Publications by authors named "John Edwards"

534 Publications

Improving uptake of Fracture Prevention drug treatments: a protocol for Development of a consultation intervention (iFraP-D).

BMJ Open 2021 08 18;11(8):e048811. Epub 2021 Aug 18.

School of Medicine, Keele University, Keele, UK.

Introduction: Prevention of fragility fractures, a source of significant economic and personal burden, is hindered by poor uptake of fracture prevention medicines. Enhancing communication of scientific evidence and elicitation of patient medication-related beliefs has the potential to increase patient commitment to treatment. The mproving uptake of cture revention drug treatments (iFraP) programme aims to develop and evaluate a theoretically informed, complex intervention consisting of a computerised web-based decision support tool, training package and information resources, to facilitate informed decision-making about fracture prevention treatment, with a long-term aim of improving informed treatment adherence. This protocol focuses on the iFraP evelopment (iFraP-D) work.

Methods And Analysis: The approach to iFraP-D is informed by the Medical Research Council complex intervention development and evaluation framework and the three-step implementation of change model. The context for the study is UK fracture liaison services (FLS), which enact secondary fracture prevention. An evidence synthesis of clinical guidelines and Delphi exercise will be conducted to identify content for the intervention. Focus groups with patients, FLS clinicians and general practitioners and a usual care survey will facilitate understanding of current practice, and investigate barriers and facilitators to change. Design of the iFraP intervention will be informed by decision aid development standards and theories of implementation, behaviour change, acceptability and medicines adherence. The principles of co-design will underpin all elements of the study through a dedicated iFraP community of practice including key stakeholders and patient advisory groups. In-practice testing of the prototype intervention will inform revisions ready for further testing in a subsequent pilot and feasibility randomised trial.

Ethics And Dissemination: Ethical approval was obtained from North West-Greater Manchester West Research Ethics Committee (19/NW/0559). Dissemination and knowledge mobilisation will be facilitated through national bodies and networks, publications and presentations.

Trial Registration Number: researchregistry5041.
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http://dx.doi.org/10.1136/bmjopen-2021-048811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375717PMC
August 2021

A mixed methods study of stakeholders' practices and attitudes on avian influenza H7N9 vaccination for the yellow broiler industry in Guangxi, China.

Transbound Emerg Dis 2021 Aug 11. Epub 2021 Aug 11.

School of Veterinary Medicine, Murdoch University, Perth, Australia.

In response to a sudden increase in H7N9 human infections, China introduced an H5/H7 bivalent inactivated vaccine for poultry in Guangxi and Guangdong provinces in July 2017, which subsequently became integrated into the existing compulsory national H5N1 vaccination programme from September 2017. Although the vaccination programme effectively reduced H7N9 infections in humans and poultry, there are ongoing arguments against continuing this long-term vaccination. These discussions have drawn policymakers to think about the possibility of stopping routine vaccination for H7N9 avian influenza viruses (AIVs) in China; however, they have not considered the poultry industry stakeholders' practices on and attitudes towards this vaccination. This study investigated H7N9 vaccination practices in the yellow broiler industry in Guangxi and stakeholders' attitudes on H7N9 vaccination, using a mixed methods design. The study found H7N9 vaccination was well adopted in the yellow broiler industry in Guangxi regardless of the source of the vaccines. Most stakeholders believed vaccination was the best measure to control H7N9 and H5N1 AIVs, and they showed a strong willingness to continue with vaccination even without government subsidies or freely provided vaccines. The motivations by stakeholders for using vaccines to control H7N9 and H5N1 were different due to the epidemiological differences between the two strains. Understanding poultry industry stakeholders' practices and attitudes on H7N9 vaccination has important practical implications in planning vaccination policies, particularly when considering the possibility of vaccination withdrawal.
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http://dx.doi.org/10.1111/tbed.14286DOI Listing
August 2021

Impact on quality of life from multimodality treatment for lung cancer: a randomised controlled feasibility trial of surgery versus no surgery as part of multimodality treatment in potentially resectable stage III-N2 NSCLC (the PIONEER trial).

BMJ Open Respir Res 2021 Jul;8(1)

Lung Cancer & Thoracic Surgery Directorate, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Introduction: Optimal treatment for 'potentially resectable' stage III-N2 non-small cell lung cancer (NSCLC) requires multimodality treatment: local treatment (surgery or radiotherapy) and systemic anticancer therapy. There is no clear evidence of superiority for survival between the two approaches and little research has explored quality of life (QOL). This study will inform the design of a phase III randomised trial of surgery versus no surgery as part of multimodality treatment for stage III-N2 NSCLC with QOL as a primary outcome.

Methods And Analysis: Patient participants will be randomised to receive multimodality treatment (1) with surgery OR (2) without surgery. The Quintet Recruitment Intervention will be used to maximise recruitment. Eligible patients will have 'potentially resectable' N2 NSCLC and have received a multidisciplinary team recommendation for multimodality treatment. Sixty-six patients and their carers will be recruited from 8 UK centres. Patient/carer QOL questionnaires will be administered at baseline, weeks 6, 9, 12 and month 6. Semistructured interviews will be conducted. Quantitative data will be analysed descriptively and qualitative data will be analysed using framework analysis.

Ethics And Dissemination: Ethical approval has been obtained. Results will be disseminated via publications, national bodies and networks, and patient and public involvement groups.

Trial Registration: NCT04540757.
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http://dx.doi.org/10.1136/bmjresp-2020-000846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286764PMC
July 2021

Determining subpopulation methylation profiles from bisulfite sequencing data of heterogeneous samples using DXM.

Nucleic Acids Res 2021 Sep;49(16):e93

Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Epigenetic changes, such as aberrant DNA methylation, contribute to cancer clonal expansion and disease progression. However, identifying subpopulation-level changes in a heterogeneous sample remains challenging. Thus, we have developed a computational approach, DXM, to deconvolve the methylation profiles of major allelic subpopulations from the bisulfite sequencing data of a heterogeneous sample. DXM does not require prior knowledge of the number of subpopulations or types of cells to expect. We benchmark DXM's performance and demonstrate improvement over existing methods. We further experimentally validate DXM predicted allelic subpopulation-methylation profiles in four Diffuse Large B-Cell Lymphomas (DLBCLs). Lastly, as proof-of-concept, we apply DXM to a cohort of 31 DLBCLs and relate allelic subpopulation methylation profiles to relapse. We thus demonstrate that DXM can robustly find allelic subpopulation methylation profiles that may contribute to disease progression using bisulfite sequencing data of any heterogeneous sample.
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http://dx.doi.org/10.1093/nar/gkab516DOI Listing
September 2021

Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia.

J Clin Oncol 2021 Jun 22:JCO2001739. Epub 2021 Jun 22.

Cellerant Therapeutics, San Carlos, CA.

Purpose: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.

Patients And Methods: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.

Results: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 3.90; = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% 47.5%; = .09), reaching a statistically significant difference from d15 to d28 (6.8% 27.9%; = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% 63.9%; = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% 63.9%; = .02) and d15-d28 (42.4% 62.3%; = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 28.7; = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.

Conclusion: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.
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http://dx.doi.org/10.1200/JCO.20.01739DOI Listing
June 2021

Cardiometabolic Safety of Lumateperone (ITI-007): Post Hoc Analyses of Short-Term Randomized Trials and an Open-Label Long-Term Study in Schizophrenia.

CNS Spectr 2021 04;26(2):152

The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; and Charité Universitat Medizin, Department of Child and Adolescent Psychiatry, Berlin, Germany.

Study Objective: Current treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI-007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated.

Method: The incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg.

Results: In the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%).

Conclusions: In this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile.

Funding: Intra-Cellular Therapies, Inc.
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http://dx.doi.org/10.1017/S1092852920002436DOI Listing
April 2021

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

J Thorac Oncol 2021 Jun 9. Epub 2021 Jun 9.

Cancer Research UK Beatson Institute, Glasgow, United Kingdom.

Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.

Methods: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.

Results: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.

Conclusions: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.
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http://dx.doi.org/10.1016/j.jtho.2021.05.018DOI Listing
June 2021

Association of Circulating Sex Hormones With Inflammation and Disease Severity in Patients With COVID-19.

JAMA Netw Open 2021 05 3;4(5):e2111398. Epub 2021 May 3.

Cardiovascular Division, Washington University School of Medicine in St Louis, Missouri.

Importance: Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition.

Objective: To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity.

Design, Setting, And Participants: This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs).

Exposures: Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized).

Main Outcomes And Measures: Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways.

Results: Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63 [16] years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (β = -0.43; 95% CI, -0.52 to -0.17; P < .001), C-reactive protein (β = -0.38; 95% CI, -0.78 to -0.16; P = .004), interleukin 1 receptor antagonist (β = -0.29; 95% CI, -0.64 to -0.06; P = .02), hepatocyte growth factor (β = -0.46; 95% CI, -0.69 to -0.25; P < .001), and interferon γ-inducible protein 10 (β = -0.32; 95% CI, -0.62 to -0.10; P = .007). Estradiol and IGF-1 concentrations were not associated with COVID-19 severity in men. Testosterone, estradiol, and IGF-1 concentrations were similar in women with and without severe COVID-19. Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16- (ie, classical) monocytes and CD14-CD16+ (ie, nonclassical) monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not.

Conclusions And Relevance: In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men. Hormone signaling pathways in monocytes did not parallel serum hormone concentrations, and further investigation is required to understand their pathophysiologic association with COVID-19.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.11398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150664PMC
May 2021

Epigenomic regulation of human T-cell leukemia virus by chromatin-insulator CTCF.

PLoS Pathog 2021 05 21;17(5):e1009577. Epub 2021 May 21.

Department of Medicine, Washington University School of Medicine, St Louis, Missouri, United States of America.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes an aggressive T-cell malignancy and a variety of inflammatory conditions. The integrated provirus includes a single binding site for the epigenomic insulator, CCCTC-binding protein (CTCF), but its function remains unclear. In the current study, a mutant virus was examined that eliminates the CTCF-binding site. The mutation did not disrupt the kinetics and levels of virus gene expression, or establishment of or reactivation from latency. However, the mutation disrupted the epigenetic barrier function, resulting in enhanced DNA CpG methylation downstream of the CTCF binding site on both strands of the integrated provirus and H3K4Me3, H3K36Me3, and H3K27Me3 chromatin modifications both up- and downstream of the site. A majority of clonal cell lines infected with wild type HTLV-1 exhibited increased plus strand gene expression with CTCF knockdown, while expression in mutant HTLV-1 clonal lines was unaffected. These findings indicate that CTCF binding regulates HTLV-1 gene expression, DNA and histone methylation in an integration site dependent fashion.
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http://dx.doi.org/10.1371/journal.ppat.1009577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174705PMC
May 2021

COVID-19 and the multidisciplinary care of patients with lung cancer: an evidence-based review and commentary.

Br J Cancer 2021 08 10;125(5):629-640. Epub 2021 May 10.

Lungs For Living Research Centre, University College London and Department of Thoracic Medicine, University College London Hospital, London, UK.

Delivering lung cancer care during the COVID-19 pandemic has posed significant and ongoing challenges. There is a lack of published COVID-19 and lung cancer evidence-based reviews, including for the whole patient pathway. We searched for COVID-19 and lung cancer publications and brought together a multidisciplinary group of stakeholders to review and comment on the evidence and challenges. A rapid review of the literature was undertaken up to 28 October 2020, producing 144 papers, with 113 full texts screened. We focused on new primary data collection (qualitative or quantitative evidence) and excluded case reports, editorials and commentaries. Following exclusions, 15 published papers were included in the review and are summarised. They included one qualitative paper and 14 quantitative studies (surveys or cohort studies), with a total of 2295 lung cancer patients data included (mean study size 153 patients; range 7-803). Review of current evidence and commentary included awareness and help-seeking; lung cancer screening; primary care assessment and referral; diagnosis and treatment in secondary care, including oncology and surgery; patient experience and palliative care. Cross-cutting themes and challenges were identified using qualitative methods for patients, healthcare professionals and service delivery, with a clear need for continued studies to guide evidence-based decision-making.
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http://dx.doi.org/10.1038/s41416-021-01361-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108433PMC
August 2021

Selective sweep for an enhancer involucrin allele identifies skin barrier adaptation out of Africa.

Nat Commun 2021 05 7;12(1):2557. Epub 2021 May 7.

Division of Dermatology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA.

The genetic modules that contribute to human evolution are poorly understood. Here we investigate positive selection in the Epidermal Differentiation Complex locus for skin barrier adaptation in diverse HapMap human populations (CEU, JPT/CHB, and YRI). Using Composite of Multiple Signals and iSAFE, we identify selective sweeps for LCE1A-SMCP and involucrin (IVL) haplotypes associated with human migration out-of-Africa, reaching near fixation in European populations. CEU-IVL is associated with increased IVL expression and a known epidermis-specific enhancer. CRISPR/Cas9 deletion of the orthologous mouse enhancer in vivo reveals a functional requirement for the enhancer to regulate Ivl expression in cis. Reporter assays confirm increased regulatory and additive enhancer effects of CEU-specific polymorphisms identified at predicted IRF1 and NFIC binding sites in the IVL enhancer (rs4845327) and its promoter (rs1854779). Together, our results identify a selective sweep for a cis regulatory module for CEU-IVL, highlighting human skin barrier evolution for increased IVL expression out-of-Africa.
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http://dx.doi.org/10.1038/s41467-021-22821-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105351PMC
May 2021

Lignite, thermally-modified and Ca/Mg-modified lignite for phosphate remediation.

Sci Total Environ 2021 Jun 5;773:145631. Epub 2021 Feb 5.

Department of Chemistry, Mississippi State University, Mississippi State, MS, USA. Electronic address:

Aqueous phosphate uptake is needed to reduce global eutrophication. Negatively charged adsorbent surfaces usually give poor phosphate sorption. Chemically- and thermally-modified lignite (CTL) was prepared by impregnating low-cost lignite (RL) with Ca and Mg cations, basified with KOH (pH ̴ 13.9), followed by a 1 h 600 °C pyrolysis under nitrogen. CTL has a positive surface (PZC = 13) due to basic surface Ca and Mg compounds, facilitating the aqueous phosphate uptake. CaCO, MgO, Ca(OH), and Mg(OH) surface phases with 0.22 μm particle sizes were verified by XRD, XPS, SEM, TEM, and EDX before and after phosphate uptake. Higher amounts of these mineral phases promoted more CTL phosphate uptake than raw lignite (RL) and thermally treated lignite (TL) without Ca/Mg modification. Phosphorous uptake by Ca/Mg occurs not by classic adsorption but by stochiometric precipitation of Mg(PO), MgHPO, Ca(PO), and CaHPO. This offers the potential of substantial uptake capacities. CTL's phosphate removal is pH-dependent; the optimum pH was 2.2. Water-washed CTL exhibited a maximum Langmuir phosphate uptake capacity of 15.5 mg/g at pH 7, 6 and 14 times higher than that of TL and RL, respectively (particle size <150 μm, adsorbent dose 50 mg, 25 mL of 25-1000 ppm phosphate concentration, 24 h, 25 °C). The unwashed CTL exhibited a maximum Langmuir phosphate removal capacity (80.6 mg/g), 5.2-times greater than the washed CTL (15.5 mg/g). Insoluble Ca and Mg phosphates/hydrophosphate particles dominated CTL's phosphate removal. Phosphates were recovered from both exhausted unwashed and washed CTL better in HCl than in NaOH. P-laden washed CTL exhibited a slow phosphate leaching rate under initial pH of 6.5-7.5 (52-57% over 20 days) after phosphate uptake, indicating it could serve as a slow-release fertilizer. Unwashed CTL retained more phosphates than washed CTL (cumulative q for 4 cycles = 391.8 mg/g vs 374.7 mg/g) and potentially improves soil fertility more.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145631DOI Listing
June 2021

LIMS1 Risk Genotype and T-Cell Mediated Rejection in Kidney Transplant Recipients.

Nephrol Dial Transplant 2021 Apr 28. Epub 2021 Apr 28.

Division of Nephrology, Saint Louis University, Saint Louis, MO, USA.

Background: This study aims to examine the association of LIM Zinc Finger Domain Containing 1 (LIMS1) genotype with allograft rejection in an independent kidney transplant cohort.

Methods: We genotyped 841 kidney transplant recipients for LIMS1 rs893403 variant by Sanger sequencing followed by PCR confirmation of the deletion. Recipients who were homozygous for LIMS1 rs893403 genotype GG were compared to AA/AG genotypes. The primary outcome was T-cell mediated (TCMR) or antibody mediated rejection (ABMR) and secondary outcome was allograft loss.

Results: After a median follow-up of 11.4 years, the rate of TCMR was higher in recipients with the GG (n = 200) compared to AA/AG (n = 641) genotypes [25 (12.5%) vs 35 (5.5%); p = 0.001] while ABMR did not differ by genotype [18 (9.0%) vs 62 (9.7%)]. Recipients with GG genotype had 2.4-times higher risk of TCMR than those who did not have this genotype (adjusted hazard ratio (aHR), 1.442.434.12, p = 0.001). A total of 189 (22.5%) recipients lost their allografts during follow up. Kaplan-Meier estimates of 5-year (94.3% vs. 94.4%, p = 0.99) and 10-year graft survival rates (86.9% vs. 83.4%, p = 0.31) did not differ significantly in those with GG compared to AA/AG groups.

Conclusions: Our study demonstrates that recipient LIMS1 risk genotype is associated with increased risk of TCMR after kidney transplantation, confirming the role of LIMS1 locus in allograft rejection. These findings may have clinical implications for the prediction and clinical management of kidney transplant rejection by pretransplant genetic testing of recipients and donors for LIMS1 risk genotype.
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http://dx.doi.org/10.1093/ndt/gfab168DOI Listing
April 2021

Value chain analysis of yellow broiler industry in Guangxi, China to inform H7N9 influenza control strategies.

Prev Vet Med 2021 May 17;190:105328. Epub 2021 Mar 17.

China Animal Health and Epidemiology Center, Qingdao, China; School of Veterinary Medicine, Murdoch University, Perth, Australia. Electronic address:

Yellow broilers are the primary source of poultry consumption in China and the predominant trade of live poultry. However, knowledge of the value chain is limited, which is vital evidence for the effective control of H7N9 and other zoonotic avian influenzas. The aim of the study was to map the yellow broiler value chain in Guangxi Zhuang Autonomous Region, China and investigate its governance structure and practices relevant to the risk of H7N9 transmission. A value chain analysis was conducted in five areas of Guangxi from May to August 2018. To map the value chain, three focus group discussions (FGDs) were conducted and stakeholders, products and premises involved and their interactions were identified. Then, 55 key informant interviews (KIIs) collected qualitative data on stakeholders' profile, practices and interactions with other stakeholders and rules/norms that exist along the value chain. On-site observations were also carried out at different types of premises along the value chain to complement and validate findings of KIIs and FGDs. Participants were also asked to provide proportional estimates of each component in the value chain where possible. The qualitative data from FGDs, KIIs and on-site observations were analysed to create stakeholder profiles and a diagram of product flows and stakeholders' interactions. Thematic analysis was used to identify the governance structure of the value chains and practices relevant to the risk of H7N9 transmission. The stakeholders and premises involved in Guangxi yellow broiler production, wholesale and retail were described, as well as their interactions. Contract farming is extensively adopted in Guangxi; consequently yellow broiler grower companies are the dominant stakeholders. The trading platform was identified as a key premise linking farms and live bird markets. The thematic analysis highlighted poor biosecurity practices in different premises along the value chain, which was supported by on-site observations. The operation of trading platforms reported in this study presents a disease risk but is not considered in the current H7N9 control programs. The study suggested that biosecurity management gaps need to be addressed through government-industry partnerships that require engagement with private stakeholders in the planning and implementation of H7N9 control strategies incentivising participation of grower companies, wholesalers and retailers.
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http://dx.doi.org/10.1016/j.prevetmed.2021.105328DOI Listing
May 2021

Developing a model Fracture Liaison Service consultation with patients, carers and clinicians: a Delphi survey to inform content of the iFraP complex consultation intervention.

Arch Osteoporos 2021 03 24;16(1):58. Epub 2021 Mar 24.

School of Medicine, Keele University, Newcastle, Staffordshire, UK.

Fracture Liaison Services are recommended to deliver best practice in secondary fracture prevention. This modified Delphi survey, as part of the iFraP (Improving uptake of Fracture Prevention drug Treatments) study, provides consensus regarding tasks for clinicians in a model Fracture Liaison Service consultation.

Purpose: The clinical consultation is of pivotal importance in addressing barriers to treatment adherence. The aim of this study was to agree to the content of the 'model Fracture Liaison Service (FLS) consultation' within the iFraP (Improving uptake of Fracture Prevention drug Treatments) study.

Methods: A Delphi survey was co-designed with patients and clinical stakeholders using an evidence synthesis of current guidelines and content from frameworks and theories of shared decision-making, communication and medicine adherence. Patients with osteoporosis and/or fragility fractures, their carers, FLS clinicians and osteoporosis specialists were sent three rounds of the Delphi survey. Participants were presented with potential consultation content and asked to rate their perception of the importance of each statement on a 5-point Likert scale and to suggest new statements (Round 1). Lowest rated statements were removed or amended after Rounds 1 and 2. In Round 3, participants were asked whether each statement was 'essential' and percentage agreement calculated; the study team subsequently determined the threshold for essential content.

Results: Seventy-two, 49 and 52 patients, carers and clinicians responded to Rounds 1, 2 and 3 respectively. One hundred twenty-two statements were considered. By Round 3, consensus was reached, with 81 statements deemed essential within FLS consultations, relating to greeting/introductions; gathering information; considering therapeutic options; eliciting patient perceptions; establishing shared decision-making preferences; sharing information about osteoporosis and treatments; checking understanding/summarising; and signposting next steps.

Conclusions: This Delphi consensus exercise has summarised for the first time patient/carer and clinician consensus regarding clearly defined tasks for clinicians in a model FLS consultation.
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http://dx.doi.org/10.1007/s11657-021-00913-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989712PMC
March 2021

Development, spread and impact of primary care and musculoskeletal communities of practice to assist rapid translation of evidence into practice.

Musculoskeletal Care 2021 Mar 23. Epub 2021 Mar 23.

The Impact Accelerator Unit, The Medical School Keele University, Keele, UK.

Background: Embedding research into practice is challenging. Barriers include: a shortage of time, lack of understanding of the evidence and a poor support in the clinical setting. A community of practice (CoP) model has been used to address these issues. Three 'Evidence into Practice' groups use a CoP model to assist the rapid translation of evidence into practice in primary and secondary care settings. We describe how a CoP model supports the functions, operations and outputs of three 'Evidence into Practice Groups'.

Method: A CoP model is used to engage a broad range of clinicians, researchers, managers, patients and librarians in the complex process of acquiring research knowledge and then translating knowledge into practice. The CoP principles of Domain, Community and Practice are used to describe three 'Evidence into Practice Groups' who cater for different elements of the care and academic sector and engage a range of professional groups. This includes primary and secondary care engaging professionals such as general practitioners (GP), practice nurses, allied health professionals, researchers and librarians. All groups are clinically led, academically supported and follow similar processes to identify the best evidence and translate it into practice. As the groups reflect the context in which they work they have different operational arrangements for example frequency and time of meetings.

Results: The CoP model enabled three 'Evidence into Practice Groups' over time to: engage over 180 clinical and academic staff; answer 130 clinical questions; improve clinical care, gain funding for two randomised controlled trials (enrolled over n = 7000 participants) and identify areas for further research, quality improvement audit and training.

Conclusion: The CoP model encourages the rapid translation of evidence into practice by engaging staff to identify areas of clinical concern in their own context, thereby stimulating their interest and involvement. This creates a meaningful link between research and practice. Clinical leadership and the CoP model ensure that practice change is quick and efficient. This model can be replicated at scale. Consideration needs to be given to the key ingredients to achieve impact.
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http://dx.doi.org/10.1002/msc.1552DOI Listing
March 2021

Infection and risk factors of human and avian influenza in pigs in south China.

Prev Vet Med 2021 May 5;190:105317. Epub 2021 Mar 5.

School of Veterinary Medicine, Murdoch University, Perth, WA, Australia; China-Australia Joint Research and Training Centre for Veterinary Epidemiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China. Electronic address:

The coinfection of swine influenza (SI) strains and avian/human-source influenza strains in piggeries can contribute to the evolution of new influenza viruses with pandemic potential. This study analyzed surveillance data on SI in south China and explored the spatial predictor variables associated with different influenza infection scenarios in counties within the study area. Blood samples were collected from 7670 pigs from 534 pig farms from 2015 to 2017 and tested for evidence of infection with influenza strains from swine, human and avian sources. The herd prevalences for EA H1N1, H1N1pdm09, classic H1N1, HS-like H3N2, seasonal human H1N1 and avian influenza H9N2 were 88.5, 64.5, 60.3, 57.8, 12.9 and 10.3 %, respectively. Anthropogenic factors including detection frequency, chicken density, duck density, pig density and human population density were found to be better predictor variables for three influenza infection scenarios (infection with human strains, infection with avian strains, and coinfection with H9N2 avian strain and at least one swine strain) than were meteorological and geographical factors. Predictive risk maps generated for the four provinces in south China highlighted that the areas with a higher risk of the three infection scenarios were predominantly clustered in the delta area of the Pearl River in Guangdong province and counties surrounding Poyang Lake in Jiangxi province. Identification of higher risk areas can inform targeted surveillance for influenza in humans and pigs, helping public health authorities in designing risk-based SI control strategies to address the pandemic influenza threat in south China.
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http://dx.doi.org/10.1016/j.prevetmed.2021.105317DOI Listing
May 2021

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

Nat Commun 2021 02 26;12(1):1334. Epub 2021 Feb 26.

Dartmouth-Hitchcock Medical Center, Pediatric Hematology Oncology, Geisel School of Medicine, Lebanon, NH, USA.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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http://dx.doi.org/10.1038/s41467-021-21588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910481PMC
February 2021

Characterization of epididymal and testicular histologic lesions and use of immunohistochemistry and PCR on formalin-fixed tissues to detect in male dogs.

J Vet Diagn Invest 2021 Mar 19;33(2):352-356. Epub 2021 Jan 19.

Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX.

In male dogs, frequently causes epididymitis, ultimately resulting in testicular atrophy and infertility. Although predominantly affects the epididymis, the misleading term "orchitis" is still commonly used by clinicians. Of additional concern, diagnosis in dogs remains challenging because of variable sensitivity and specificity of serologic assays and fluctuations in bacteremia levels in infected dogs, reducing the sensitivity of blood culture. We describe here the histologic lesions in the scrotal contents of 8 dogs suspected of being infected with and clinically diagnosed with orchitis. We explored the possibility of using immunohistochemistry (IHC) and real-time PCR (rtPCR) in formalin-fixed, paraffin-embedded (FFPE) tissues to detect the presence of . Epididymitis of variable chronicity was identified in all 8 dogs, with only 3 also exhibiting orchitis. Using rtPCR, the presence of was identified in 4 of 8 dogs, with 3 of these 4 dogs also positive by IHC. These results suggest that rtPCR and IHC are promising techniques that can be used in FFPE tissues to detect when other detection techniques are unavailable. Additionally, accurate recognition of epididymitis rather than orchitis in suspect cases could aid in accurate diagnosis.
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http://dx.doi.org/10.1177/1040638720986883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953107PMC
March 2021

Mucoricin is a ricin-like toxin that is critical for the pathogenesis of mucormycosis.

Nat Microbiol 2021 03 18;6(3):313-326. Epub 2021 Jan 18.

Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, USA.

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We demonstrate that Mucorales fungi produce a toxin, which plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro and prevent hypovolemic shock, organ necrosis and death in mice with mucormycosis. Inhibition of the toxin in Rhizopus delemar through RNA interference compromises the ability of the fungus to damage host cells and attenuates virulence in mice. This 17 kDa toxin has structural and functional features of the plant toxin ricin, including the ability to inhibit protein synthesis through its N-glycosylase activity, the existence of a motif that mediates vascular leak and a lectin sequence. Antibodies against the toxin inhibit R. delemar- or toxin-mediated vascular permeability in vitro and cross react with ricin. A monoclonal anti-ricin B chain antibody binds to the toxin and also inhibits its ability to cause vascular permeability. Therefore, we propose the name 'mucoricin' for this toxin. Not only is mucoricin important in the pathogenesis of mucormycosis but our data suggest that a ricin-like toxin is produced by organisms beyond the plant and bacterial kingdoms. Importantly, mucoricin should be a promising therapeutic target.
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http://dx.doi.org/10.1038/s41564-020-00837-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914224PMC
March 2021

G6PD activity contributes to the regulation of histone acetylation and gene expression in smooth muscle cells and to the pathogenesis of vascular diseases.

Am J Physiol Heart Circ Physiol 2021 03 8;320(3):H999-H1016. Epub 2021 Jan 8.

Department of Pharmacology, New York Medical College, Valhalla, New York.

We aimed to determine ) the mechanism(s) that enables glucose-6-phosphate dehydrogenase (G6PD) to regulate serum response factor (SRF)- and myocardin (MYOCD)-driven smooth muscle cell (SMC)-restricted gene expression, a process that aids in the differentiation of SMCs, and ) whether G6PD-mediated metabolic reprogramming contributes to the pathogenesis of vascular diseases in metabolic syndrome (MetS). Inhibition of G6PD activity increased (>30%) expression of SMC-restricted genes and concurrently decreased (40%) the growth of human and rat SMCs ex vivo. Expression of SMC-restricted genes decreased (>100-fold) across successive passages in primary cultures of SMCs isolated from mouse aorta. G6PD inhibition increased (47%) while decreasing (>50%) , a stem cell marker, in cells passaged seven times. Similarly, CRISPR-Cas9-mediated expression of the loss-of-function Mediterranean variant of G6PD (S188F; G6PD) in rats promoted transcription of SMC-restricted genes. G6PD knockdown or inhibition decreased (48.5%) histone deacetylase HDAC) activity, enriched (by 3-fold) H3K27ac on the promoter, and increased and expression. Interestingly, G6PD activity was significantly higher in aortas from JCR rats with MetS than control Sprague-Dawley (SD) rats. Treating JCR rats with epiandrosterone (30 mg/kg/day), a G6PD inhibitor, increased expression of SMC-restricted genes, suppressed and , and reduced blood pressure. Moreover, feeding SD control (littermates) and G6PD rats a high-fat diet for 4 mo increased and expression and mean arterial pressure in SD but not G6PD rats. Our findings demonstrate that G6PD downregulates transcription of SMC-restricted genes through HDAC-dependent deacetylation and potentially augments the severity of vascular diseases associated with MetS. This study gives detailed mechanistic insight about the regulation of smooth muscle cell (SMC) phenotype by metabolic reprogramming and glucose-6-phosphate dehydrogenase (G6PD) in diabetes and metabolic syndrome. We demonstrate that G6PD controls the chromatin modifications by regulating histone deacetylase (HDAC) activity, which deacetylates histone 3-lysine 9 and 27. Notably, inhibition of G6PD decreases HDAC activity and enriches H3K27ac on myocardin gene promoter to enhance the expression of SMC-restricted genes. Also, we demonstrate for the first time that G6PD inhibitor treatment accentuates metabolic and transcriptomic reprogramming to reduce neointimal formation in coronary artery and large artery elastance in metabolic syndrome rats.
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http://dx.doi.org/10.1152/ajpheart.00488.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988761PMC
March 2021

Kidney-disease-associated variants of Apolipoprotein L1 show gain of function in cation channel activity.

J Biol Chem 2021 Jan-Jun;296:100238. Epub 2021 Jan 9.

Nephrology Division, Department of Internal Medicine, Saint Louis University, St Louis, Missouri, USA. Electronic address:

Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles.
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http://dx.doi.org/10.1074/jbc.RA120.013943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948812PMC
August 2021

Ex vivo comparison of ultrasonographic intestinal wall layering with histology in horses: A feasibilty study.

Vet Radiol Ultrasound 2021 May 27;62(3):316-330. Epub 2020 Dec 27.

Department of Clinical Studies, New Bolton Center, University of Pennsylvania, Kennett Square, Pennsylvania.

Ultrasonography is increasingly being used as a clinical and research method for evaluating the gastrointestinal tract in horses, however published studies comparing ultrasonographic and histologic characteristics of equine intestinal wall layers are currently lacking. Objectives of this prospective, observational, methods comparison, case series study were to compare the layering pattern and thickness of the intestinal wall layers determined using ex vivo and in vivo ultrasonography with those determined using histology. For the ex vivo study, twelve horses were euthanized for reasons unrelated to gastrointestinal disease, and samples of the duodenum, jejunum, ileum, cecum, right dorsal colon, and small colon were collected and imaged sonographically ex vivo in an isotonic bath within 1 hour of euthanasia. For the in vivo study, ultrasonography was performed in four clinical cases, and findings were compared with histopathology. A 5-layer pattern of alternating echogenicity was observed in 70 of 72 ex vivo samples. Agreement between histologic and sonographic measurements was deemed good for all segments except the ileum. Formalin fixation did not alter the sonographic appearance or wall measurements. Findings from the four clinical cases illustrated the feasibility of also obtaining ultrasonographic images with sufficient sonographic detail in vivo to recognize wall layering and obtain comparable results to pathologic lesions. Findings from the current study can serve as background for future studies comparing ultrasonographic characteristics of the intestinal wall in horses with different gastrointestinal diseases.
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http://dx.doi.org/10.1111/vru.12946DOI Listing
May 2021

An oxindole efflux inhibitor potentiates azoles and impairs virulence in the fungal pathogen Candida auris.

Nat Commun 2020 12 22;11(1):6429. Epub 2020 Dec 22.

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.

Candida auris is an emerging fungal pathogen that exhibits resistance to multiple drugs, including the most commonly prescribed antifungal, fluconazole. Here, we use a combinatorial screening approach to identify a bis-benzodioxolylindolinone (azoffluxin) that synergizes with fluconazole against C. auris. Azoffluxin enhances fluconazole activity through the inhibition of efflux pump Cdr1, thus increasing intracellular fluconazole levels. This activity is conserved across most C. auris clades, with the exception of clade III. Azoffluxin also inhibits efflux in highly azole-resistant strains of Candida albicans, another human fungal pathogen, increasing their susceptibility to fluconazole. Furthermore, azoffluxin enhances fluconazole activity in mice infected with C. auris, reducing fungal burden. Our findings suggest that pharmacologically targeting Cdr1 in combination with azoles may be an effective strategy to control infection caused by azole-resistant isolates of C. auris.
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http://dx.doi.org/10.1038/s41467-020-20183-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755909PMC
December 2020

Identification of Candida glabrata Transcriptional Regulators That Govern Stress Resistance and Virulence.

Infect Immun 2021 02 16;89(3). Epub 2021 Feb 16.

Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.

The mechanisms by which resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable to withstand these classes of stressors, a library of 215 transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified eight mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, six were deleted for genes that were predicted to specify proteins involved in histone modification. These genes were , , , , , and Deletion of , , and also increased susceptibility to mammalian host defense peptides. The Δ and Δ mutants had increased susceptibility to other stressors, such as HO and SDS. In the model of disseminated infection, the Δ and Δ mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the Δ and Δ mutants was decreased. Thus, histone modification plays a central role in enabling to survive host defense peptides and caspofungin, and Ada2 and Rpd3 are essential for the maximal virulence of this organism during disseminated infection.
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http://dx.doi.org/10.1128/IAI.00146-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097273PMC
February 2021

Nephrotic range proteinuria associated with focal segmental glomerulosclerosis reversed with pioglitazone therapy in a patient with Dunnigan type lipodystrophy.

Diabetes Res Clin Pract 2021 Feb 13;172:108620. Epub 2020 Dec 13.

Department of Internal Medicine, Division of Endocrinology, Diabetes & Metabolism, Saint Louis University School of Medicine, United States.

Familial partiallipodystrophy (FPLD)is a rare disorder associated withsevere insulin resistance, hypertriglyceridemia, lowserumHDLcholesterol and proteinuricrenaldisease. Although proteinuric renal disease is not common among in patients with partial lipodystrophy, we report a patient with Dunnigan type FPLD complicated by nephrotic syndrome which resolved following treatment with thePPARγagonist pioglitazone, CPAP, diet, and exercise.
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http://dx.doi.org/10.1016/j.diabres.2020.108620DOI Listing
February 2021

Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716.

Lung Cancer 2020 12 20;150:145-151. Epub 2020 Oct 20.

Sheffield Experimental Cancer Medicine Centre and Weston Park Cancer Centre, University of Sheffield, Weston Park Hospital, Sheffield, UK.

Objectives: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM.

Materials And Methods: Patients with MPM received 1 × 10iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response.

Results: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks.

Conclusions: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.007DOI Listing
December 2020
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