Publications by authors named "Michael Kennedy"

287 Publications

Proportion of SARS-CoV - 2 positive tests and Vaccination in VA Community Living Centers.

J Am Geriatr Soc 2021 Apr 16. Epub 2021 Apr 16.

Office of Geriatrics and Extended Care, Veterans Health Administration, Department of Veterans Affairs, Washington, District of Columbia, United States.

Background/objectives: COVID-19 has caused significant morbidity and mortality in nursing homes. Vaccination against SARS-COV-2 holds promise for reduction in COVID-19. This operational analysis describes the proportion of SARS-COV-2 positive tests before, during, and after vaccination.

Design: Retrospective longitudinal cohort analysis from October 1, 2020 until February 14, 2021.

Setting: 130 Department of Veterans Affairs (VA) Community Living Centers (CLC), analogous to nursing homes.

Intervention: Vaccination for SARS-CoV-2.

Measurements: The primary measure is the proportion of SARS-CoV-2 positive tests among CLC residents. In a pooled analysis of weekly testing and vaccine data, the proportion of positive tests was compared for the unvaccinated, 1st dose, and 2nd dose. For each CLC, we identified the week in which 50% of CLC residents were vaccinated (index week). The analysis aligned the index week for CLCs and examined the proportion of SARS-CoV-2 positive tests at the CLC level before and after. As a reference, we plotted the proportion of positive tests in nursing homes in the same county as the CLC using publicly reported data.

Results: Within the pooled VA CLCs, the first SARS-CoV-2 vaccine dose was delivered to 50% of CLC residents within 1 week of availability and second dose within 5 weeks. Relative to the index week, the risk ratio of SARS-CoV-2 positive tests in the vaccinated relative to unvaccinated was significantly lower in week 4 (RR 0.37, 95%CI 0.20, 0.68). Throughout the study period, the proportion of SARS-CoV-2 positive tests in community nursing homes was higher compared to VA CLC and also declined after vaccine availability.

Conclusion: The proportion of SARS-CoV-2 positive tests significantly declined in VA CLCs four weeks after vaccine delivery and continued to decline in vaccinated and unvaccinated residents. The results describe the importance of SARS-CoV-2 surveillance and vaccination in VA nursing home residents.
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http://dx.doi.org/10.1111/jgs.17180DOI Listing
April 2021

NMR-Based Serum and Urine Metabolomic Profile Reveals Suppression of Mitochondrial Pathways in Experimental Sepsis-Associated Acute Kidney Injury.

Am J Physiol Renal Physiol 2021 Apr 12. Epub 2021 Apr 12.

Chemistry and Biochemistry, Miami University, United States.

Sepsis-associated acute kidney injury (SA-AKI) is a significant problem in the critically ill that causes increased death. Emerging understanding of this disease implicates metabolic dysfunction in its pathophysiology. This study sought to identify specific metabolic pathways amenable to potential therapeutic intervention. Using a murine model of sepsis, blood and tissue samples were collected for assessment of systemic inflammation, kidney function, and renal injury. Nuclear magnetic resonance (NMR)-based metabolomics quantified dozens of metabolites in serum and urine which were subsequently submitted to pathway analysis. Kidney tissue gene expression analysis confirmed implicated pathways. Septic mice had elevated circulating levels of inflammatory cytokines and increased levels of blood urea nitrogen and creatinine, indicating both systemic inflammation and poor kidney function. Renal tissue showed only mild histologic evidence of injury in sepsis. NMR metabolomic analysis identified the involvement of mitochondrial pathways associated with branched-chain amino acid (BCAA) metabolism, fatty acid oxidation, and de novo nicotinamide adenine dinucleotide (NAD) biosynthesis in SA-AKI. Renal cortical gene expression of enzymes associated with those pathways was predominantly suppressed. Similar to humans, septic mice demonstrate renal dysfunction without significant tissue disruption, pointing to metabolic derangement as an important contributor to SA-AKI pathophysiology. Metabolism of BCAAs and fatty acids and NAD synthesis, which all center on mitochondrial function, appear to be suppressed. Developing interventions to activate these pathways may provide new therapeutic opportunities for SA-AKI.
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http://dx.doi.org/10.1152/ajprenal.00582.2020DOI Listing
April 2021

Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): A randomized placebo controlled clinical trial.

EClinicalMedicine 2021 Mar 27;33:100763. Epub 2021 Feb 27.

Ottawa Hospital Research Institute, Ottawa, Canada.

Background: Despite curative intent resection in patients with non-small cell lung cancer (NSCLC), recurrence leading to mortality remains too common. Melatonin has shown promise for the treatment of patients with lung cancer; however, its effect following cancer resection has not been studied. We evaluated if melatonin taken after complete resection reduces lung cancer recurrence and mortality, or impacts quality of life (QOL), symptomatology or immune function.

Methods: Participants received melatonin (20 mg) or placebo nightly for one year following surgical resection of primary NSCLC. The primary outcome was two-year disease-free survival (DFS). Secondary outcomes included five-year DFS, adverse events, QOL, fatigue, sleep, depression, anxiety, pain, and biomarkers assessing for immune function/inflammation. This study is registered at https://clinicaltrials.gov NCT00668707.

Findings: 709 patients across eight centres were randomized to melatonin ( = 356) versus placebo ( = 353). At two years, melatonin showed a relative risk of 1·01 (95% CI 0·83-1·22),  = 0·94 for DFS. At five years, melatonin showed a hazard ratio of 0·97 (95% CI 0·86-1·09),  = 0·84 for DFS. When stratified by cancer stage (I/II and III/IV), a hazard reduction of 25% (HR 0·75, 95% CI 0·61-0·92,  = 0·005) in five-year DFS was seen for participants in the treatment arm with advanced cancer (stage III/IV). No meaningful differences were seen in any other outcomes.

Interpretation: Adjuvant melatonin following resection of NSCLC does not affect DFS for patients with resected early stage NSCLC, yet may increase DFS in patients with late stage disease. Further study is needed to confirm this positive result. No beneficial effects were seen in QOL, symptoms, or immune function.

Funding: This study was funded by the Lotte and John Hecht Memorial Foundation and the Gateway for Cancer Research Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2021.100763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930365PMC
March 2021

Certified Nurse-Midwives in Rural Kansas Hospitals: A Survey of Senior Hospital Administrators.

J Midwifery Womens Health 2021 Mar 4. Epub 2021 Mar 4.

Office of Rural Medical Education, The University of Kansas School of Medicine, Kansas City, Kansas.

Introduction: Little is known about the nurse-midwifery workforce in rural Kansas hospitals, despite Kansas facing a shortage of primary care physicians providing maternity care rurally. This study investigated the current number of hospitals with certified nurse-midwives (CNMs) with privileges to attend births in Kansas hospitals located in frontier, rural, and densely settled rural counties and anticipated trends in the size of the CNM workforce at hospitals over the next 5 years.

Methods: Electronic surveys were distributed to senior hospital administrators at 94 hospitals in rural Kansas from June to July 2019. The survey included both open and closed-ended questions related to scope of CNM privileges, collaborative agreements, and forecasted trends in the CNM workforce in rural Kansas.

Results: Fifty-six hospitals completed the survey. Only one hospital reported having CNM-attended births. Twenty-eight of 37 hospital administrators agreed CNMs should have collaborative agreements with physicians. Most respondents did not anticipate the number of CNMs with privileges to increase at their hospitals over the next 5 years.

Discussion: Future research should focus on understanding the factors limiting CNM expansion in rural Kansas, because CNMs represent an untapped, additional maternity care workforce for rural Kansas.
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http://dx.doi.org/10.1111/jmwh.13201DOI Listing
March 2021

Kansas maternity deserts: a cross-sectional study of rural obstetric providers.

Rural Remote Health 2021 Mar 1;21(1):6137. Epub 2021 Mar 1.

Office of Rural Medicine, School of Medicine, University of Kansas, Kansas City, KS 66160, USA

Introduction: Kansas is a predominantly rural state that had 9853 rural births in 2018. The Kansas Rural Obstetrical Access Task Force was formed to study and address factors affecting these births. One of these factors is the distance between mothers and the location of maternity services. Poor access leading to increased travel times between mothers and maternity care providers has been associated with a greater rate of pregnancy complications, premature birth, and higher cost of care. In Kansas, the current state of access is not clearly described. Adding to the concern were reports of rural hospital closures and provider cessation of maternity care services. This was likely leading to 'maternity deserts': entire counties that have no maternity care providers. The goal of this project was to identify who currently delivers babies in Kansas, map their location, and determine future plans for maternity care service provision.

Methods: The study began by dividing the state of Kansas into counties by population density and by identifying current practitioners in the state. Once identified, providers were sent a 72-item mixed methods survey with content including demographics, practice location, provision of maternity care, and intents on future practice changes.

Results: Analysis of the survey responses led to a clearer picture of the current state of maternity care provider distribution in Kansas. This revealed multiple existing maternity deserts and a projected expansion of these deserts over the next 10 years.

Conclusion: The current distribution of maternity care services in Kansas reveals numerous maternity deserts, and provider survey projections as far forward as 2030 show expansion of these deserts. This poor access to care may be contributing to unnecessary pregnancy complications. With the extent of this issue identified, targeted efforts toward narrowing the current and expanding maternity deserts are being implemented.
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http://dx.doi.org/10.22605/RRH6137DOI Listing
March 2021

Clinical trials with cannabis medicines-guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience.

Trials 2020 Nov 17;21(1):932. Epub 2020 Nov 17.

Chris O'Brien Lifehouse Comprehensive Cancer Hospital, Camperdown, New South Wales, Australia.

With cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein 'HREC', Australia's nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors' experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.
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http://dx.doi.org/10.1186/s13063-020-04862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673085PMC
November 2020

Effects of theophylline and theobromine on exercise performance and implications for competition sport: A systematic review.

Authors:
Michael Kennedy

Drug Test Anal 2021 Jan 30;13(1):36-43. Epub 2020 Dec 30.

Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital Medical School, UNSW, Sydney, Australia.

A systematic review was undertaken to evaluate studies on the effects of theophylline and theobromine on exercise performance in normal (healthy) subjects. Theophylline was found to have been studied on eight occasions and theobromine on one, the number of subjects per study ranging from seven to 15. In two exercise investigations, theophylline was superior to placebo at a p < 0.05 level and no different in four including one that was conducted in artificial hypoxia. In a treadmill time trial over 3 km, theobromine was superior to placebo and equal to caffeine, at the <0.05 level. In strength studies, theophylline increased wrist strength in one and showed a slight but not statistically significant increase in limb strength in four of the seven subjects in the other. Theophylline caused adverse effects in six participants. There were no adverse effects in the theobromine investigation. Although the studies showed contradicting results and/or insufficient data to draw solid conclusions, it appears both drugs have potential to enhance performance and could be considered for inclusion on the WADA banned list.
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http://dx.doi.org/10.1002/dta.2970DOI Listing
January 2021

Differences in Human Milk Lactose and Citrate Concentrations Based on Gestational Diabetes Status.

Breastfeed Med 2020 12 19;15(12):798-802. Epub 2020 Oct 19.

Department of Chemistry and Biochemistry, Miami University, Oxford, Mississippi, USA.

Exclusive breastfeeding is the optimal manner of early infant nutrition but women with gestational diabetes mellitus (GDM) often experience challenges with lactation in the early postpartum period. Increases in the colostral metabolites of lactose and citrate have been found to indicate increased milk production. A follow-up study of 133 postpartum women with and without GDM was conducted to examine differences in specific colostral metabolite levels using enzymatic methods to determine transition to lactogenesis II during the first week postpartum. We used linear mixed models for repeated measures over time to examine the effect of GDM on colostral metabolite levels at baseline and follow-up with fixed effects of GDM status, time, covariates, and interactions between time and GDM, between time and time, and between time, time and GDM into the model allowing quadratic trends over time. Over time, lactose and citrate levels increased for all mothers ( < 0.001 and  < 0.001, respectively), although mothers with GDM had consistently lower lactose and citrate levels compared with nondiabetic mothers ( = 0.004 and  = 0.014, respectively). Age, prepregnancy body mass index, mode of birth, and parity did not independently influence colostral concentrations of lactose and citrate. Findings suggest that the rate of change overtime in lactose and citrate concentrations differ by GDM status. Further research examining the trajectory of colostral metabolite levels by GDM status is warranted.
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http://dx.doi.org/10.1089/bfm.2020.0051DOI Listing
December 2020

Are Respiratory Responses to Cold Air Exercise Different in Females Compared to Males? Implications for Exercise in Cold Air Environments.

Int J Environ Res Public Health 2020 09 13;17(18). Epub 2020 Sep 13.

Department of Sport Science, University of Innsbruck, 6020 Innsbruck, Austria.

Research has shown that cold air exercise causes significant respiratory dysfunction, especially in female athletes. However, how female and male athletes respond to cold air exercise is not known. Thus, we aimed to compare acute respiratory responses (function, recovery and symptoms) in males and females after high-intensity cold air exercise. Eighteen (nine female) athletes completed two environmental chamber running trials at 0 °C and -20 °C (humidity 34 ± 5%) on different days in a randomized starting order. Spirometry was performed pre, 3, 6, 10, 15 and 20 min post. Respiratory symptoms were measured posttrial and heart rate and rating of perceived exertion were assessed during each trial. No significant differences in delta change (pre to post) were found at either temperature between sexes for FEV, FVC, FEF50% and FEF25-75%. At -20 °C, FEV decreased similarly in both sexes (males: 7.5%, females: 6.3%) but not at 0 °C, = 0.003. Postexertion respiratory function recovery and reported symptoms were not different between sexes at either temperature. These results indicate no sex-based differences in acute respiratory responses (function, recovery and symptoms) to cold air exercise. However, intense exercise at -20 °C is challenging to the respiratory system in both sexes and may lead to altered respiratory responses compared to mild winter conditions like 0 °C.
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http://dx.doi.org/10.3390/ijerph17186662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559764PMC
September 2020

Session Rating of Perceived Exertion Is a Superior Method to Monitor Internal Training Loads of Functional Fitness Training Sessions Performed at Different Intensities When Compared to Training Impulse.

Front Physiol 2020 12;11:919. Epub 2020 Aug 12.

Athlete Health Lab, Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, AB, Canada.

Despite its increase in popularity, little is known about how to best quantify internal training loads from functional fitness training (FFT) sessions. The purpose of this study was to assess which method [training impulse (TRIMP) or session rating of perceived exertion (sRPE)] is more accurate to monitor training loads in FFT. Eight trained males (age 28.1 ± 6.0 years) performed an ALL-OUT FFT session and an intensity-controlled session (RPE of six out of 10). Internal load was determined Edward's TRIMP (eTRIMP), Bannister's TRIMP (bTRIMP), and sRPE. Heart rate was measured continuously during the session, while blood lactate and rate of perceived exertion were measured at baseline, and immediately and 30 min after the sessions. ALL-OUT blood lactate and RPE were significantly higher immediately and 30 min after the session compared to the RPE6 condition. ALL-OUT training load was significantly different between conditions using bTRIMP (61.1 ± 10.6 vs. 55.7 ± 12.4 AU) and sRPE (91.7 ± 30.4 vs. 42.6 ± 14.9 AU), with sRPE being more sensitive to such differences [ = 0.045, effect size (ES) = 0.76 and = 0.002, ES = 1.82, respectively]. No differences in the training loads of the different sessions were found using eTRIMP (93.1 ± 9.5 vs. 84.9 ± 13.7 AU, = 0.085). Only sRPE showed a significant correlation with lactate 30 min post session ( = 0.015; = 0.596, large). sRPE was more accurate than both TRIMP methods to represent the overall training load of the FFT sessions. While the use of sRPE is advised, further research is necessary to establish its ability to reflect changes in fitness, fatigue, and performance during a period of training.
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http://dx.doi.org/10.3389/fphys.2020.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435063PMC
August 2020

Effect of Elevated Ambient Temperature on Simulator-Derived Oscillometric Blood Pressure Measurement.

Am J Hypertens 2021 03;34(2):157-162

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background: Oscillometric blood pressure (BP) devices are typically labeled for use up to 40 °C. Many geographic regions have ambient temperatures exceeding 40 °C. We assessed the effect of increased ambient temperature (40-55 °C) on simulator-derived oscillometric BP measurement.

Methods: Three Omron BP769CAN devices, 3 A&D Medical UA-651BLE devices, and accompanying cuffs were used. A custom heat chamber heated each device to the specified temperature. A noninvasive BP simulator was used to take 3 measurements with each device at differing temperatures (22, 40, 45, 50, and 55 °C) and BP thresholds: 80/50, 100/60, 120/80, 140/90, 160/110, and 180/130 mm Hg. Using each device as its own control (22 °C), we determined the relative differences in mean BP for each device at each temperature and BP setting, assessed graphical trends with increasing temperature, and examined variability.

Results: Graphical trends of mean simulator-subtracted BP differences from room temperature showed no discernable pattern, with differences clustered around zero. Overall mean difference in BP (combined elevated temperatures minus room temperature) was -0.8 ± 2.1 (systolic ± SD)/1.2 ± 3.5 (diastolic ± SD) mm Hg for the A&D device and 0.2 ± 0.4 (systolic ± SD)/-0.1 ± 0.1 (diastolic ± SD) mm Hg for the Omron. All individual elevated temperature differences (elevated temperature minus room temperature) except A&D diastolic BP at 50 °C were within 5 mm Hg.

Conclusions: In this simulator-based study assessing within-device differences, higher ambient temperatures resulted in oscillometric BP measurements that were comparable to those performed at room temperature.
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http://dx.doi.org/10.1093/ajh/hpaa141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951051PMC
March 2021

Type I beta turns make a new twist in pentapeptide repeat proteins: Crystal structure of Alr5209 from Nostoc sp. PCC 7120 determined at 1.7 angström resolution.

J Struct Biol X 2019 Jul-Sep;3:100010. Epub 2019 Aug 14.

Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, United States.

Pentapeptide repeat proteins (PRPs) are found abundantly in cyanobacteria, numbering in the dozens in some genomes, e.g. in Nostoc sp. PCC 7120. PRPs, comprised of a repeating consensus sequence of five amino acids, adopt a distinctive right-handed quadrilateral β-helical structure, also referred to as a repeat five residue (Rfr) fold, made up of stacks of coils formed by four consecutive pentapeptide repeats. The right-handed quadrilateral β-helical PRP structure is constructed by repeating β turns at each of four corners in a given coil, each causing a 90° change in direction of the polypeptide chain. Until now, all PRP structures have consisted either of type II and IV β turns or exclusively of type II β turns. Here, we report the first structure of a PRP comprised of type I and II β turns, Alr5209 from Nostoc sp. PCC 7120. The gene encodes 129 amino acids containing 16 tandem pentapeptide repeats. The Alr5209 structure was analyzed in comparison to all other PRPs to determine how type I β turns can be accommodated in Rfr folds and the consequences of type I β turns on the right-handed quadrilateral β-helical structure. Given that Alr5209 represents the first PRP structure containing type I β turns, the PRP consensus sequence was reevaluated and updated. Despite a growing number of PRP structural investigations, their function remains largely unknown. Genome analysis indicated that resides in a five-gene operon (-) with Alr5211 annotated to be a NADH dehydrogenase indicating Alr5209 may be involved in oxidative phosphorylation.
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http://dx.doi.org/10.1016/j.yjsbx.2019.100010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337050PMC
August 2019

Structural dynamics of pentapeptide repeat proteins.

Proteins 2020 11 11;88(11):1493-1512. Epub 2020 Jul 11.

Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.

Pentapeptide repeat proteins (PRPs) represent a large superfamily with more than 38 000 sequences in nearly 3500 species, the majority belonging to cyanobacteria but represented among all branches of life. PRPs contain at least eight consecutive pentapeptide repeats with the consensus (A/C/S/V/T/L/I)(D/N/S/K/E/I/R)(L/F)(S/T/R/E/Q/K/V/D)(G/D/E/N/R/Q/K). PRPs fold into right-handed quadrilateral β helices, also known as repeat-five-residue (Rfr)-folds, with four consecutive pentapeptide repeats comprising a single coil, the ~90° change in polypeptide direction in square-shaped coils achieved by type I, II and IV β turns, and hydrogen bonds between coils establishing β ladders on each Rfr-fold face. PRPs are broadly categorized into group 1 and 2 involved in antibiotic resistance and group 3 currently having unknown functions. Motivated by their intriguing structures, we are investigating PRP biophysical characteristics, including Rfr-fold thermal stability, β turn and β ladder hydrogen bond amide exchange rates and backbone dynamics. Here, we present analysis of 20 ns molecular dynamics (MD) simulations and all atom normal mode analysis (aaNMA) calculations for four group 1 and group 2 and four group 3 PRPs whose structures have been determined by X-ray crystallography. The MD cross-correlation matrices and aaNMA indicated strong correlated motion between adjacent coils and weak coupled motion between coils separated by one or more intervening coils. Slow anticorrelated motions were detected between adjacent coils in aaNMA modes that we hypothesize are requisite to access exchange-competent states necessary to permit solvent exchange of amide hydrogens involved in β-ladder and β-turns hydrogen bonds, which can have lifetimes on the order of months.
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http://dx.doi.org/10.1002/prot.25969DOI Listing
November 2020

Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.

Bioorg Med Chem Lett 2020 07 25;30(14):127214. Epub 2020 Apr 25.

Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States.

A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.
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http://dx.doi.org/10.1016/j.bmcl.2020.127214DOI Listing
July 2020

Safety and efficacy of autologous tumour cell vaccines as a cancer therapeutic to treat solid tumours and haematological malignancies: a meta-analysis protocol for two systematic reviews.

BMJ Open 2020 06 8;10(6):e034714. Epub 2020 Jun 8.

Cancer Therapeutic Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Introduction: Autologous cancer cell vaccines are promising personalised immunotherapeutic options for solid and haematological malignancies that uses the patient's own cells to arm an immune response. Evidence suggests that among patients receiving these vaccines, those who mount an immune response against their own tumour cells have better prognosis, and a myriad of preclinical studies have demonstrated the same. Recently, two autologous cell vaccines Vigil and OncoVAX have made it to phase III clinical trials. Here, we outline a protocol to be used for two separate systematic reviews using a parallel approach for inclusion criteria, data extraction and analysis for autologous cell vaccines in (1) solid and (2) haematological malignancies. We aim to review evidence from controlled and uncontrolled interventional studies of autologous cell vaccines administered to patients with cancer to determine their historical efficacy (with or without associated adjuvants or modifications) with clinical response rates and safety outcomes being of particular importance.

Methods And Analysis: We will search MEDLINE (OVID interface, including In-Process and Epub Ahead of Print), Embase (OVID interface) and the Cochrane Central Register of Controlled Trials (Wiley interface) for articles published from 1947 until 30 July 2018 (date search was performed). Studies will be screened first by title and abstract, then by full-text in duplicate. Interventional trials that report the use of an autologous cell vaccine to patients with cancer of any age will be included. The primary outcomes of interest in this review are clinical response (complete or overall/objective response) and safety outcomes (adverse events). Secondary outcomes include immune response, disease-free survival and overall survival. The risk of bias within studies will be assessed using the appropriate Cochrane Risk of Bias tool. If appropriate, a random effects meta-analysis will be performed to synthesise the data and report summary estimates of effect. Statistical heterogeneity will be assessed using the I statistic.

Ethics And Dissemination: Ethics approval is not required for this systematic review protocol as the review will solely use published literature. Results will be submitted to peer-reviewed journals for publication and presented to relevant stakeholders and scientific meetings.

Prospero Registration Number: CRD42019140187.
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http://dx.doi.org/10.1136/bmjopen-2019-034714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282323PMC
June 2020

A Method of Assessment of Human Natural Killer Cell Phenotype and Function in Whole Blood.

Front Immunol 2020 20;11:963. Epub 2020 May 20.

Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

The majority of data on human Natural Killer (NK) cell phenotype and function has been generated using cryopreserved peripheral blood mononuclear cells (PBMCs). However, cryopreservation can have adverse effects on PBMCs. In contrast, investigating immune cells in whole blood can reduce the time, volume of blood required, and potential artefacts associated with manipulation of the cells. Whole blood collected from healthy donors and cancer patients was processed by three separate protocols that can be used independently or in parallel to assess extracellular receptors, intracellular signaling protein phosphorylation, and intracellular and extracellular cytokine production in human NK cells. To assess extracellular receptor expression, 200 μL of whole blood was incubated with an extracellular staining (ECS) mix and cells were subsequently fixed and RBCs lysed prior to analysis. The phosphorylation status of signaling proteins was assessed in 500 μL of whole blood following co-incubation with interleukin (IL)-2/12 and an ECS mix for 20 min prior to cell fixation, RBC lysis, and subsequent permeabilization for staining with an intracellular staining (ICS) mix. Cytokine production (IFNγ) was similarly assessed by incubating 1 mL of whole blood with PMA-ionomycin or IL-2/12 prior to incubation with ECS and subsequent ICS antibodies. In addition, plasma was collected from stimulated samples prior to ECS for quantification of secreted IFNγ by ELISA. Results were consistent, despite inherent inter-patient variability. Although we did not investigate an exhaustive list of targets, this approach enabled quantification of representative ECS surface markers including activating (NKG2D and DNAM-1) and inhibitory (NKG2A, PD-1, TIGIT, and TIM-3) receptors, cytokine receptors (CD25, CD122, CD132, and CD212) and ICS markers associated with NK cell activation following stimulation, including signaling protein phosphorylation (p-STAT4, p-STAT5, p-p38 MAPK, p-S6) and IFNγ in both healthy donors and cancer patients. In addition, we compared extracellular receptor expression using whole blood vs. cryopreserved PBMCs and observed a significant difference in the expression of almost all receptors. The methods presented permit a relatively rapid parallel assessment of immune cell receptor expression, signaling protein activity, and cytokine production in a minimal volume of whole blood from both healthy donors and cancer patients.
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http://dx.doi.org/10.3389/fimmu.2020.00963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251181PMC
March 2021

Molecular basis of P[II] major human rotavirus VP8* domain recognition of histo-blood group antigens.

PLoS Pathog 2020 03 24;16(3):e1008386. Epub 2020 Mar 24.

Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, United States of America.

Initial cell attachment of rotavirus (RV) to specific cell surface glycan receptors, which is the essential first step in RV infection, is mediated by the VP8* domain of the spike protein VP4. Recently, human histo-blood group antigens (HBGAs) have been identified as receptors or attachment factors for human RV strains. RV strains in the P[4] and P[8] genotypes of the P[II] genogroup share common recognition of the Lewis b (Leb) and H type 1 antigens, however, the molecular basis of receptor recognition by the major human P[8] RVs remains unknown due to lack of experimental structural information. Here, we used nuclear magnetic resonance (NMR) spectroscopy-based titration experiments and NMR-derived high ambiguity driven docking (HADDOCK) methods to elucidate the molecular basis for P[8] VP8* recognition of the Leb (LNDFH I) and type 1 HBGAs. We also used X-ray crystallography to determine the molecular details underlying P[6] recognition of H type 1 HBGAs. Unlike P[6]/P[19] VP8*s that recognize H type 1 HBGAs in a binding surface composed of an α-helix and a β-sheet, referred as the "βα binding site", the P[8] and P[4] VP8*s bind Leb HBGAs in a previously undescribed pocket formed by the edges of two β-sheets, referred to as the "ββ binding site". Importantly, the P[8] and P[4] VP8*s retain binding capability to non-Leb type 1 HBGAs using the βα binding site. The presence of two distinct binding sites for Leb and non-Leb HBGA glycans in the P[8] and P[4] VP8* domains suggests host-pathogen co-evolution under structural and functional adaptation of RV pathogens to host glycan polymorphisms. Assessment and understanding of the precise impact of this co-evolutionary process in determining RV host ranges and cross-species RV transmission should facilitate improved RV vaccine development and prediction of future RV strain emergence and epidemics.
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http://dx.doi.org/10.1371/journal.ppat.1008386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122821PMC
March 2020

Mutual impact of clinically translatable near-infrared dyes on photoacoustic image contrast and in vitro photodynamic therapy efficacy.

J Biomed Opt 2020 02;25(6):1-12

Tufts University, Department of Biomedical Engineering, Medford, Massachusetts, United States.

Photodynamic therapy (PDT), a spatially localized phototoxic therapy that involves irradiation of a photosensitizer (PS) with specific wavelengths of light, has shown exceptional promise in impacting cancer treatment outcomes, particularly oral cancer. To reduce PDT outcome variability, attempts toward image-guided personalized PDT are being pursued by monitoring PS uptake either via fluorescence or photoacoustic imaging (PAI), a nonionizing modality dependent on optical absorption properties of the tissue. PAI-guided PDT requires a near-infrared contrast agent for deep tissue imaging with minimal photobleaching effect. We evaluate the impact of PDT agent, benzoporphyrin derivative (BPD), on PAI agent indocyanine green (ICG) and vice versa, given that they have different optical absorption properties and singlet oxygen quantum yields for PDT. Specifically, we demonstrate in two oral squamous cell carcinoma lines (FaDu and SCC4) that ICG has minimal effect on BPD PDT efficacy when irradiated with either a continuous or pulsed laser. Furthermore, the impact of BPD on ICG photodegradation was monitored with PAI in tissue-mimicking phantoms. These studies inform us that the combination of BPD and ICG can be utilized for PAI-guided PDT. However, researchers need to consider the photodegradation effects of ICG in the presence of BPD when designing their drug delivery strategies for PAI-guided PDT.
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http://dx.doi.org/10.1117/1.JBO.25.6.063808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048201PMC
February 2020

Crystal structure of Alr1298, a pentapeptide repeat protein from the cyanobacterium Nostoc sp. PCC 7120, determined at 2.1 Å resolution.

Proteins 2020 09 24;88(9):1143-1153. Epub 2020 Feb 24.

Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio.

Nostoc sp. PCC 7120 are filamentous cyanobacteria capable of both oxygenic photosynthesis and nitrogen fixation, with the latter taking place in specialized cells known as heterocysts that terminally differentiate from vegetative cells under conditions of nitrogen starvation. Cyanobacteria have existed on earth for more than 2 billion years and are thought to be responsible for oxygenation of the earth's atmosphere. Filamentous cyanobacteria such as Nostoc sp. PCC 7120 may also represent the oldest multicellular organisms on earth that undergo cell differentiation. Pentapeptide repeat proteins (PRPs), which occur most abundantly in cyanobacteria, adopt a right-handed quadrilateral β-helical structure, also referred to as a repeat five residue (Rfr) fold, with four-consecutive pentapeptide repeats constituting a single coil in the β-helical structure. PRPs are predicted to exist in all compartments within cyanobacteria including the thylakoid and cell-wall membranes as well as the cytoplasm and thylakoid periplasmic space. Despite their intriguing structure and importance to understanding ancient cyanobacteria, the biochemical function of PRPs in cyanobacteria remains largely unknown. Here we report the crystal structure of Alr1298, a PRP from Nostoc sp. PCC 7120 predicted to reside in the cytoplasm. The structure displays the typical right-handed quadrilateral β-helical structure and includes a four-α-helix cluster capping the N-terminus and a single α-helix capping the C-terminus. A gene cluster analysis indicated that Alr1298 may belong to an operon linked to cell proliferation and/or thylakoid biogenesis. Elevated alr1298 gene expression following nitrogen starvation indicates that Alr1298 may play a role in response to nitrogen starvation and/or heterocyst differentiation.
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http://dx.doi.org/10.1002/prot.25882DOI Listing
September 2020

Agreement of sleep specialists with registered nurses' sleep study orders in supervised clinical practice.

J Clin Sleep Med 2020 02 13;16(2):279-283. Epub 2020 Jan 13.

VA Puget Sound Health Care System, Seattle, Washington.

Study Objectives: Incorporating registered nurses (RN-level) into obstructive sleep apnea (OSA) management decisions has the potential to augment the workforce and improve patient access, but the appropriateness of such task-shifting in typical practice is unclear.

Methods: Our medical center piloted a nurse triage program for sleep medicine referrals. Using a sleep specialist-designed decision-making tool, nurses triaged patients referred for initial sleep studies to either home sleep apnea test (HSAT) or in-laboratory polysomnography (PSG). During the first 5 months of the program, specialists reviewed all nurse triages. We compared agreement between specialists and nurses.

Results: Of 280 consultations triaged by nurses, nurses deferred management decisions to sleep specialists in 6.1% (n = 17) of cases. Of the remaining 263 cases, there was 88% agreement between nurses and specialists (kappa 0.80, 95% confidence interval 0.74-0.87). In the 8.8% (n = 23) of cases where supervising specialists changed sleep study type, specialists changed from HSAT to PSG in 16 cases and from PSG to HSAT in 7. The most common indication for change in sleep study type was disagreement regarding OSA pretest probability (n = 14 of 23). Specialists changed test instructions in 3.0% (n = 8) of cases, with changes either related to the use of transcutaneous carbon dioxide monitoring (n = 4) or adaptive servo-ventilation (n = 4).

Conclusions: More than 80% of sleep study triages by registered nurses in a supervised setting required no sleep specialist intervention. Future research should focus on how to integrate nurses into the sleep medicine workforce in a manner that maximizes efficiency while preserving or improving patient outcomes.
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http://dx.doi.org/10.5664/jcsm.8182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053017PMC
February 2020

Futureproofing triathlon: expert suggestions to improve health and performance in triathletes.

BMC Sports Sci Med Rehabil 2020 10;12. Epub 2020 Jan 10.

1Athlete Health Lab, Faculty of Kinesiology, Sport, & Recreation, University of Alberta, 4-230 Van Vliet Complex, Edmonton, AB Canada.

Background: Given the multi-modal nature of triathlon (swimming, cycling, running), training for a triathlon event has numerous potential health benefits including physical fitness. However, triathletes also have a high prevalence of health issues including overuse injury, illness, fatigue, and burnout. To address the ongoing prevalence of health issues, roundtable discussions were organized at the International Triathlon Union Science of Triathlon 2017 conference to develop strategic objectives deemed necessary to "futureproof triathlon". Futureproofing as a concept serves to design new approaches and ways of thinking to reduce consequences in the future. In this case, the futureproof process aimed to develop key recommendations for triathlon.

Methods: This qualitative study had 22 participants including athletes, coaches, practitioners, academics, and policy makers who participated in roundtable discussions at the Science of Triathlon conference. Seven of these participants completed follow-up semi-structured interviews on the same topics. The data collected from the roundtable discussions and the semi-structured interviews was analyzed using thematic analysis.

Results: Five main themes were produced: "Critical appraisal and application of knowledge"; "Integrated approaches to developing, disseminating, and using research and expertise"; "Appropriate development and use of measures for monitoring training and recovery"; "Knowing your athletes and adopting holistic approaches to athlete/person-development", and; "Challenging accepted cultural and sporting norms". Participants indicated the need to reduce the knowledge gap between research and practice as well as a more collaborative approach to triathlon research development amongst coaches/practitioners and academics. It was stated that current monitoring tools require more research to determine which are most useful to informed decision making for coaches/practitioners. It was cautioned that data driven assessments should be used judiciously and be athlete centered. Triathlon as a sport should also have a greater focus on healthy participation and development of youth athletes.

Conclusions: A series of applied implications were developed based on these five themes as guiding principles for how to futureproof triathlon. Additionally, roundtable and interview participants who held varying positions and opinions within the sport of triathlon agreed that the unique challenge of training for and competing in a triathlon should not be forgotten in the futureproofing of the sport.
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http://dx.doi.org/10.1186/s13102-019-0153-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953181PMC
January 2020

Spatial variations in gut permeability are linked to type 1 diabetes development in non-obese diabetic mice.

BMJ Open Diabetes Res Care 2019 15;7(1):e000793. Epub 2019 Dec 15.

Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.

Objectives: To determine if spatial variations in gut permeability play a role in regulating type 1 diabetes (T1D) progression.

Research Design And Methods: Spatially resolved duodenum, jejunum, ileum, and large intestine sections from end-stage T1D non-obese diabetic (NOD) mice were probed by immunohistochemistry to quantify zonulin levels as a measure of gut permeability in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR/LtJ control mice.

Results: Zonulin levels were elevated in the small and large intestines in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR control mice. In early-onset mice, elevated zonulin levels were maximum in the duodenum and jejunum and decreased in the ileum and large intestine. In late-progressor mice, zonulin levels were elevated almost evenly along the small and large intestines. In non-progressor NOD mice, zonulin levels were comparable with NOR control levels in both the small and large intestines.

Conclusions: Elevated zonulin expression levels indicated that gut permeability was increased both in the small and large intestines in NOD mice that progressed to end-stage T1D in comparison with non-progressor NOD mice and healthy NOR control mice. Highest elevations in zonulin levels were observed in the duodenum and jejunum followed by the ileum and large intestines. Spatial variations in gut permeability appeared to play a role in regulating the rate and severity of T1D progression in NOD mice indicating that spatial variations in gut permeability should be investigated as a potentially important factor in human T1D progression.
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http://dx.doi.org/10.1136/bmjdrc-2019-000793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936454PMC
September 2020

The Problematic Nature of Fibromyalgia Diagnosis in the Community.

ACR Open Rheumatol 2019 Mar 15;1(1):43-51. Epub 2019 Mar 15.

National Data Bank for Rheumatic Diseases Wichita KS.

Background: Recently, some studies suggested that clinical diagnosis of fibromyalgia is inaccurate and does not reflect current definitions. However, this hypothesis has not been tested. We examined whether fibromyalgia was accurately diagnosed in the community.

Methods: We surveyed 3276 primary care patients to determine current fibromyalgia status by criteria (CritFM). We also determined whether the patients had a physician's diagnosis of fibromyalgia (MDFM) and the level of symptom severity as measured by the polysymptomatic distress scale (PSD).

Results: The prevalence of MDFM and CritFM was 6.1% (95% confidence interval [CI] 5.3%, 6.9%) and 5.5% (95% CI 4.8%, 6.3%), respectively. However, only 32.2% with MDFM met 2016 criteria (CritFM), and only 35.4% with CritFM also had MDFM. The kappa statistic for diagnostic agreement was 0.296 (minimal agreement). The mean PSD score was 12.4 and 18.4 in MDFM and CritFM, respectively. The odds ratio for being a woman compared with being a man was 3.2 for MDFM versus 1.9 for CritFM, = 0.023. Of the patients with MDFM, 68.3% received specific fibromyalgia pharmacotherapy.

Conclusions: There is little agreement between MDFM and CritFM. Only one-third of MDFM satisfy fibromyalgia criteria, and only one-third of patients who meet the criteria have a clinical diagnosis of fibromyalgia. Physician diagnosis is biased and more likely in women. Fibromyalgia treatment is common in MDFM (70.7%). Overall, MDFM appears subjective and unrelated to fibromyalgia criteria. There appears to be no common definition of fibromyalgia in the community.
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http://dx.doi.org/10.1002/acr2.1006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857982PMC
March 2019

Effects of a heat and moisture exchanger on respiratory function and symptoms post-cold air exercise.

Scand J Med Sci Sports 2020 Mar 6;30(3):591-601. Epub 2019 Dec 6.

Department of Sport Science, University of Innsbruck, Innsbruck, Austria.

Purpose: Exercise at temperatures below -15°C induces drying and cooling of lung airways which causes exercise-induced bronchoconstriction (EIB) and respiratory symptoms, especially in winter sport athletes. The objective of this study was to evaluate whether a heat and moisture exchanger (HME) worn during intense cold air exercise improves lung function and reduces respiratory symptoms in healthy winter sport athletes.

Methods: Seven active males and six active females (maximum oxygen uptake 61.9 ± 6.9 and 52.2 ± 5.3 mL/kg/min), all active or former winter sport athletes, completed running trials with and without HME in random order on 2 days in an environmental chamber (-20°C temperature, humidity 46.2%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV ), forced expiratory flow at 25%-75% (FEF ), and FEF at 50% (FEF ) were measured pre- and post-exercise (3, 6, 10, 15, and 20 minutes). Respiratory symptoms were reported after exercise.

Results: Significant interaction effects were observed for FEV and FEF . Mean decrease of FVC (-5.9%, P ≤ .001) and FEV (-4.2%, P = .003) was largest 3 minutes post-exercise without HME. There was an increase of FEV , FEF , and FEF post-exercise compared to pre-exercise with HME. More respiratory symptoms overall were reported without HME (P = .046).

Conclusion: Intense cold air exercise likely causes transient acute bronchoconstriction and symptoms of cough in individuals participating in winter sports. However, this study finds that the application of an HME during intense cold air exercise improves lung function and reduces prevalence of EIB-associated symptoms compared to unprotected intense cold air exercise.
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http://dx.doi.org/10.1111/sms.13603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027737PMC
March 2020

Structural insight into the length-dependent binding of ssDNA by SP_0782 from Streptococcus pneumoniae, reveals a divergence in the DNA-binding interface of PC4-like proteins.

Nucleic Acids Res 2020 01;48(1):432-444

State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan National Laboratory for Optoelectronics, Wuhan 430071, China.

SP_0782 from Streptococcus pneumoniae is a dimeric protein that potentially binds with single-stranded DNA (ssDNA) in a manner similar to human PC4, the prototype of PC4-like proteins, which plays roles in transcription and maintenance of genome stability. In a previous NMR study, SP_0782 exhibited an ssDNA-binding property different from YdbC, a prokaryotic PC4-like protein from Lactococcus lactis, but the underlying mechanism remains unclear. Here, we show that although SP_0782 adopts an overall fold similar to those of PC4 and YdbC, the ssDNA length occupied by SP_0782 is shorter than those occupied by PC4 and YdbC. SP_0782 exhibits varied binding patterns for different lengths of ssDNA, and tends to form large complexes with ssDNA in a potential high-density binding manner. The structures of SP_0782 complexed with different ssDNAs reveal that the varied binding patterns are associated with distinct capture of nucleotides in two major DNA-binding regions of SP_0782. Moreover, a comparison of known structures of PC4-like proteins complexed with ssDNA reveals a divergence in the binding interface between prokaryotic and eukaryotic PC4-like proteins. This study provides insights into the ssDNA-binding mechanism of PC4-like proteins, and benefits further study regarding the biological function of SP_0782, probably in DNA protection and natural transformation.
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http://dx.doi.org/10.1093/nar/gkz1045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145681PMC
January 2020

Influence of Drying Method on NMR-Based Metabolic Profiling of Human Cell Lines.

Metabolites 2019 Oct 31;9(11). Epub 2019 Oct 31.

Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.

Metabolic profiling of cell line and tissue extracts involves sample processing that includes a drying step prior to re-dissolving the cell or tissue extracts in a buffer for analysis by GC/LC-MS or NMR. Two of the most commonly used drying techniques are centrifugal evaporation under vacuum (SpeedVac) and lyophilization. Here, NMR spectroscopy was used to determine how the metabolic profiles of hydrophilic extracts of three human pancreatic cancer cell lines, MiaPaCa-2, Panc-1 and AsPC-1, were influenced by the choice of drying technique. In each of the three cell lines, 40-50 metabolites were identified as having statistically significant differences in abundance in redissolved extract samples depending on the drying technique used during sample preparation. In addition to these differences, some metabolites were only present in the lyophilized samples, for example, n-methyl-α-aminoisobutyric acid, n-methylnicotimamide, sarcosine and 3-hydroxyisovaleric acid, whereas some metabolites were only present in SpeedVac dried samples, for example, trimethylamine. This research demonstrates that the choice of drying technique used during the preparation of samples of human cell lines or tissue extracts can significantly influence the observed metabolome, making it important to carefully consider the selection of a drying method prior to preparation of such samples for metabolic profiling.
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http://dx.doi.org/10.3390/metabo9110256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918379PMC
October 2019

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial.

Ther Adv Med Oncol 2019 24;11:1758835919864236. Epub 2019 Jul 24.

Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.

Background: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients.

Methods: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF).

Results: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ TN was 95% 57%. None of the measured biomarkers predicted the development of cardiotoxicity.

Conclusions: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further.

Trial Registration: ClinicalTrials.gov Identifier: NCT00911716.
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http://dx.doi.org/10.1177/1758835919864236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657121PMC
July 2019

Cold air exercise screening for exercise induced bronchoconstriction in cold weather athletes.

Respir Physiol Neurobiol 2019 11 29;269:103262. Epub 2019 Jul 29.

Neurovascular Health Lab, Faculty of Kinesiology, Sport and Recreation, University of Alberta, Edmonton, Alberta, Canada.

Exercise Induced Bronchoconstriction (EIB) prevalence in cold weather athletes is high. Currently, no standardized cold air exercise provocation test exists. Thus we aimed to determine EIB prevalence using a Cold Air Test (CAT; 5 km outdoor running; -15 °C) compared to the most common EIB screen the Eucapnic Voluntary Hyperpnea (EVH) test in cold weather athletes. Sixteen (9 male; 20-35 years old) cold weather athletes completed EVH 72 h before CAT. Spirometry, Fractional Expired Nitric Oxide (FENO), respiratory symptoms were measured and atopy status was determined. Five and 7 participants were EIB + on the EVH and CAT, respectively. Level of agreement was 50% between tests. FEV recovery was significantly prolonged and Peak Expiratory Flow was decreased after CAT compared to EVH. Predictive characteristics of EIB + included FENO >12 ppb, FEV/FVC ratio (<0.75) and BMI < 20. EVH does not always reflect EIB triggered by cold weather exercise. More research is required to understand the best EIB screens for cold weather athletes.
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http://dx.doi.org/10.1016/j.resp.2019.103262DOI Listing
November 2019

Solution NMR structure and ligand identification of human Gas7 SH3 domain reveal a typical SH3 fold but a non-canonical ligand-binding mode.

Biochem Biophys Res Commun 2019 09 9;516(4):1190-1195. Epub 2019 Jul 9.

State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, Wuhan National Laboratory for Optoelectronics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Growth arrest specific 7 (Gas7) protein is a cytoskeleton regulator playing a crucial role in neural cell development and function, and has been implicated in Alzheimer disease, schizophrenia and cancers. In human, three Gas7 isoforms can be expressed from a single Gas7 gene, while only the longest isoform, hGas7c, possesses an SH3 domain at the N-terminus. To date, the structure and function of hGas7 SH3 domain are still unclear. Here, we reported the solution NMR structure of hGas7 SH3 domain (hGas7-SH3), which displays a typical SH3 β-barrel fold comprising five β-strands and one 3-helix. Structural and sequence comparison showed that hGas7-SH3 shares high similarity with Abl SH3 domain, which binds to a high-affinity proline-rich peptide P41 in a canonical SH3-ligand binding mode through two hydrophobic pockets and a specificity site in the RT-loop. However, unlike Abl-SH3, only six residues in the RT-loop and two residues adjacent to but not in the two hydrophobic pockets of hGas7-SH3 showed significant chemical shift perturbations in NMR titrations, suggesting a low affinity and a non-canonical binding mode of hGas7-SH3 for P41. Furthermore, four peptides selected from phage-displayed libraries also bound weakly to hGas7-SH3, and the binding region of hGas7-SH3 was mainly located in the RT-loop as well. The ligand identifications through structural similarity searching and peptide library screening in this study imply that although hGas7-SH3 adopts a typical SH3 fold, it probably possesses distinctive ligand-binding specificity.
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http://dx.doi.org/10.1016/j.bbrc.2019.07.004DOI Listing
September 2019