human life survival. However, the processing techniques of an engineered implant largely determine its preciseness, surface characteristics, and interactive ability with the adjacent tissue(s) in a particular biological environment. Moreover, the high cost-effective manufacturing of an implant under tight tolerances remains a challenge. In this regard, several subtractive or additive manufacturing techniques are employed to manufacture patient-specific implants, depending primarily on the required biocompatibility, bioactivity, surface integrity, and fatigue strength. The present paper reviews numerous non-degradable and degradable metallic implant biomaterials such as stainless steel (SS), titanium (Ti)-based, cobalt (Co)-based, nickel-titanium (NiTi), and magnesium (Mg)-based alloys, followed by their processing via traditional turning, drilling, and milling including the high-speed multi-axis CNC machining, and non-traditional  abrasive water jet machining (AWJM), laser beam machining (LBM), ultrasonic machining (USM), and electric discharge machining (EDM) types of subtractive manufacturing techniques. However, the review further funnels down its primary focus on Mg, NiTi, and Ti-based alloys on the basis of the increasing trend of their implant applications in the last decade due to some of their outstanding properties. In the recent years, the incorporation of cryogenic coolant-assisted traditional subtraction of biomaterials has gained researchers' attention due to its sustainability, environment-friendly nature, performance, and superior biocompatible and functional outcomes fitting for medical applications. However, some of the latest studies reported that the medical implant manufacturing requirements could be more remarkably met using the non-traditional subtractive manufacturing approaches. Altogether, cryogenic  machining among the traditional routes and EDM among the non-traditional means along with their variants, were identified as some of the most effective subtractive manufacturing techniques for achieving the dimensionally accurate and biocompatible metallic medical implants with significantly modified surfaces.
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http://dx.doi.org/10.1007/s00170-022-08770-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865884PMC
February 2022

Development of a thermal spray coating aerosol generator and inhalation exposure system.

Toxicol Rep 2022 25;9:126-135. Epub 2022 Jan 25.

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26508, United States.

Thermal spray coating involves spraying a product (oftentimes metal) that is melted by extremely high temperatures and then applied under pressure onto a surface. Large amounts of a complex metal aerosol (e.g., Fe, Cr, Ni, Zn) are formed during the process, presenting a potentially serious risk to the operator. Information about the health effects associated with exposure to these aerosols is lacking. Even less is known about the chemical and physical properties of these aerosols. The goal was to develop and test an automated thermal spray coating aerosol generator and inhalation exposure system that would simulate workplace exposures. An electric arc wire-thermal spray coating aerosol generator and exposure system was designed and separated into two areas: (1) an enclosed room where the spray coating occurs; (2) an exposure chamber with different measurement devices and controllers. The physicochemical properties of aerosols generated during electric arc wire-thermal spray coating using five different consumable wires were examined. The metal composition of each was determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES), including two stainless-steel wires [PMET720 (82 % Fe, 13 % Cr); PMET731(66 % Fe, 26 % Cr)], two Ni-based wires [PMET876 (55 % Ni, 17 % Cr); PMET885 (97 % Ni)], and one Zn-based wire [PMET540 (99 % Zn)]. The particles generated regardless of composition were poorly soluble, complex metal oxides and mostly arranged as chain-like agglomerates and similar in size distribution as determined by micro-orifice uniform deposit impactor (MOUDI) and electrical low-pressure impactor (ELPI). To allow for continuous, sequential spray coating during a 4-hr exposure period, a motor rotated the metal pipe to be coated in a circular and up-and-down direction. In a pilot animal study, male Sprague-Dawley rats were exposed to aerosols (25 mg/m × 4 h/d × 9 d) generated from electric arc wire- thermal spray coating using the stainless-steel PMET720 consumable wire. The targeted exposure chamber concentration was achieved and maintained during a 4-hr period. At 1 d after exposure, lung injury and inflammation were significantly elevated in the group exposed to the thermal spray coating aerosol compared to the air control group. The system was designed and constructed for future animal exposure studies to generate continuous metal spray coating aerosols at a targeted concentration for extended periods of time without interruption.
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http://dx.doi.org/10.1016/j.toxrep.2022.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810300PMC
January 2022

Comparative analysis of cyclotide-producing plant cell suspensions presents opportunities for cyclotide plant molecular farming.

Phytochemistry 2022 Mar 16;195:113053. Epub 2021 Dec 16.

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, 4072, Australia. Electronic address:

Cyclotides are a class of ribosomally-synthesized plant peptides that function in plants as a defense against insects and fungal pathogens. Their unique structure comprises a cyclized peptide backbone threaded by three disulfide bonds, that imparts structural stability, a desirable quality for peptide-based therapeutics or insecticides. Producing these peptides synthetically is challenging due to the amount of chemical waste produced and inefficiency of folding certain cyclotides. Thus, it is desirable to develop a means to access cyclotide biosynthesis in their native hosts, cultured in defined conditions, at both laboratory and commercial scale. Here we developed suspension cell cultures from two species previously unexplored for cyclotide production in suspension cells, Clitoria ternatea L., Hybanthus enneaspermus F. Muell., as well as with Oldenlandia affinis (Roem. & Schult.) DC., a species reported previously to accumulate cyclotides in cell suspensions. We assessed the growth rate, cyclotide production and gene expression for the various species. We found that while many cyclotides had reduced expression in Oldenlandia affinis suspension cells when compared to plant organs, those in Clitoria ternatea and Hybanthus enneaspermus maintained or increased expression levels. The cyclotides that continued to be expressed in suspension cultures shared similar sequence and biophysical properties as a group, regardless of phylogenetic origin of the host. Of particular interest was the discovery of inducibility by NaCl of cyclotide expression in O. affinis, cycloviolacin O2 expression in O. affinis, and the scale up of cycloviolacin O2 production in H. enneaspermus. Together the results presented here highlight the utility of plant cell suspensions as modalities to produce macrocyclic peptides.
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http://dx.doi.org/10.1016/j.phytochem.2021.113053DOI Listing
March 2022

Scalable and Efficient In Planta Biosynthesis of Sunflower Trypsin Inhibitor-1 (SFTI) Peptide Therapeutics.

Methods Mol Biol 2022 ;2371:117-142

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD, Australia.

Sunflower trypsin inhibitor-1 (SFTI-1) is a 14 amino acid cyclic peptide which has been effectively employed as a scaffold for engineering a range of peptide therapeutic candidates. Typically, synthesis of SFTI-1-based therapeutics is performed via solid-phase peptide synthesis and native chemical ligation, with significant financial and environmental costs associated. In planta synthesis of SFTI-1 based therapeutics serves as a greener approach for environmentally sustainable production. Here, we detail the methods for the transient expression, production, and purification of SFTI-1-based therapeutic peptides in Nicotiana benthamiana using a scalable and high-throughput approach. We demonstrate that a prerequisite for this is the co-expression of specialized asparaginyl endopeptidases (AEPs) that perform the backbone cyclization of SFTI-1. In our founding study, we were able to achieve in planta yields of a plasmin inhibitor SFTI-1 peptide at yields of ~60 μg/g of dried plant material.
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http://dx.doi.org/10.1007/978-1-0716-1689-5_7DOI Listing
January 2022

MYO10 drives genomic instability and inflammation in cancer.

Sci Adv 2021 Sep 15;7(38):eabg6908. Epub 2021 Sep 15.

Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.

Genomic instability is a hallmark of human cancer; yet the underlying mechanisms remain poorly understood. Here, we report that the cytoplasmic unconventional Myosin X (MYO10) regulates genome stability, through which it mediates inflammation in cancer. MYO10 is an unstable protein that undergoes ubiquitin-conjugating enzyme H7 (UbcH7)/β-transducin repeat containing protein 1 (β-TrCP1)–dependent degradation. MYO10 is upregulated in both human and mouse tumors and its expression level predisposes tumor progression and response to immune therapy. Overexpressing MYO10 increased genomic instability, elevated the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)–dependent inflammatory response, and accelerated tumor growth in mice. Conversely, depletion of MYO10 ameliorated genomic instability and reduced the inflammation signaling. Further, inhibiting inflammation or disrupting significantly suppressed the growth of both human and mouse breast tumors in mice. Our data suggest that MYO10 promotes tumor progression through inducing genomic instability, which, in turn, creates an immunogenic environment for immune checkpoint blockades.
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http://dx.doi.org/10.1126/sciadv.abg6908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443186PMC
September 2021

Low-Dose Lung Radiation Therapy for COVID-19 Lung Disease: A Preclinical Efficacy Study in a Bleomycin Model of Pneumonitis.

Int J Radiat Oncol Biol Phys 2022 01 31;112(1):197-211. Epub 2021 Aug 31.

Institute of Cancer Sciences, University of Glasgow, United Kingdom. Electronic address:

Purpose: Low-dose whole lung radiation therapy (LDLR) has been proposed as a treatment for patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection, and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling, and mechanisms of action.

Methods And Materials: Female C57BL/6 mice were treated with intranasal bleomycin sulfate (7.5 or 11.25 units/kg, day 0) and then exposed to whole lung radiation therapy (0.5, 1.0, or 1.5 Gy, or sham; day 3). Bodyweight was measured daily, and lung tissue was harvested for histology and flow cytometry on day 10. Computed tomography lung imaging was performed before radiation (day 3) and pre-endpoint (day 10).

Results: Bleomycin caused pneumonitis of variable severity, which correlated with weight loss. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight, and a proportion of these mice exhibited less severe histopathologic lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. In addition, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells (DCs), and neutrophil-DC hybrids. Overall, bleomycin-treated mice exhibited significantly higher percentages of nonaerated lung in left than right lungs, and LDLR (1.0 Gy) limited further reductions in aerated lung volume in right but not left lungs. LDLR at 0.5 and 1.5 Gy did not improve bodyweight, flow cytometric, or radiologic readouts of bleomycin-induced pneumonitis.

Conclusions: Our data support the concept that LDLR can ameliorate acute inflammatory lung injury, identify 1.0 Gy as the most effective dose, and provide evidence that it is more effective in the context of moderate than severe pneumonitis. Mechanistically, LDLR at 1.0 Gy significantly suppressed bleomycin-induced accumulation of pulmonary interstitial macrophages, CD103+ DCs, and neutrophil-DC hybrids.
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http://dx.doi.org/10.1016/j.ijrobp.2021.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406661PMC
January 2022

Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides.

Mol Pharm 2021 10 27;18(10):3820-3831. Epub 2021 Aug 27.

Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.

Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. "match" oligonucleotides complementary to the telomerase RNA template subunit (hTR) and "scramble" (control) oligonucleotides were conjugated to diethylenetriamine pentaacetate (DTPA) for In-labeling. AuNPs (15.5 nm) were decorated with a monofunctional layer of oligonucleotides (ON-AuNP) or a multifunctional layer of oligonucleotides, PEG(polethylene glycol)800-SH (to reduce AuNP aggregation) and the cell-penetrating peptide Tat (ON-AuNP-Tat). Match-AuNP enhanced the cellular uptake of radiolabeled oligonucleotides while retaining the ability to inhibit telomerase activity. The addition of Tat to AuNPs increased nuclear localization. In-Match-AuNP-Tat induced DNA double-strand breaks and caused a dose-dependent reduction in clonogenic survival of telomerase-positive cells but not telomerase-negative cells. hTR inhibition has been reported to sensitize cancer cells to ionizing radiation, and In-Match-AuNP-Tat therefore holds promise as a vector for delivery of radionuclides into cancer cells while simultaneously sensitizing them to the effects of the emitted radiation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493550PMC
October 2021

The effect of meniscal pathology and management with ACL reconstruction on patient-reported outcomes, strength, and jump performance ten months post-surgery.

Knee 2021 Oct 20;32:72-79. Epub 2021 Aug 20.

Sports Medicine Department, Sports Surgery Clinic, Dublin, Ireland; Queen's School of Engineering, University of Bristol, Bristol, UK; Department of Sport and Exercise Sciences, Manchester Metropolitan University, Manchester, UK.

Background: The purpose of this study was to examine the differences in patient-reported outcome measures, isokinetic strength, plyometric ability and ability to meet return to play criteria ten months after anterior cruciate ligament (ACL) reconstruction surgery between those who underwent meniscectomy, those who underwent meniscal repair and those with no meniscal intervention alongside ACL reconstruction surgery.

Methods: Three hundred and thirteen athletes with clinically and radiologically confirmed ACL ruptures were included in this study. Participants were grouped according to their intra-operative procedures (isolated ACL reconstruction surgery n = 155, ACL reconstruction surgery with meniscectomy n = 128, ACL reconstruction surgery with meniscal repair n = 30). Participants completed patient-reported outcome measures questionnaires (Marx Activity Rating Scale, the ACL Return to Sport after Injury and the International Knee Documentation Committee Score) and completed a battery of objective functional testing including isokinetic dynamometry and jump performance testing (countermovement jump and drop jump) between 9 and 11 months after surgery.

Results: No significant between-group differences were identified in any metric relating to patient-reported outcome measures (p = .611), strength and jump measures (p = .411) or the ability to achieve symmetry-based return to play criteria (p = .575).

Conclusions: Clinically, these results suggest that concomitant meniscal surgery has no significant effects on patient-reported outcome measures, strength and jump metrics at the return to play stage post-operatively and can inform the pre-operative counselling of those awaiting ACL reconstruction surgery with likely meniscal intervention.
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http://dx.doi.org/10.1016/j.knee.2021.07.005DOI Listing
October 2021

Surgical resection and graft replacement for primary inferior vena cava leiomyosarcoma: A multicenter experience.

J Vasc Surg Venous Lymphat Disord 2022 05 14;10(3):617-625. Epub 2021 Jul 14.

Division of Vascular Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

Objective: Primary leiomyosarcoma of the inferior vena cava (IVC) is best managed with surgical resection when technically feasible. However, consensus is lacking regarding the best choice of conduit and reconstruction technique. The aim of the present multicenter study was to perform a comprehensive assessment through the VLFDC (Vascular Low Frequency Disease Consortium) to determine the most effective method for caval reconstruction after resection of primary leiomyosarcoma of the IVC.

Methods: A multicenter, standardized database review of patients who had undergone surgical resection and reconstruction of the IVC for primary leiomyosarcoma from 2007 to 2017 was performed. The demographics, periprocedural details, and postoperative outcomes were analyzed.

Results: A total of 92 patients (60 women and 32 men), with a mean age of 60.1 years (range, 30-88 years) were treated. Metastatic disease was present in 22%. The tumor location was below the renal veins in 49 (53%), between the renal and hepatic veins in 52 (57%), and above the hepatic veins in 13 patients (14%). The conduits used for reconstruction included ringed polytetrafluoroethylene (PTFE; n = 80), nonringed PTFE (n = 1), Dacron (n = 1), autogenous vein (n = 1), bovine pericardium (n = 4), and cryopreserved tissue (n = 5). Complete R0 resection was accomplished in 73 patients (79%). In-hospital mortality was 2%, with a median length of stay of 8 days. The primary patency of PTFE reconstructed IVCs was 97% and 92% at 1 and 5 years, respectively, compared with 73% at 1 and 5 years for the non-PTFE reconstructed IVCs. The overall 1-, 3-, and 5-year survival for the entire cohort were 94%, 86%, and 65%, respectively CONCLUSIONS: The findings from our multi-institutional study have demonstrated that complete en bloc resection of IVC leiomyosarcoma with vascular surgical reconstruction in selected patients results in low perioperative mortality and is associated with excellent long-term patency. A ringed PTFE graft was the most commonly used conduit for caval reconstruction, yielding excellent long-term primary patency.
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http://dx.doi.org/10.1016/j.jvsv.2021.06.021DOI Listing
May 2022

Evaluation of a First-in-Class Proteasome Inhibitor in Patients With Moderate to Severe Rosacea.

J Drugs Dermatol 2021 Jun;20(6):660-664

Background: Novel, effective, affordable therapies for rosacea are needed. Innovative methods of assessing response for rosacea treatments are needed as well. This trial was designed to evaluate efficacy and safety of ACU-D1, a novel inhibitor of the 26S protea-some for the treatment of moderate to severe rosacea in a first in human pilot study. In addition, this is the first trial to our knowledge to use Canfield imaging to quantitatively assess responses.

Methods: This was a 14-week, randomized, double-blinded, placebo-controlled study, performed at two well established rosacea clini-cal trial sites, which randomized 40 adult subjects with moderate to severe rosacea (Investigator’s Global Assessment [IGA]=3/4) to either ACU-D1 (27) or comparator vehicle (13) twice daily. In addition, Canfield imaging was used to assess responses both qualitatively and quantitatively Results: A total of 39 subjects participated, with 38 completing the study. ACU-D1 displayed efficacy in 92% (25 of 27) of patients in reducing inflammatory lesions and a 2 plus grade IGA reduction of clear to near clear in 27% of patients. There was a trend toward improvement in erythema as well in the active arm.

Conclusion: This study demonstrates that topical ACU-D1 is safe and well-tolerated by patients in the study and demonstrates efficacy in reducing inflammatory lesions and erythema in patients with rosacea. Improvement was also noted on Canfield imaging, and this modality is likely to be used as an objective measure in the future. Further studies are warranted based on these initial positive results. ClinicalTrials.gov Identifier: NCT03064438 J Drugs Dermatol. 2021;20(6):660-664. doi:10.36849/JDD.5925.
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http://dx.doi.org/10.36849/JDD.2021.5925DOI Listing
June 2021

Return to Play After Patellar Tendon Autograft for Primary Anterior Cruciate Ligament Reconstruction in Rugby Players.

Orthop J Sports Med 2021 May 3;9(5):23259671211000460. Epub 2021 May 3.

Sports Surgery Clinic, Dublin, Ireland.

Background: There is scant literature on outcomes after anterior cruciate ligament (ACL) reconstruction in rugby players, and no prior study has evaluated the outcomes of bone-patellar tendon-bone (BTB) autograft ACL reconstruction.

Purpose: To assess the rate of return to play, the timing of that return, and the subsequent graft reinjury rate among rugby players after ACL reconstruction with BTB autograft.

Methods: The ACL registry at a single hospital was screened for professional and amateur rugby players who had undergone a primary ACL reconstruction with BTB autograft. Professional rugby players were those playing for one of the professional provincial teams in Ireland. Outcomes were analyzed for the rate and timing of return to play, functional outcomes, and subsequent graft ruptures. Additionally, outcomes were compared between professional and amateur athletes.

Study Design: Case series; Level of evidence, 4.

Results: A total of 126 patients with 24 months of follow-up were enrolled. The overall rate of return to play was 84.9%, with 75.4% returning to the same level of play; 8.7% of patients did not return to play secondary to non-knee-related issues. The mean time to return was 10.9 ± 4.9 months. Among professional rugby players, 93.3% were able to return at a mean time of 9.7 ± 4.4 months; 80% returned to the same level. The mean Anterior Cruciate Ligament-Return to Sport after Injury score was 78.4 ± 20.2, the Cincinnati knee score was 92.5 ± 8.0, the International Knee Documentation Committee score was 88.2 ± 8.1, and the Marx score was 9.7 ± 5.3. Two patients sustained a subsequent rerupture of the reconstructed ACL, and 4 players sustained a contralateral ACL injury within the follow-up interval of 2 years.

Conclusion: Rugby players receiving BTB ACL reconstruction demonstrated good clinical outcomes with a high rate of return to sport, with the majority returning before 12 months. The rate of a subsequent ACL injury was low among the authors' cohort at short-term follow-up.
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http://dx.doi.org/10.1177/23259671211000460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114267PMC
May 2021

Biomechanical but Not Strength or Performance Measures Differentiate Male Athletes Who Experience ACL Reinjury on Return to Level 1 Sports.

Am J Sports Med 2021 03 22;49(4):918-927. Epub 2021 Feb 22.

Department of Life Sciences, University of Roehampton, London, UK.

Background: Performance measures such as strength, jump height/length, and change of direction (CoD) time during anterior cruciate ligament (ACL) rehabilitation have been used to determine readiness to return to play and identify those who may be at risk of rerupture. However, athletes may reach these criteria despite ongoing biomechanical deficits when performing these tests. Combining return-to-play criteria with an assessment of movement through 3-dimensional (3D) biomechanics in male field sports athletes to identify risk factors for ACL rerupture has not been explored previously.

Purpose: To prospectively examine differences in strength, jump, and CoD performance and movement using 3D biomechanics in a cohort of male athletes playing level 1 sports (ie, multidirectional field sports that involve landing, pivoting, or CoD) between those who reinjured the reconstructed ACL (RI group) and those with no reinjury (NRI group) after 2 years of follow-up and to examine the ability of these differences to predict reinjury.

Study Design: Cohort study; Level of evidence, 2.

Methods: After primary ACL reconstruction (ACLR), 1045 male athletes were recruited and underwent testing 9 months after surgery including isokinetic strength, jump, and CoD performance measures as well as patient-reported outcomes and 3D biomechanical analyses. Participants were followed up after 2 years regarding ACL reinjury status. Differences were determined between the RI and NRI groups in patient-reported outcomes, performance measures, and 3D biomechanics on the ACLR side and symmetry between limbs. The ability of these measures to predict ACL reinjury was determined through logistic regression.

Results: No differences were identified in strength and performance measures on the ACLR side or in symmetry. Biomechanical analysis indicated differences on the ACLR side primarily in the sagittal plane for the double-leg drop jump (effect size, 0.59-0.64) and greater asymmetry primarily in the frontal plane during unplanned CoD (effect size, 0.61-0.69) in the RI group. While these biomechanical test results were different between groups, multivariate regression modeling demonstrated limited ability (area under the curve, 0.67 and 0.75, respectively) to prospectively predict ACL reinjury.

Conclusion: Commonly reported return-to-play strength, jump, and timed CoD performance measures did not differ between the RI and NRI groups. Differences in movement based on biomechanical measures during double-leg drop jump and unplanned CoD were identified, although they had limited ability to predict reinjury. Targeting these variables during rehabilitation may reduce reinjury risk in male athletes returning to level 1 sports after ACLR.

Registration: NCT02771548 (ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/0363546520988018DOI Listing
March 2021

Can Biomechanical Testing After Anterior Cruciate Ligament Reconstruction Identify Athletes at Risk for Subsequent ACL Injury to the Contralateral Uninjured Limb?

Am J Sports Med 2021 03 9;49(3):609-619. Epub 2021 Feb 9.

Department of Life Sciences, Roehampton University, London, UK.

Background: Athletes are twice as likely to rupture the anterior cruciate ligament (ACL) on their healthy contralateral knee than the reconstructed graft after ACL reconstruction (ACLR). Although physical testing is commonly used after ACLR to assess injury risk to the operated knee, strength, jump, and change-of-direction performance and biomechanical measures have not been examined in those who go on to experience a contralateral ACL injury, to identify factors that may be associated with injury risk.

Purpose: To prospectively examine differences in biomechanical and clinical performance measures in male athletes 9 months after ACLR between those who ruptured their previously uninjured contralateral ACL and those who did not at 2-year follow-up and to examine the ability of these differences to predict contralateral ACL injury.

Study Design: Case-control study; Level of evidence, 3.

Methods: A cohort of male athletes returning to level 1 sports after ACLR (N = 1045) underwent isokinetic strength testing and 3-dimensional biomechanical analysis of jump and change-of-direction tests 9 months after surgery. Participants were followed up at 2 years regarding return to play or at second ACL injury. Between-group differences were analyzed in patient-reported outcomes, performance measures, and 3-dimensional biomechanics for the contralateral limb and asymmetry. Logistic regression was applied to determine the ability of identified differences to predict contralateral ACL injury.

Results: Of the cohort, 993 had follow-up at 2 years (95%), with 67 experiencing a contralateral ACL injury and 38 an ipsilateral injury. Male athletes who had a contralateral ACL injury had lower quadriceps strength and biomechanical differences on the contralateral limb during double- and single-leg drop jump tests as compared with those who did not experience an injury. Differences were related primarily to deficits in sagittal plane mechanics and plyometric ability on the contralateral side. These variables could explain group membership with fair to good ability (area under the curve, 0.74-0.80). Patient-reported outcomes, limb symmetry of clinical performance measures, and biomechanical measures in change-of-direction tasks did not differentiate those at risk for contralateral injury.

Conclusion: This study highlights the importance of sagittal plane control during drop jump tasks and the limited utility of limb symmetry in performance and biomechanical measures when assessing future contralateral ACL injury risk in male athletes. Targeting the identified differences in quadriceps strength and plyometric ability during late-stage rehabilitation and testing may reduce ACL injury risk in healthy limbs in male athletes playing level 1 sports.

Clinical Relevance: This study highlights the importance of assessing the contralateral limb after ACLR and identifies biomechanical differences, particularly in the sagittal plane in drop jump tasks, that may be associated with injury to this limb. These factors could be targeted during assessment and rehabilitation with additional quadriceps strengthening and plyometric exercises after ACLR to potentially reduce the high risk of injury to the previously healthy knee.

Registration: NCT02771548 (ClinicalTrials.gov identifier).
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March 2021

The majority of athletes fail to return to play following anterior cruciate ligament reconstruction due to reasons other than the operated knee.

Knee Surg Sports Traumatol Arthrosc 2021 Nov 28;29(11):3877-3882. Epub 2021 Jan 28.

Sports Surgery Clinic, Northwood Avenue, Santry, Santry Demesne, Dublin 9, Ireland.

Purpose: The purpose of this study is to evaluate the reasons why athletes do not return to play (RTP) following anterior cruciate ligament (ACL) reconstruction from a large single-centre database.

Methods: The institutional ACL registry was screened for patients that had undergone a primary ACLR and had RTP status reported at 24-month follow-up. The reasons that patients were unable to RTP at 24 months were evaluated. The ACL-Return to Sport Index (ACL-RSI) was evaluated at baseline and 24-month follow-up to evaluate psychological ability to RTP.

Results: At 2 years, 1140 patients returned to play, and 222 had not returned to play. The most common reasons athletes were unable to return was fear of reinjury (27.5%), lack of confidence in performance on return (19.4%) and external life factors (16.6%), i.e. work commitments and family reasons. Other reasons for athletes not returning to play were residual knee pain (10%) and subsequent injury (5%). The ACL-RSI score was significantly lower at diagnosis (40.3 vs. 49.3; p = 0.003) and 2 years (41.8 vs. 78.7; p < 0.0001) in athletes who did not return to play vs. those that did RTP.

Conclusion: The majority of patients that report they have not returned to play do so due to external life and psychological factors associated with their injury, including fear of reinjury and lack of confidence in performance. A small minority of patients were unable to return due to residual knee symptoms or reinjury. Pre-operative psychological assessment and intervention may identify those less likely to RTP and provide an opportunity for targeted interventions to further improve RTP outcomes.

Level Of Evidence: III.
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http://dx.doi.org/10.1007/s00167-020-06407-5DOI Listing
November 2021

Aberrant Induction of a Mesenchymal/Stem Cell Program Engages Senescence in Normal Mammary Epithelial Cells.

Mol Cancer Res 2021 04 22;19(4):651-666. Epub 2020 Dec 22.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Although frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine, oncostatin M, activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGFβ effector, SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSCs can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers. IMPLICATIONS: These studies reveal how a normal cell's arduous escape from senescence can bestow aggressive features early in the transformation process, and how this persistent mesenchymal/SC program can create a novel potential targetability following tumor development.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867383PMC
April 2021

Limited Sensitivity of Hippocampal Synaptic Function or Network Oscillations to Unmodulated Kilohertz Electric Fields.

eNeuro 2020 Nov-Dec;7(6). Epub 2020 Dec 16.

Neural Engineering Laboratory, Department of Biomedical Engineering, The City College of the City University of New York, City College Center for Discovery and Innovation, New York, 10031 NY.

Understanding the cellular mechanisms of kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation including forms of transcranial electrical stimulation, interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membranes suggests minimal neuronal polarization in respond to charge-balanced kHz stimulation. The hippocampal brain slice model is among the most studied systems in neuroscience and exhaustively characterized in screening the effects of electrical stimulation. High-frequency electric fields of varied amplitudes (1-150 V/m), waveforms (sinusoidal, symmetrical pule, asymmetrical pulse) and frequencies (1 and10 kHz) were tested. Changes in single or paired-pulse field EPSPs (fEPSP) in CA1 were measured in response to radial-directed and tangential-directed electric fields, with brief (30 s) or long (30 min) application times. The effects of kHz stimulation on ongoing endogenous network activity were tested in carbachol-induced γ oscillation of CA3a and CA3c. Across 23 conditions evaluated, no significant changes in fEPSP were resolved, while responses were detected for within-slice control direct current (DC) fields; 1-kHz sinusoidal and pulse stimulation (≥60 V/m), but not 10 kHz, induced changes in oscillating neuronal network. We thus report no responses to low-amplitude 1-kHz or any 10-kHz fields, suggesting that any brain sensitivity to these fields is via yet to be-determined mechanism(s) of action which were not identified in our experimental preparation.
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http://dx.doi.org/10.1523/ENEURO.0368-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773889PMC
June 2021

Production of a structurally validated cyclotide in rice suspension cells is enabled by a supporting biosynthetic enzyme.

Planta 2020 Nov 5;252(6):97. Epub 2020 Nov 5.

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD, 4072, Australia.

Main Conclusion: We demonstrate the production of a structurally correct cyclotide in rice suspension cells with co-expression of a ligase-type AEP, which unlocks monocotyledons as production platforms to produce cyclotides. Cyclotides are a class of backbone-cyclic plant peptides that harbor a cystine knot composed of three disulfide bonds. These structural features make cyclotides particularly stable, and thus they have attracted significant attention for their use in biotechnological applications such as drug design. Currently, chemical synthesis is the predominant strategy to produce cyclotides for research purposes. However, synthetic production becomes costly both economically and environmentally at large scale. Plants offer an attractive alternative to chemical synthesis because of their lower cost and environmental footprint. In this study, rice suspension cells were engineered to produce the prototypical cyclotide, kalata B1 (kB1), a cyclotide with insecticidal properties from the African plant Oldenlandia affinis. Engineered rice cells produced structurally validated kB1 at yields of 64.21 µg/g (DW), which was dependent on the co-expression of a peptide ligase-competent asparaginyl endopeptidase OaAEP1 from O. affinis. Without co-expression, kB1 was predominantly produced as linear peptide. Through HPLC-MS co-elution, reduction, alkylation, enzymatic digestion, and proton NMR analysis, kB1 produced in rice was shown to be structurally identical to native kB1. This study reports the first example of an engineered plant suspension cell culture with the required molecular machinery for efficient production and cyclisation of a heterologous cyclotide.
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http://dx.doi.org/10.1007/s00425-020-03505-zDOI Listing
November 2020

Biological effects of inhaled hydraulic fracturing sand dust VII. Neuroinflammation and altered synaptic protein expression.

Toxicol Appl Pharmacol 2020 12 22;409:115300. Epub 2020 Oct 22.

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, United States of America.

Hydraulic fracturing (fracking) is a process used to recover oil and gas from shale rock formation during unconventional drilling. Pressurized liquids containing water and sand (proppant) are used to fracture the oil- and natural gas-laden rock. The transportation and handling of proppant at well sites generate dust aerosols; thus, there is concern of worker exposure to such fracking sand dusts (FSD) by inhalation. FSD are generally composed of respirable crystalline silica and other minerals native to the geological source of the proppant material. Field investigations by NIOSH suggest that the levels of respirable crystalline silica at well sites can exceed the permissible exposure limits. Thus, from an occupational safety perspective, it is important to evaluate the potential toxicological effects of FSD, including any neurological risks. Here, we report that acute inhalation exposure of rats to one FSD, i.e., FSD 8, elicited neuroinflammation, altered the expression of blood brain barrier-related markers, and caused glial changes in the olfactory bulb, hippocampus and cerebellum. An intriguing observation was the persistent reduction of synaptophysin 1 and synaptotagmin 1 proteins in the cerebellum, indicative of synaptic disruption and/or injury. While our initial hazard identification studies suggest a likely neural risk, more research is necessary to determine if such molecular aberrations will progressively culminate in neuropathology/neurodegeneration leading to behavioral and/or functional deficits.
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http://dx.doi.org/10.1016/j.taap.2020.115300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758814PMC
December 2020

Make it or break it: Plant AEPs on stage in biotechnology.

Biotechnol Adv 2020 12 23;45:107651. Epub 2020 Oct 23.

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address:

Asparaginyl endopeptidases (AEPs) are cysteine proteases that control a myriad of cellular functions in plants, including maturation of seed storage proteins and programmed cell death. Recently, several noteworthy AEPs have been discovered that primarily function as transpeptidases rather than hydrolases, to instead catalyse the formation of new peptide bonds. These AEPs appear to have evolved for the cyclisation of a large class of plant defence peptides called cyclotides. Here we describe recent insights into the structural differences between AEPs that preference peptide ligation over hydrolysis. This knowledge is instrumental for the deployment of AEP ligases as biotechnological tools for in vitro applications such as protein labelling and or cyclization, and for plant molecular farming applications.
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http://dx.doi.org/10.1016/j.biotechadv.2020.107651DOI Listing
December 2020

Pulmonary and systemic toxicity in rats following inhalation exposure of 3-D printer emissions from acrylonitrile butadiene styrene (ABS) filament.

Inhal Toxicol 2020 Sep - Oct;32(11-12):403-418. Epub 2020 Oct 20.

National Institute for Occupational Safety and Health, Morgantown, WV, USA.

Background: Fused filament fabrication 3-D printing with acrylonitrile butadiene styrene (ABS) filament emits ultrafine particulates (UFPs) and volatile organic compounds (VOCs). However, the toxicological implications of the emissions generated during 3-D printing have not been fully elucidated.

Aim And Methods: The goal of this study was to investigate the toxicity of ABS-emissions from a commercial desktop 3-D printer. Male Sprague Dawley rats were exposed to a single concentration of ABS-emissions or air for 4 hours/day, 4 days/week for five exposure durations (1, 4, 8, 15, and 30 days). At 24 hours after the last exposure, rats were assessed for pulmonary injury, inflammation, and oxidative stress as well as systemic toxicity.

Results And Discussion: 3-D printing generated particulate with average particle mass concentration of 240 ± 90 µg/m³, with an average geometric mean particle mobility diameter of 85 nm (geometric standard deviation = 1.6). The number of macrophages increased significantly at day 15. In bronchoalveolar lavage, IFN-γ and IL-10 were significantly higher at days 1 and 4, with IL-10 levels reaching a peak at day 15 in ABS-exposed rats. Neither pulmonary oxidative stress responses nor histopathological changes of the lungs and nasal passages were found among the treatments. There was an increase in platelets and monocytes in the circulation at day 15. Several serum biomarkers of hepatic and kidney functions were significantly higher at day 1.

Conclusions: At the current experimental conditions applied, it was concluded that the emissions from ABS filament caused minimal transient pulmonary and systemic toxicity.
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http://dx.doi.org/10.1080/08958378.2020.1834034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673646PMC
March 2021

Biological effects of inhaled hydraulic fracturing sand dust. II. Particle characterization and pulmonary effects 30 d following intratracheal instillation.

Toxicol Appl Pharmacol 2020 12 15;409:115282. Epub 2020 Oct 15.

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, United States of America.

Hydraulic fracturing ("fracking") is used in unconventional gas drilling to allow for the free flow of natural gas from rock. Sand in fracking fluid is pumped into the well bore under high pressure to enter and stabilize fissures in the rock. In the process of manipulating the sand on site, respirable dust (fracking sand dust, FSD) is generated. Inhalation of FSD is a potential hazard to workers inasmuch as respirable crystalline silica causes silicosis, and levels of FSD at drilling work sites have exceeded occupational exposure limits set by OSHA. In the absence of any information about its potential toxicity, a comprehensive rat animal model was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems (Fedan, J.S., Toxicol Appl Pharmacol. 00, 000-000, 2020). The present report, part of the larger investigation, describes: 1) a comparison of the physico-chemical properties of nine FSDs, collected at drilling sites, and MIN-U-SIL® 5, a reference silica dust, and 2) a comparison of the pulmonary inflammatory responses to intratracheal instillation of the nine FSDs and MIN-U-SIL® 5. Our findings indicate that, in many respects, the physico-chemical characteristics, and the biological effects of the FSDs and MIN-U-SIL® 5 after intratracheal instillation, have distinct differences.
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http://dx.doi.org/10.1016/j.taap.2020.115282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818045PMC
December 2020

Biological effects of inhaled hydraulic fracturing sand dust. IV. Pulmonary effects.

Toxicol Appl Pharmacol 2020 12 15;409:115284. Epub 2020 Oct 15.

Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, United States of America. Electronic address:

Hydraulic fracturing creates fissures in subterranean rock to increase the flow and retrieval of natural gas. Sand ("proppant") in fracking fluid injected into the well bore maintains fissure patency. Fracking sand dust (FSD) is generated during manipulation of sand to prepare the fracking fluid. Containing respirable crystalline silica, FSD could pose hazards similar to those found in work sites where silica inhalation induces lung disease such as silicosis. This study was performed to evaluate the possible toxic effects following inhalation of a FSD (FSD 8) in the lung and airways. Rats were exposed (6 h/d × 4 d) to 10 or 30 mg/m of a FSD collected at a gas well, and measurements were performed 1, 7, 27 and, in one series of experiments, 90 d post-exposure. The following ventilatory and non-ventilatory parameters were measured in vivo and/or in vitro: 1) lung mechanics (respiratory system resistance and elastance, tissue damping, tissue elastance, Newtonian resistance and hysteresivity); 2) airway reactivity to inhaled methacholine (MCh); airway epithelium integrity (isolated, perfused trachea); airway efferent motor nerve activity (electric field stimulation in vitro); airway smooth muscle contractility; ion transport in intact and cultured epithelium; airway effector and sensory nerves; tracheal particle deposition; and neurogenic inflammation/vascular permeability. FSD 8 was without large effect on most parameters, and was not pro-inflammatory, as judged histologically and in cultured epithelial cells, but increased reactivity to inhaled MCh at some post-exposure time points and affected Na transport in airway epithelial cells.
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http://dx.doi.org/10.1016/j.taap.2020.115284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736927PMC
December 2020
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