Publications by authors named "Peter Hart"

110 Publications

Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5-MEP50 Complex.

Chembiochem 2021 Feb 24. Epub 2021 Feb 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

The PRMT5-MEP50 methyltransferase complex plays a key role in various cancers and is regulated by different protein-protein interactions. Several proteins have been reported to act as adaptor proteins that recruit substrate proteins to the active site of PRMT5 for the methylation of arginine residues. To define the interaction between these adaptor proteins and PRMT5, we employed peptide truncation and mutation studies and prepared truncated protein constructs. We report the characterisation of the interface between the TIM barrel of PRMT5 and the adaptor proteins pICln, RioK1 and COPR5, and identify the consensus amino acid sequence GQF[D/E]DA[E/D] involved in binding. Protein crystallography revealed that the RioK1 derived peptide interacts with a novel PPI site.
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http://dx.doi.org/10.1002/cbic.202100079DOI Listing
February 2021

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer.

Int J Mol Sci 2021 Jan 16;22(2). Epub 2021 Jan 16.

College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA.

Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease's progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.
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http://dx.doi.org/10.3390/ijms22020867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830067PMC
January 2021

C-Reactive Protein and Cancer-Diagnostic and Therapeutic Insights.

Front Immunol 2020 19;11:595835. Epub 2020 Nov 19.

Roosevelt University, College of Science, Health and Pharmacy, Schaumburg, IL, United States.

Cancer disease describes any pathology involving uncontrolled cell growth. As cells duplicate, they can remain localized in defined tissues, forming tumor masses and altering their microenvironmental niche, or they can disseminate throughout the body in a metastatic process affecting multiple tissues and organs. As tumors grow and metastasize, they affect normal tissue integrity and homeostasis which signals the body to trigger the acute phase inflammatory response. C-reactive protein (CRP) is a predominant protein of the acute phase response; its blood levels have long been used as a minimally invasive index of any ongoing inflammatory response, including that occurring in cancer. Its diagnostic significance in assessing disease progression or remission, however, remains undefined. By considering the recent understanding that CRP exists in multiple isoforms with distinct biological activities, a unified model is advanced that describes the relevance of CRP as a mediator of host defense responses in cancer. CRP in its monomeric, modified isoform (mCRP) modulates inflammatory responses by inserting into activated cell membranes and stimulating platelet and leukocyte responses associated with acute phase responses to tumor growth. It also binds components of the extracellular matrix in involved tissues. Conversely, CRP in its pentameric isoform (pCRP), which is the form quantified in diagnostic measurements of CRP, is notably less bioactive with weak anti-inflammatory bioactivity. Its accumulation in blood is associated with a continuous, low-level inflammatory response and is indicative of unresolved and advancing disease, as occurs in cancer. Herein, a novel interpretation of the diagnostic utility of CRP is presented accounting for the unique properties of the CRP isoforms in the context of the developing pro-metastatic tumor microenvironment.
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http://dx.doi.org/10.3389/fimmu.2020.595835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727277PMC
November 2020

Case report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis.

BMC Nephrol 2020 11 19;21(1):496. Epub 2020 Nov 19.

Department of Nephrology, Cook County Health, Chicago, IL, USA.

Background: Glomerular involvement in rheumatoid arthritis has been known to be associated with treatment side effects from medications and secondary amyloidosis. However, limited basic science and clinical studies have been performed to address the potential disease specific immune-mediated mechanisms causing secondary glomerular pathology, its various types of presentation, and the potential treatments.

Case Presentation: A 41-year-old man with chronic active rheumatoid arthritis presented with nephrotic syndrome and was found to have membranous nephropathy with eosinophilic intracapillary thrombi on renal biopsy. Proteinuria persisted despite complete withdrawal from non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). Throughout the disease course, he developed cryoglobulinemic vasculitis and pulmonary sarcoidosis, both of which achieved clinical resolution with glucocorticoids. However, only partial improvement was observed in proteinuria with treatment of steroids and Rituximab.

Conclusion: Our case presented a unique and complicated clinical phenotype of active rheumatoid arthritis, with clinical features of cryoglobulinemic vasculitis, histopathologic features of membranous and cryoglobulinemic nephropathy in the absence of DMARDs use, as well as pulmonary sarcoidosis. We speculate that there is a wider spectrum of glomerular disease in patients with untreated rheumatoid arthritis. In addition, the potential association between rheumatoid arthritis and cryoglobulinemic vasculitis should probably be revisited and requires further studies to elucidate the underlying mechanisms and treatment options.
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http://dx.doi.org/10.1186/s12882-020-02161-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676473PMC
November 2020

Mucosal Therapy of Multi-Drug Resistant Tuberculosis With IgA and Interferon-γ.

Front Immunol 2020 20;11:582833. Epub 2020 Oct 20.

Institute for Infection and Immunity, St. George's University, London, United Kingdom.

New evidence has been emerging that antibodies can be protective in various experimental models of tuberculosis. Here, we report on protection against multidrug-resistant (MDR-TB) infection using a combination of the human monoclonal IgA 2E9 antibody against the alpha-crystallin (Acr, HspX) antigen and mouse interferon-gamma in mice transgenic for the human IgA receptor, CD89. The effect of the combined mucosal IgA and IFN-γ; treatment was strongest (50-fold reduction) when therapy was applied at the time of infection, but a statistically significant reduction of lung bacterial load was observed even when the therapy was initiated once the infection had already been established. The protection involving enhanced phagocytosis and then neutrophil mediated killing of infected cells was IgA isotype mediated, because treatment with an IgG version of 2E9 antibody was not effective in human IgG receptor CD64 transgenic mice. The Acr antigen specificity of IgA antibodies for protection in humans has been indicated by their elevated serum levels in latent tuberculosis unlike the lack of IgA antibodies against the virulence-associated MPT64 antigen. Our results represent the first evidence for potential translation of mucosal immunotherapy for the management of MDR-TB.
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http://dx.doi.org/10.3389/fimmu.2020.582833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606302PMC
October 2020

Health-Related Quality of Life, Depressive Symptoms, and Kidney Transplant Access in Advanced CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Kidney Med 2020 Sep-Oct;2(5):600-609.e1. Epub 2020 Aug 11.

Department of Medicine, Loyola University Medical Center, Maywood, IL.

Rationale & Objective: Among individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list.

Study Design: Prospective cohort study.

Setting & Population: 1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m at study entry or during follow-up.

Exposures: HRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory.

Outcomes: Time to kidney transplant wait-listing and time to pre-emptive wait-listing.

Analytic Approach: Time-to-event analysis using Cox proportional hazards regression.

Results: During a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85;  < 0.001) and Effects scales (wait-listing aHR, 0.74; 95% CI, 0.59-0.92;  = 0.007). Participants with fewer depressive symptoms (ie, Beck Depression Inventory score < 14) had lower wait-listing rates than those with more depressive symptoms (aHR, 0.81; 95% CI, 0.66-0.99;  = 0.04). Participants with lower Burden and Effects scale scores and those with higher Symptoms and PCS scores had higher pre-emptive wait-listing rates (aHR in highest tertile of PCS relative to lowest tertile, 1.58; 95% CI, 1.12-2.23;  = 0.01).

Limitations: Unmeasured confounders.

Conclusions: Self-reported health in late-stage CKD may influence the timing of kidney transplantation.
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http://dx.doi.org/10.1016/j.xkme.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568061PMC
August 2020

Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48.

Angew Chem Int Ed Engl 2021 01 24;60(4):1813-1820. Epub 2020 Nov 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar K value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs.
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http://dx.doi.org/10.1002/anie.202009749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894522PMC
January 2021

How C-Reactive Protein Structural Isoforms With Distinctive Bioactivities Affect Disease Progression.

Front Immunol 2020 10;11:2126. Epub 2020 Sep 10.

Roosevelt University College of Pharmacy, Schaumburg, IL, United States.

C-reactive protein (CRP) is a widely known, hepatically synthesized protein whose blood levels change rapidly and pronouncedly in response to any tissue damaging event associated with an inflammatory response. The synthesis and secretion of CRP is stimulated by interleukin-6, an early pleiotropic cytokine released by macrophages, endothelial, and other cells that are activated when localized normal tissue structures are compromised by trauma or disease. Serum CRP levels can change rapidly and robustly from 10-100-fold within 6-72 h of any tissue damaging event. Elevated blood levels correlate with the onset and extent of both activated inflammation and the acute phase biochemical response to the tissue insult. Because its functional bioactivity as the prototypic acute phase reactant has eluded clear definition for decades, diagnosticians of various conditions and diseases use CRP blood levels as a simple index for ongoing inflammation. In many pathologies, which involves many different tissues, stages of disease, treatments, and responses to treatments, its interpretive diagnostic value requires a deeper understanding of the localized tissue processes and events that contribute signals which regulate protective or pathological host defense bioactivities. This report presents concepts that describe how local tissue activation events can lead to a non-proteolytic, conformational rearrangement of CRP into a unique isoform with distinctive solubility, antigenicity, binding reactivities and bioactivities from that protein widely known and measured in serum. By describing factors that control the expression, tissue localization, half-life and pro-inflammatory amplification activity of this CRP isoform, a unifying explanation for the diagnostic significance of CRP measurement in disease is advanced.
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http://dx.doi.org/10.3389/fimmu.2020.02126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511658PMC
September 2020

Relationship between fitness performance and a newly developed continuous body composition score in U.S. adolescent boys.

Authors:
Peter Hart

Int J Adolesc Med Health 2020 Sep 23. Epub 2020 Sep 23.

Health Promotion Research, Health Demographics, 930 4th Ave, Havre, 59501,MT, USA.

Objectives Body composition (BC) assessment typically requires the administration of a single test and can have different evaluation outcomes depending on the selected test and the specific population. The purpose of this study was twofold. Firstly, to develop and validate a novel continuous body composition (CBC) score using the continuous response model (CRM). Secondly, to examine the relationship between CBC scores and fitness performance. Methods Data from the 2012 NHANES National Youth Fitness Survey (NNYFS) were used and consisted of n=212 adolescent boys 12-15 years of age. CBC scale variables included body mass (BM), body mass index (BMI), arm circumference (AC), waist circumference (WC), calf circumference (CC), calf skinfold (CSF), triceps skinfold (TSF), and subscapular skinfold (SSF). Fitness performance variables included cardiorespiratory fitness (CRF, mL/kg/min), leg strength (LS, lb), modified pull-ups (MPU, #), grip strength (GS, kg), and plank (PL, sec). Samejima's CRM, factor analysis, convergent validity coefficients and score reliability were used to validate the CBC scale. Multinomial logistic regression and multiple linear regression were used to examine the relationship between CBC scores and fitness performance variables. Results Factor analysis of the CBC scale variables retained a single factor (loadings >0.81, 88% explained variance) with strong internal consistency (α=0.96). The CRM analysis indicated all CBC scale variables fit a unidimensional construct with adequate discrimination (as: 0.71-2.16) and difficulty (bs: -0.04-1.44). CBC scores (Mean=0, SD=1.00) displayed strong reliability (SEE.θ=0.22, r.θ=0.95) with lower values representing smaller-more-lean individuals and higher values representing larger-less-lean individuals. All fully adjusted regression models showed significant (ps<0.05) negative relationships between CBC scores and CRF, MPU, and PL and positive relationships between CBC scores and LS and GS. Conclusion The CRM-derived CBC score is a novel measure of BC and found to be positively associated with strength performance and negatively associated with endurance performance in U.S. adolescent boys.
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http://dx.doi.org/10.1515/ijamh-2020-0198DOI Listing
September 2020

Insights into the Potential of Hardwood Kraft Lignin to Be a Green Platform Material for Emergence of the Biorefinery.

Polymers (Basel) 2020 Aug 11;12(8). Epub 2020 Aug 11.

Department of Forest Biomaterials, North Carolina State University, 2820 Faucette Dr. Campus Box 8005, Raleigh, NC 27695, USA.

Lignin is an abundant, renewable, and relatively cheap biobased feedstock that has potential in energy, chemicals, and materials. Kraft lignin, more specifically, has been used for more than 100 years as a self-sustaining energy feedstock for industry after which it has finally reached more widespread commercial appeal. Unfortunately, hardwood kraft lignin (HWKL) has been neglected over these years when compared to softwood kraft lignin (SWKL). Therefore, the present work summarizes and critically reviews the research and development (R&D) dealing specifically with HWKL. It will also cover methods for HWKL extraction from black liquor, as well as its structure, properties, fractionation, and modification. Finally, it will reveal several interesting opportunities for HWKL that include dispersants, adsorbents, antioxidants, aromatic compounds (chemicals), and additives in briquettes, pellets, hydrogels, carbon fibers and polymer blends and composites. HWKL shows great potential for all these applications, however more R&D is needed to make its utilization economically feasible and reach the levels in the commercial lignin market commensurate with SWKL. The motivation for this critical review is to galvanize further studies, especially increased understandings in the field of HWKL, and hence amplify much greater utilization.
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http://dx.doi.org/10.3390/polym12081795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464338PMC
August 2020

The exercise pressor response to indoor rock climbing.

J Appl Physiol (1985) 2020 08 9;129(2):404-409. Epub 2020 Jul 9.

Institute of Respiratory Medicine and Exercise Physiology, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California.

This paper assessed the blood pressure, heart rate, and mouth-pressure responses to indoor rock climbing (bouldering) and associated training exercises. Six well-trained male rock climbers (mean ± SD age, 27.7 ± 4.7 yr; stature, 177.7 ± 7.3 cm; mass, 69.8 ± 12.1 kg) completed two boulder problems (6b and 7a+ on the Fontainebleau Scale) and three typical training exercises [maximum voluntary contraction (MVC) isometric pull-up, 80% MVC pull-ups to fatigue, and campus board to fatigue]. Blood pressure and heart rate were measured via an indwelling femoral arterial catheter, and mouth pressure via a mouthpiece manometer. Bouldering evoked a peak systolic pressure of 200 ± 17 mmHg (44 ± 21% increase from baseline), diastolic pressure of 142 ± 26 mmHg (70 ± 32% increase), mean arterial pressure of 163 ± 18 mmHg (56 ± 25% increase), and heart rate of 176 ± 22 beats/min (76 ± 35% increase). The highest systolic pressure was observed during the campus board exercise (218 ± 33 mmHg), although individual values as high as 273/189 mmHg were recorded. Peak mouth pressure during climbing was 31 ± 46 mmHg, and this increased independently of climb difficulty. We concluded that indoor rock climbing and associated exercises evoke a substantial pressor response resulting in high blood pressures that may exceed those observed during other upper-limb resistance exercises. These findings may inform risk stratification for climbers. This case study provides original data on the exercise pressor response to indoor rock climbing and associated training exercises through the use of an indwelling femoral arterial catheter. Our subjects exhibited systolic/diastolic blood pressures that exceeded values often reported during upper-limb resistance exercise. Our data extend the understanding of the cardiovascular stress associated with indoor rock climbing.
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http://dx.doi.org/10.1152/japplphysiol.00357.2020DOI Listing
August 2020

Insights into the Use of C-Reactive Protein as a Diagnostic Index of Disease Severity in COVID-19 Infections.

Am J Trop Med Hyg 2020 08 25;103(2):561-563. Epub 2020 Jun 25.

Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky.

Approximately 20% of patients infected with SARS-CoV-2 (COVID-19) develop potentially life-threatening pathologies involving hyperinflammation, cytokine storm, septic shock complications, coagulation dysfunction, and multiple organ failure. Blood levels of the prototypic acute phase reactant, C-reactive protein (CRP), which is hepatically synthesized and released in response to interleukin-6 stimulation, is markedly elevated in patients with COVID-19. Markedly high CRP levels correlate with poor prognosis for survival. Insights into CRP structure-function relationships have uncovered both pro- and anti-inflammatory isoforms that may be used to monitor the extent of tissue damage associated with COVID-19 pathologies and prognoses. Herein, rationale is given for interpretation of CRP blood levels as a simple, rapid, and cost-effective way to assess disease severity and help guide therapeutic options in COVID-19 patients.
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http://dx.doi.org/10.4269/ajtmh.20-0473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410479PMC
August 2020

Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk.

Cell Rep 2019 12;29(12):4086-4098.e6

Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA. Electronic address:

The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin.
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http://dx.doi.org/10.1016/j.celrep.2019.11.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218928PMC
December 2019

Grip Strength and Health-Related Quality of Life in U.S. Adult Males.

Authors:
Peter D Hart

J Lifestyle Med 2019 Jul 31;9(2):102-110. Epub 2019 Jul 31.

Health Promotion Research, Havre, MT, USA.

Background: A need exists for a population-based evaluation of muscular strength in terms of its association with health-related quality of life (HRQOL) in males. Therefore, the purpose of this study was to examine the relationship between grip strength and HRQOL in a representative sample of U.S. men.

Methods: This study used data from adult males 20+ years of age participating in the 2013-2014 National Health and Nutrition Examination Survey. Grip strength (kg) was measured in both hands using a handgrip dynamometer. HRQOL was assessed by a single question asking participants to rate their general health. Additionally, measures of moderate-to-vigorous physical activity (PA), body mass index, waist circumference, TV time, sedentary time, and smoking were assessed. Multiple linear regression modeling for complex samples was used to examine the effect of HRQOL on grip strength while controlling for confounding variables.

Results: Overall, males with good HRQOL ( = 47.5 kg, = 0.31) had significantly greater grip strength than males with poor HRQOL ( = 44.5 kg, = 0.51, p < 0.001). In fully adjusted models, males with good HRQOL had greater grip strength ( = 2.5 kg, = 0.57, p = 0.001) than their poor HRQOL counterparts. Additionally, HRQOL was a significant predictor of grip strength in male adults who did not meet PA guidelines but not in those who did meet PA guidelines.

Conclusion: Results from this study indicate that muscular strength and HRQOL are related in U.S. men. Furthermore, the muscular strength and HRQOL relationship appears to remain in adult males who do not meet PA guidelines.
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http://dx.doi.org/10.15280/jlm.2019.9.2.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894447PMC
July 2019

Incidence of, Risk Factors for, and Mortality Associated With Severe Acute Kidney Injury After Gunshot Wound.

JAMA Netw Open 2019 12 2;2(12):e1917254. Epub 2019 Dec 2.

Division of Nephrology, John H. Stroger Jr Hospital of Cook County, Chicago, Illinois.

Importance: Acute kidney injury increases the risk of mortality in hospitalized patients. However, incidence of severe acute kidney injury (SAKI) and its association with mortality in civilians with gunshot wounds (GSWs) is not known.

Objective: To determine the incidence of and risk factors associated with SAKI and acute kidney injury requiring dialysis (AKI-D) after GSWs and the association of SAKI and AKI-D with mortality among civilians in the United States.

Design, Setting, And Participants: This retrospective cross-sectional study included civilians with GSW reported to the National Trauma Data Bank between July 1, 2010, and June 30, 2015. Torso GSWs were included in study; GSWs to the head were excluded. The data were analyzed between September and November 2018.

Exposure: Civilians with GSW.

Main Outcomes And Measures: Incidence of SAKI and AKI-D; association of SAKI and AKI-D with mortality.

Results: Most of the 64 059 civilian GSWs affected men (57 431 [89.7%]) and racial/ethnic minorities (36 205 [56.5%] African American individuals; 9681 [15.1%] Hispanic individuals). Incidence of SAKI was 2.3% (1450 of 64 059), and incidence of AKI-D was 0.9% (588 of 64 059). On multivariate analysis, SAKI was associated with older age (odds ratio [OR], 1.02; 95% CI, 1.01-1.02; P < .001), male sex (OR, 1.37; 95% CI, 1.12-1.66; P = .002), diabetes (OR, 1.55; 95% CI, 1.20-2.00; P = .001), hypertension (OR, 1.76; 95% CI, 1.46-2.11; P < .001), Glasgow Coma Scale score (OR, 0.98; 95% CI, 0.96-0.99; P = .002), sepsis (OR, 13.83; 95% CI, 11.77-16.24; P < .001), hollow viscus injury (OR, 2.31; 95% CI, 2.05-2.59; P < .001), and injury severity score (OR, 1.02; 95% CI, 1.01-1.02; P < .001); AKI-D was associated with systolic blood pressure (OR, 0.99; 95% CI, 0.99-1.00; P < .001), sepsis (OR, 1.56; 95% CI, 1.18-2.04; P = .001), and injury severity score (OR, 1.01; 95% CI, 1.01-1.02; P = .001). Mortality was significantly higher in patients with AKI-D (167 of 588 patients [28.4%]) compared with patients with SAKI (172 of 862 [20.0%]) and no SAKI or AKI-D (5521 of 62 609 [8.8%]) (P < .001). Mortality was associated with older age (OR, 1.01; 95% CI, 1.01-1.01; P < .001), systolic blood pressure (OR, 0.997; 95% CI, 0.997-0.998; P < .001), Glasgow Coma Scale score (OR, 0.87; 95% CI, 0.87-0.88; P < .001), SAKI (OR, 2.32; 95% CI, 1.93-2.79; P < .001), AKI-D (OR, 1.46; 95% CI, 1.12-1.90; P < .001), hollow viscus injury (OR, 1.87; 95% CI, 1.76-1.98; P < .001), and higher injury severity score (OR, 1.01; 95% CI, 1.01-1.01; P < .001). After matching for variables except SAKI or AKI-D, patients with SAKI were twice as likely to die than patients without SAKI (320 of 1391 [23.0%] vs 158 of 1391 [11.4%]; P < .001).

Conclusions And Relevance: In this cross-sectional study, SAKI among civilians who experienced GSWs was associated with mortality.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991197PMC
December 2019

Desmopressin and bleeding risk after percutaneous kidney biopsy.

BMC Nephrol 2019 11 15;20(1):413. Epub 2019 Nov 15.

Division of Nephrology, Cook County Health, 1950 W. Polk Street, 5th Floor, Chicago, IL, 60605, USA.

Background: Desmopressin is used to reduce bleeding after kidney biopsy but evidence supporting its use is weak, especially in patients with elevated creatinine. The present study was undertaken to evaluate efficacy of desmopressin in reducing bleeding after percutaneous kidney biopsy.

Methods: Retrospective cohort study. 269 of 322 patients undergoing percutaneous kidney biopsy between January 1, 2014 and January 31, 2018 were included. Patients had normal bleeding time, platelet count and coagulation profile. Primary outcome was defined as composite of hemoglobin drop ≥1 g/dL, hematoma on post biopsy ultrasound, gross hematuria, erythrocyte transfusion or angiography to stop bleeding. Association of desmopressin with outcomes was assessed using linear (for continuous variables) and logistic (for binary variables) regression models. Propensity score was used to minimize potential confounding.

Results: Desmopressin was administered to 100/269 (37.17%) patients. After propensity score adjustment patients who received desmopressin had increased odds of post biopsy bleeding [OR 3.88 (1.95-7.74), p < 0.001]. Creatinine at time of biopsy influenced bleeding risk; gender, emergent vs elective biopsy, obesity, AKI, diabetes, hypertension or bleeding time did not influence bleeding risk. Administration of desmopressin to patients with serum creatinine ≥1.8 mg/dL decreased bleeding risk [OR 2.11 (95% CI 0.87-5.11), p = 0.09] but increased bleeding risk when serum creatinine was < 1.8 mg/dL (OR 9.72 (95% CI 2.95-31.96), p < 0.001).

Conclusion: Desmopressin should not be used routinely prior to percutaneous kidney biopsy in patients at low risk for bleeding but should be reserved for patients who are at high risk for bleeding.
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http://dx.doi.org/10.1186/s12882-019-1595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858772PMC
November 2019

Paratope Duality and Gullying are Among the Atypical Recognition Mechanisms Used by a Trio of Nanobodies to Differentiate Ebolavirus Nucleoproteins.

J Mol Biol 2019 12 15;431(24):4848-4867. Epub 2019 Oct 15.

Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA. Electronic address:

We had previously shown that three anti-Marburg virus nanobodies (VHH or single-domain antibody [sdAb]) targeted a cryptotope within an alpha-helical assembly at the nucleoprotein (NP) C-terminus that was conserved through half a century of viral evolution. Here, we wished to determine whether an anti-Ebola virus sdAb, that was cross-reactive within the Ebolavirus genus, recognized a similar structural feature upstream of the ebolavirus NP C-terminus. In addition, we sought to determine whether the specificities of a less cross-reactive anti-Zaire ebolavirus sdAb and a totally specific anti-Sudan ebolavirus sdAb were the result of exclusion from this region. Binding and X-ray crystallographic studies revealed that the primary determinant of cross-reactivity did indeed appear to be a preference for the helical feature. Specificity, in the case of the Zaire ebolavirus-specific sdAb, arose from the footprint shifting away from the helices to engage more variable residues. While both sdAbs used CDRs, they also had atypical side-on approaches, with framework 2 helping to accommodate parts of the epitope in sizeable paratope gullies. The Sudan ebolavirus-specific sdAb was more remarkable and appeared to bind two C-terminal domains simultaneously via nonoverlapping epitopes-"paratope duality." One mode involved paratope gullying, whereas the other involved only CDRs, with CDR3 restructuring to wedge in between opposing walls of an interdomain crevice. The varied routes used by sdAbs to engage antigens discovered here deepen our appreciation of the small scaffold's architectural versatility and also reveal lucrative opportunities within the ebolavirus NP C-termini that might be leveraged for diagnostics and novel therapeutic targeting.
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http://dx.doi.org/10.1016/j.jmb.2019.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990103PMC
December 2019

SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer.

Proc Natl Acad Sci U S A 2019 11 7;116(47):23534-23541. Epub 2019 Oct 7.

Department of Medicine, Division of Endocrinology, Medical College of Wisconsin, Milwaukee, WI 53226;

Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of "stemness" genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2 and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2 turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.
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http://dx.doi.org/10.1073/pnas.1902308116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876149PMC
November 2019

Immunization With Antigens Encapsulated in Phosphatidylserine Liposomes Improves Protection Afforded by BCG.

Front Immunol 2019 12;10:1349. Epub 2019 Jun 12.

Institute for Infection and Immunity, St. George's University of London, London, United Kingdom.

Liposomes have been long considered as a vaccine delivery system but this technology remains to be fully utilized. Here, we describe a novel liposome-based subunit vaccine formulation for tuberculosis (TB) based on phosphatidylserine encapsulating two prominent TB antigens, Ag85B, and ESAT-6. We show that the resulting liposomes (Lipo-AE) are stable upon storage and can be readily taken up by antigen presenting cells and that their antigenic cargo is delivered and processed within endosomal cell compartments. The Lipo-AE vaccine formulation combined with the PolyIC adjuvant induced a mixed Th1/Th17-Th2 immune response to Ag85B but only a weak response to ESAT-6. An immunization regimen based on systemic delivery followed by mucosal boost with Lipo-AE resulted in the accumulation of resident memory T cells in the lungs. Most importantly though, when Lipo-AE vaccine candidate was administered to BCG-immunized mice subsequently challenged with low dose aerosol , we observed a significant reduction of the bacterial load in the lungs and spleen compared to BCG alone. We therefore conclude that the immunization with mycobacterial antigens delivered by phosphatidylserine based liposomes in combination with Poly:IC adjuvant may represent a novel BCG boosting vaccination strategy.
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http://dx.doi.org/10.3389/fimmu.2019.01349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598733PMC
October 2020

Intermittent pneumatic compression in patients with ESRD. A systematic review.

Hemodial Int 2019 10 8;23(4):433-444. Epub 2019 Jul 8.

Department of Medicine, Division of Vascular Medicine, NorthShore University Health System, Evanston, Illinois, USA.

Introduction: Patients with end-stage renal disease (ESRD) experience frequent hemodialysis (HD) complications. Intradialytic hypotension (IDH) is a common complication presenting in approximately between 20 and 50% of HD sessions. Available interventions such as volume replacement or vasoactive medications are associated with significant side effects. Intermittent pneumatic compression (IPC) has been proposed as a feasible intervention for the prevention of IDH, treatment of peripheral arterial disease and venous ulcers. These devices apply intermittent pressure to the legs improving arterial blood flow, mobilization of pooled blood with an increase in venous return increasing the effective circulatory volume. Our goal was to identify the published clinical evidence on whether IPC has a circulatory benefit and is it well-tolerated among patients receiving HD.

Methods: We conducted a systematic review to identify studies assessing the efficacy and safety of IPC in patients with ESRD. Our primary outcome was IDH. Secondary outcomes such as HD comfort, ultrafiltration volume, and physical activity were collected. No restrictions where used and we included all observational and interventional studies. Two reviewers performed screening and study quality assessment.

Findings: We included seven studies. Out of the seven studies, five addressed IDH, and the rest were included for secondary outcomes such as physical capacity and HD comfort. In one randomized crossover trial comparing exercise against IPC, 21 patients were randomized to 3 different arms (no intervention, cycling, IPC) a decrease in the rates of IDH with IPC was described (43%, 38%, and 24% respectively P = 0.014). The smaller studies corroborated these results. All studies where at high risk of bias.

Discussion: IPC might offer significant benefits for patients undergoing HD not limited to prevention of IDH but also improvement of hemodialysis comfort and physical capacity. However, our results should be interpreted in the context of its limitations.
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http://dx.doi.org/10.1111/hdi.12771DOI Listing
October 2019

Disulfide bond of Mycoplasma pneumoniae community-acquired respiratory distress syndrome toxin is essential to maintain the ADP-ribosylating and vacuolating activities.

Cell Microbiol 2019 08 9;21(8):e13032. Epub 2019 May 9.

Department of Microbiology, Immunology and Molecular Genetics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Mycoplasma pneumoniae is the leading cause of bacterial community-acquired pneumonia among hospitalised children in United States and worldwide. Community-acquired respiratory distress syndrome (CARDS) toxin is a key virulence determinant of M. pneumoniae. The N-terminus of CARDS toxin exhibits ADP-ribosyltransferase (ADPRT) activity, and the C-terminus possesses binding and vacuolating activities. Thiol-trapping experiments of wild-type (WT) and cysteine-to-serine-mutated CARDS toxins with alkylating agents identified disulfide bond formation at the amino terminal cysteine residues C230 and C247. Compared with WT and other mutant toxins, C247S was unstable and unusable for comparative studies. Although there were no significant variations in binding, entry, and retrograde trafficking patterns of WT and mutated toxins, C230S did not elicit vacuole formation in intoxicated cells. In addition, the ADPRT domain of C230S was more sensitive to all tested proteases when compared with WT toxin. Despite its in vitro ADPRT activity, the reduction of C230S CARDS toxin-mediated ADPRT activity-associated IL-1β production in U937 cells and the recovery of vacuolating activity in the protease-released carboxy region of C230S indicated that the disulfide bond was essential not only to maintain the conformational stability of CARDS toxin but also to properly execute its cytopathic effects.
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http://dx.doi.org/10.1111/cmi.13032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612593PMC
August 2019

Urine exosomal ceruloplasmin: a potential early biomarker of underlying kidney disease.

Clin Exp Nephrol 2019 Aug 6;23(8):1013-1021. Epub 2019 Apr 6.

Division of Nephrology, John H. Stroger, Jr. Hospital of Cook County, 1950 West Polk Street, Suites 5-56, Professional Building, Chicago, IL, 60612, USA.

Background: Previously we found that kidney tissue and urinary exosomes from patients of diabetic kidney disease showed high levels of ceruloplasmin (CP). Because CP is an acute-phase protein of kidney origin, it could be an early marker of many other kidney diseases. To investigate this hypothesis, we first measured urine exosomal and kidney expression of CP in non-diabetic chronic kidney disease (CKD) patients (membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis and IgA nephropathy) followed by a longitudinal study in rat passive Heymann nephritis (PHN), a model of human membranous nephropathy.

Methods: Urinary exosomes were isolated from urine of patients (and rats) by differential centrifugation. The exosomal extracts were used for measuring CP using ELISA. Kidney expression of CP was evaluated by immune-staining biopsy tissues. Similar techniques were applied in rat PHN model (produced by injection of anti-gp600 antiserum) to analyze urine exosomal and kidney CP.

Results: Urine exosomal CP levels were 10-20 times higher in CKD patients than in controls; consistent with this we found high immune-reactive CP localized in tubules and collecting ducts of biopsies of CKD patients. In the PHN model urinary exosomal CP level was significantly higher prior to the onset of proteinuria. Early rise of urine exosomal CP, which preceded proteinuria, correlated with high immunoreactive CP found in rat kidneys at this time.

Conclusion: We propose that urine exosomal CP, observed to increase prior to proteinuria, makes it a potential urinary biomarker to diagnose early kidney disease.
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http://dx.doi.org/10.1007/s10157-019-01734-5DOI Listing
August 2019

Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism.

Nature 2019 04 6;568(7751):254-258. Epub 2019 Mar 6.

Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.

Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC). Here we show that BTB and CNC homology1 (BACH1), a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.
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http://dx.doi.org/10.1038/s41586-019-1005-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698916PMC
April 2019

Bacillus Calmette-Guérin Induces PD-L1 Expression on Antigen-Presenting Cells via Autocrine and Paracrine Interleukin-STAT3 Circuits.

Sci Rep 2019 03 6;9(1):3655. Epub 2019 Mar 6.

Infection and Immunity, St George's Medical School, University of London, London, UK.

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB), and is also used as an immunotherapy for bladder cancer and other malignancies due to its immunostimulatory properties. Mycobacteria spp., however, are well known for their numerous immune evasion mechanisms that limit the true potential of their therapeutic use. One such major mechanism is the induction of programmed death ligand-1 (PD-L1), which mitigates adaptive immune responses. Here, we sought to unravel the molecular pathways behind PD-L1 up-regulation on antigen-presenting cells (APCs) by BCG. We found that infection of APCs with BCG induced PD-L1 up-regulation, but that this did not depend on direct infection, suggesting a soluble mediator for this effect. BCG induced potent quantities of IL-6 and IL-10, and the downstream transcription factor STAT3 was hyper-phosphorylated. Intracellular analyses revealed that levels of PD-L1 molecules were associated with the STAT3 phosphorylation state, suggesting a causal link. Neutralisation of the IL-6 or IL-10 cytokine receptors dampened STAT3 phosphorylation and BCG-mediated up-regulation of PD-L1 on APCs. Pharmacological inhibition of STAT3 achieved the same effect, confirming an autocrine-paracrine cytokine loop as a mechanism for BCG-mediated up-regulation of PD-L1. Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. These novel findings could lead to refinement of BCG as both a vaccine for infectious disease and as a cancer immunotherapy.
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http://dx.doi.org/10.1038/s41598-019-40145-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403281PMC
March 2019

Inhibition of fascin in cancer and stromal cells blocks ovarian cancer metastasis.

Gynecol Oncol 2019 05 20;153(2):405-415. Epub 2019 Feb 20.

Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, United States of America. Electronic address:

Objective: Ovarian cancer (OvCa) metastasis requires the coordinated motility of both cancer and stromal cells. Cellular movement is a dynamic process that involves the synchronized assembly of f-actin bundles into cytoskeletal protrusions by fascin. Fascin directly binds f-actin and is an integral component of filopodia, lamellapodia and stress fibers. Here, we examine the expression pattern and function of fascin in the cancer and stromal cells of OvCa tumors.

Methods: Fascin expression was evaluated in human cells and tissues using immunohistochemistry and immunofluorescence. The functional role of fascin in cancer and stromal cells was assessed with in vitro functional assays, an ex vivo colonization assay and in vivo metastasis assays using siRNA/shRNA and an inhibitor. The effect of fascin inhibition on Cdc42 and Rac1 activity was evaluated using GTPase activity assays and immunofluorescence.

Results: Fascin expression was found to be higher in the stromal cell, when compared to the cancer cell, compartment of ovarian tumors. The low expression of fascin in the cancer cells of the primary tumor indicated a favorable prognosis for non-serous OvCa patients. In vitro, both knockdown and pharmacologic inhibition of fascin decreased the migration of cancer and stromal cells. The inhibition of fascin impaired Cdc42 and Rac1 activity in cancer cells, and cytoskeletal reorganization in the cancer and stromal cells. Inhibition of fascin ex vivo blocked OvCa cell colonization of human omental tissue and in vivo prevented and reduced OvCa metastases in mice. Likewise, knockdown of fascin specifically in the OvCa cells using a fascin-specific lentiviral-shRNA also blocked metastasis in vivo.

Conclusion: This study reveals the therapeutic potential of pharmacologically inhibiting fascin in both cancer and stromal cells of the OvCa tumor microenvironment.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486884PMC
May 2019

The effect of resistance training on health-related quality of life in older adults: Systematic review and meta-analysis.

Health Promot Perspect 2019 23;9(1):1-12. Epub 2019 Jan 23.

Health Promotion Program, Montana State University - Northern, Havre, MT 59501, USA.

Resistance training (RT) is recommended as part of our national physical activity guidelines which includes working all major muscle groups on two or more days a week.Older adults can gain many health benefits from RT, such as increased muscle strength,increased muscle mass, and maintenance of bone density. Additionally, certain dimensions of health-related quality of life (HRQOL) have been shown to improve in older adults due to RT intervention. The purpose of this study was to use systematic review and meta-analytic techniques to examine the effect of RT on HRQOL in older adults. A systematic review of current studies (2008 thru 2017) was conducted using PubMed. Studies were included if they used a randomized controlled design, had RT as an intervention, measured HRQOL using the SF-36/12 assessment, and included adults 50+ years of age. Eight dimension scores (physical functioning, bodily pain, physical role function, general health, mental health, emotional role function, social function, and vitality) and two summary scores (physical component and mental component) were extracted. Ten meta-analyses were performed using standardized mean effect sizes and random effects models. Study quality,moderator and sensitivity analyses were conducted. A total of 16 studies were included in the analyses with a mean Physiotherapy Evidence Database (PEDro) score of 4.9 (SD=1.0). Among the mental health measures, RT had the greatest effect on mental health (Effect size [ES]=0.64, 95% CI: 0.30-0.99, I=79.7). Among the physical health measures, RT had the largest effect on body pain (ES=0.81, 95% CI: 0.26-1.35, I=85.9).Initially, RT did not significantly affect measures of emotional role function, social function or physical role function. However, after removing a single study, RT significantly increased all HRQOL measures. The meta-analytic evidence presented in this research clearly supports the promotion of RT in improving HRQOL in older adults.
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http://dx.doi.org/10.15171/hpp.2019.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377696PMC
January 2019

SPHK1 Is a Novel Target of Metformin in Ovarian Cancer.

Mol Cancer Res 2019 04 17;17(4):870-881. Epub 2019 Jan 17.

Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois.

The role of phospholipid signaling in ovarian cancer is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion, and stem-like phenotypes in ovarian cancer cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of ovarian cancer, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anticancer effects. Here, we found that ovarian cancer patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when ovarian cancer cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, ovarian cancer cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin, whereas ovarian cancer cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote ovarian cancer progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin. IMPLICATIONS: Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation, and self-renewal.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445689PMC
April 2019

PROTRACTED ACUTE HYPERVOLEMIC HYPERNATREMIA UNMASKED AFTER VASOPRESSIN THERAPY: CASE REPORT, LITERATURE REVIEW, AND PROPOSED ALGORITHMIC APPROACH.

AACE Clin Case Rep 2019 Mar-Apr;5(2):e95-e98. Epub 2018 Oct 5.

Objective: Acute hypervolemic hypernatremia (HHN) is the most common form of hypernatremia in critical care settings. Previous reports implicated acute kidney injury and vasopressin withdrawal-induced central diabetes insipidus.

Methods: We present the case of a 52-year-old woman who developed HHN after treatment of septic shock due to complicated bowel perforation.

Results: After discontinuation of a 30-hour infusion of vasopressin analog, the patient manifested hypernatremia (150 to 156 mEq/L, equivalent to mmol/L) with hyponatriuria (49 mEq/L), hypoosmotic urine (163 mOsm/L), and polyuria (6.9 L/day) in a setting of cumulative positive fluid balance of 20.1 L. A trial of desmopressin yielded incomplete urinary concentration suggestive of renal resistance to desmopressin likely due to fluid overload. Despite positive water balance, her urine sodium was low at 36 to 49 mEq/L compared to serum sodium of 152 to 156 mEq/L. The hypernatremia with polyuria persisted for 16 days and resolved after treatment of the positive cumulative water balance (with controlled diuresis prioritizing natriuresis).

Conclusion: HHN may result in insufficient urine sodium clearance. We propose modifying the diagnostic/treatment algorithm by including HHN in a critical care setting, and recommending judicious administration of a loop diuretic to prioritize natriuria in hypernatremia with extreme cumulative fluid overload.
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http://dx.doi.org/10.4158/ACCR-2018-0363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873852PMC
October 2018

Peptiduria: a potential early predictor of diabetic kidney disease.

Clin Exp Nephrol 2019 Jan 31;23(1):56-64. Epub 2018 Jul 31.

Division of Nephrology, John H. Stroger, Jr. Hospital of Cook County (JSH), 1900 West Polk Street, Suite 643, Chicago, IL, 60612, USA.

Background: To protect the kidney effectively with medication in type 2 diabetics, it is crucial to identify such at-risk patients early for treatment. We investigated whether peptiduria precedes proteinuria (the earliest urinary marker in our model), and thereby serve as an early predictor of diabetic nephropathy.

Methods: A longitudinal study was performed in a rat model of diabetic nephropathy. Peptides, defined as degradation products of proteins of < 13 kD size, were quantified by a previously validated method using a combination of Lowry and Biorad protein assays. Peptides in urine were also confirmed by chromatographically separating low molecular weight fractions from urine and quantifying albumin fragments in these fractions by enzyme immunoassay. Also, the mechanism of peptiduria was addressed by measuring acid phosphatase, a marker of lysosomal activity, in urine and on kidney sections (histochemically).

Results: In rats with diabetic nephropathy, proteinuria occurred after 12 weeks of diabetes, while peptiduria occurred as early as 2 weeks after diabetes. Peptiduria was confirmed by showing that the chromatographically separated low molecular weight fractions of urine containing albumin fragments is in proportion to the level of peptiduria. The time course of peptiduria paralleled the increase in urinary acid phosphatase suggesting that the mechanism of early peptiduria could be due to upregulation of lysosomal enzyme activity in the tubules.

Conclusions: Our results showing that peptiduria precedes proteinuria in diabetic nephropathy provide a compelling rationale to perform a prospective human clinical trial to investigate whether peptiduria can serve as an early predictor of diabetic nephropathy.
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http://dx.doi.org/10.1007/s10157-018-1620-0DOI Listing
January 2019

A polymeric immunoglobulin-antigen fusion protein strategy for enhancing vaccine immunogenicity.

Plant Biotechnol J 2018 12 21;16(12):1983-1996. Epub 2018 Jul 21.

Institute for Infection and Immunity, St. George's University of London, London, UK.

In this study, a strategy based on polymeric immunoglobulin G scaffolds (PIGS) was used to produce a vaccine candidate for Mycobacterium tuberculosis. A genetic fusion construct comprising genes encoding the mycobacterial Ag85B antigen, an immunoglobulin γ-chain fragment and the tailpiece from immunoglobulin μ chain was engineered. Expression was attempted in Chinese Hamster Ovary (CHO) cells and in Nicotiana benthamiana. The recombinant protein assembled into polymeric structures (TB-PIGS) in N. benthamiana, similar in size to polymeric IgM. These complexes were subsequently shown to bind to the complement protein C1q and FcγRs with increased affinity. Modification of the N-glycans linked to TB-PIGS by removal of xylose and fucose residues that are normally found in plant glycosylated proteins also resulted in increased affinity for low-affinity FcγRs. Immunization studies in mice indicated that TB-PIGS are highly immunogenic with and without adjuvant. However, they did not improve protective efficacy in mice against challenge with M. tuberculosis compared to conventional vaccination with BCG, suggesting that additional or alternative antigens may be needed to protect against this disease. Nevertheless, these results establish a novel platform for producing polymeric antigen-IgG γ-chain molecules with inherent functional characteristics that are desirable in vaccines.
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http://dx.doi.org/10.1111/pbi.12932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230950PMC
December 2018