Publications by authors named "Patricia Castro"

117 Publications

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma: A multi-site validation study.

J Clin Invest 2021 Mar 2. Epub 2021 Mar 2.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, United States of America.

Background: p16 positive oropharyngeal squamous cell carcinoma (OPSCC) patients are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure in p16 positive OPSCC. Pathologist-based visual assessment of tumor cell multinucleation has been shown to be independently prognostic of disease-free survival in p16 positive OPSCC. However, its quantification is time-intensive, subjective, and at risk of interobserver variability.

Methods: We present a deep learning-based metric, the multi-nucleation index (MuNI), for prognostication in p16 positive OPSCC. This approach quantifies tumor multi-nucleation from digitally scanned hematoxylin eosin (H&E)-stained slides. Representative H&E whole slide images from 1,094 previously untreated p16 positive OPSCC patients were acquired from six institutions for optimizing and validating MuNI.

Results: MuNI was prognostic for disease-free (DFS), overall (OS), or distant metastasis-free (DMFS) survival in p16 positive OPSCC with HRs of 1.78(95%CI:1.37-2.30), 1.94(1.44-2.60), and 1.88(1.43-2.47), respectively, independent of age, smoking status, treatment type, and T/N-categories in multivariable analyses. It was also prognostic for DFS, OS, and DMFS in OPSCC patients at stages I and III.

Conclusion: MuNI holds promise as a low-cost, tissue non-destructive, H&E stain based digital biomarker test for counseling, treatment, and surveillance of p16 positive OPSCC patients. These data support further confirmation of MuNI in prospective trials.

Funding: This work was supported by the National Cancer Institute of the National Institutes of Health (under award numbers 1U24CA199374-01, R01CA202752-01A, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, 1U01CA239055-01), the National Institute for Biomedical Imaging and Bioengineering (1R43EB028736-01), the National Center for Research Resources (1C06RR12463-01), the VA Merit Review Award (IBX004121A) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DoD Breast Cancer Research Program Breakthrough Level 1 Award (W81XWH-19-1-0668), the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering, and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University, the Michael E. DeBakey VA Medical Center, an institutional pilot grant (1IK2CX001953) and Dan L Duncan Comprehensive Cancer Center Support Grant (NCI-CA125123). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government.
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http://dx.doi.org/10.1172/JCI145488DOI Listing
March 2021

An investigation of community-dwelling older adults' opinions about their nutritional needs and risk of malnutrition; a scoping review.

Clin Nutr 2020 Dec 23. Epub 2020 Dec 23.

School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin 4, Republic of Ireland; UCD Institute of Food and Health, University College Dublin, Dublin 4, Republic of Ireland. Electronic address:

Background & Aims: Understanding how older adults perceive their nutritional needs and malnutrition risk is important to inform strategies to improve prevention and management of the condition. This scoping review aimed to identify, characterize and summarize the findings from studies analysing community-dwelling older adults' opinions and perceptions towards their nutritional needs and malnutrition risk.

Methods: An electronic literature search was carried out using three databases, Pubmed, Embase, and CINAHL up to January 2020. Articles were reviewed following PRISMA guidelines.

Results: A total of 16,190 records were identified and reviewed with 15 studies being included, all of which were conducted in high income countries. Common conceptual categories that were identified included; older community-dwelling adults consider that a healthy diet for them is the same as that recommended for the general population, consisting of fruits, vegetables, reduced fat and reduced sugar. Weight loss was seen as a positive outcome and a normal component of the ageing process. Lack of appetite was identified by participants in the majority of studies as a barrier to food intake.

Conclusions: This review shows how older community-dwelling adults, with a high risk of malnutrition, follow dietary public health recommendations for the general population and have a greater awareness of the risks of overweight. The implementation of nutritional guidelines that consider the nutritional needs of all older adults and education of non-dietetic community healthcare professionals on providing appropriate nutritional advice to this population are warranted.
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http://dx.doi.org/10.1016/j.clnu.2020.12.024DOI Listing
December 2020

Genomic and phenotypic analysis of COVID-19-associated pulmonary aspergillosis isolates of .

bioRxiv 2020 Nov 6. Epub 2020 Nov 6.

The ongoing global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) first described from Wuhan, China. A subset of COVID-19 patients has been reported to have acquired secondary infections by microbial pathogens, such as fungal opportunistic pathogens from the genus . To gain insight into COVID-19 associated pulmonary aspergillosis (CAPA), we analyzed the genomes and characterized the phenotypic profiles of four CAPA isolates of obtained from patients treated in the area of North Rhine-Westphalia, Germany. By examining the mutational spectrum of single nucleotide polymorphisms, insertion-deletion polymorphisms, and copy number variants among 206 genes known to modulate virulence, we found that CAPA isolate genomes do not exhibit major differences from the genome of the Af293 reference strain. By examining virulence in an invertebrate moth model, growth in the presence of osmotic, cell wall, and oxidative stressors, and the minimum inhibitory concentration of antifungal drugs, we found that CAPA isolates were generally, but not always, similar to reference strains Af293 and CEA17. Notably, CAPA isolate D had more putative loss of function mutations in genes known to increase virulence when deleted (e.g., in the gene, which encodes a lectin recognized by macrophages). Moreover, CAPA isolate D was significantly more virulent than the other three CAPA isolates and the reference strains tested. These findings expand our understanding of the genomic and phenotypic characteristics of isolates that cause CAPA.
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http://dx.doi.org/10.1101/2020.11.06.371971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654854PMC
November 2020

Safety And Risk Factors For The Morbidity And Mortality Of Pneumonectomy: A Retrospective 10- Year Study In A Single Institution.

Rev Port Cir Cardiotorac Vasc 2020 Jul-Sep;27(3):203-208

Cardiothoracic Surgery Department, Centro Hospitalar de Vila Nova de Gaia/Espinho-EPE, Vila Nova de Gaia, Portugal; Faculty of Medicine of the University of Porto, Oporto, Portugal.

Objectives: Pneumonectomy is a procedure with high post-operative morbidity and mortality. This study aims to assess and identify possible risk factors that can affect post-operative outcome, therefore determining the safety of pneumonectomy in specific groups.

Methods: A total of 63 patients submitted to pneumonectomy at our centre, from February 2008 to February 2018, were included in our retrospective study. Age, gender, side of intervention, diagnosis, pre-operative symptoms, substance abuse and comorbidities were assessed. Early and late post-operative complications, as well as death were our major outcomes. We analysed the impact of preoperative variables on major outcomes using SPSS statistics.

Results: We found a 9,8% surgery-related mortality and 1-year survival rate of 76,2%. The incidence of early complications in our population was of 35% while eleven patients (17,4%) developed late post-operative complications. No statistical difference was found when comparing survival time between genders or age groups. Right sided pneumonectomies seem to be associated with an higher mortality risk. No other association between risk factors and outcomes reached statistical significance in both univariate and multivariate analysis.

Conclusions: Pneumonectomy is a viable option regardless of age whenever the patient has a good functional and cardiopulmonary status. Gender and diagnostic group do not seem to influence adverse event risk, although right-sided pneumonectomies show an increased risk for post-operative death. Care should be taken with patients submitted to neoadjuvant therapy. All patients should be encouraged to cease smoking as early as possible before surgery, given the increased risks for post-operative complications.
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December 2020

Aspergillus fumigatus G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence.

mBio 2020 10 13;11(5). Epub 2020 Oct 13.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

G-protein coupled receptors (GPCRs) are extracellular signaling receptors that sense environmental cues. Fungi sense their environment primarily through GPCR-mediated signaling pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. is an important human pathogen that causes aspergillosis, a heterogeneous group of diseases that present a wide range of clinical manifestations. Here, we investigate in detail the role of the GPCRs GprM and GprJ in growth and gene expression. GprM and GprJ are important for melanin production and the regulation of the cell wall integrity (CWI) pathway. Overexpression of and causes a 20 and 50% reduction in growth rate compared to the wild-type (WT) strain and increases sensitivity to cell wall-damaging agents. Phosphorylation of the CWI protein kinase MpkA is increased in the Δ and Δ strains and decreased in the overexpression mutants compared to the WT strain. Furthermore, differences in cell wall polysaccharide concentrations and organization were observed in these strains. Transcriptome sequencing suggests that GprM and GprJ negatively regulate genes encoding secondary metabolites (SMs). Mass spectrometry analysis confirmed that the production of fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, and fumitremorgin is reduced in the Δ and Δ strains, at least partially through the activation of MpkA. Overexpression of also resulted in the regulation of many transcription factors, with AsgA predicted to function downstream of GprM and MpkA signaling. Finally, we show that the Δ and Δ mutants are reduced in virulence in the insect model of invasive aspergillosis. is the main etiological agent of invasive pulmonary aspergillosis, a life-threatening fungal disease that occurs in severely immunocompromised humans. Withstanding the host environment is essential for virulence, and sensing of extracellular cues occurs primarily through G-protein coupled receptors (GPCRs) that activate signal transduction pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. The genome encodes 15 putative classical GPCRs, with only three having been functionally characterized to date. In this work, we show that the two GPCRs GprM and GprJ regulate the phosphorylation of the mitogen-activated protein kinase MpkA and thus control the regulation of the cell wall integrity pathway. GprM and GprJ are also involved in the regulation of the production of the secondary metabolites fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, melanin, and fumitremorgin, and this regulation partially occurs through the activation of MpkA. Furthermore, GprM and GprJ are important for virulence in the insect model This work therefore functionally characterizes two GPCRs and shows how they regulate several intracellular pathways that have been shown to be crucial for virulence.
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http://dx.doi.org/10.1128/mBio.02458-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554674PMC
October 2020

Dissociated motor learning and de-adaptation in patients with functional gait disorders.

Brain 2020 08;143(8):2594-2606

Department of Brain Sciences, Neuro-otology Unit, Imperial College London, London, UK.

Walking onto a stationary platform that had been previously experienced as moving generates a locomotor after-effect-the so-called 'broken escalator' phenomenon. The motor responses that occur during locomotor after-effects have been mapped theoretically using a hierarchal Bayesian model of brain function that takes into account current sensory information that is weighted according to prior contextually-relevant experiences; these in turn inform automatic motor responses. Here, we use the broken escalator phenomenon to explore motor learning in patients with functional gait disorders and probe whether abnormal postural mechanisms override ascending sensory information and conscious intention, leading to maladaptive and disabling gait abnormalities. Fourteen patients with functional gait disorders and 17 healthy control subjects walked onto a stationary sled ('Before' condition, five trials), then onto a moving sled ('Moving' condition, 10 trials) and then again onto the stationary sled ('After' condition, five trials). Subjects were warned of the change in conditions. Kinematic gait measures (trunk displacement, step timing, gait velocity), EMG responses, and subjective measures of state anxiety/instability were recorded per trial. Patients had slower gait velocities in the Before trials (P < 0.05) but were able to increase this to accommodate the moving sled, with similar learning curves to control subjects (P = 0.87). Although trunk and gait velocity locomotor after-effects were present in both groups, there was a persistence of the locomotor after-effect only in patients (P < 0.05). We observed an increase in gait velocity during After trials towards normal values in the patient group. Instability and state anxiety were greater in patients than controls (P < 0.05) only during explicit phases (Before/After) of the task. Mean 'final' gait termination EMG activity (right gastrocnemius) was greater in the patient group than controls. Despite a dysfunctional locomotor system, patients show normal adaptive learning. The process of de-adaptation, however, is prolonged in patients indicating a tendency to perpetuate learned motor programmes. The trend to normalization of gait velocity following a period of implicit motor learning has implications for gait rehabilitation potential in patients with functional gait disorders and related disorders (e.g. fear of falling).
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http://dx.doi.org/10.1093/brain/awaa190DOI Listing
August 2020

Erratum to "Mitogen activated protein kinases (MAPK) and protein phosphatases are involved in adhesion and biofilm formation" [Cell Surf. 1 (2018) 43-56].

Cell Surf 2020 Dec 23;6:100035. Epub 2020 Jan 23.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.

[This corrects the article DOI: 10.1016/j.tcsw.2018.03.002.].
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http://dx.doi.org/10.1016/j.tcsw.2020.100035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389343PMC
December 2020

The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence.

PLoS Pathog 2020 07 15;16(7):e1008645. Epub 2020 Jul 15.

Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirão Preto, Brazil.

Aspergillus fumigatus is an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), which contribute to enhancing fungal fitness and growth within the mammalian host. Gliotoxin (GT) is a SM that interferes with the function and recruitment of innate immune cells, which are essential for eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and self-protection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT, by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important for virulence in a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA). Homologues of RglT and GliT are present in eurotiomycete and sordariomycete fungi, including the non-GT-producing fungus A. nidulans, where a conservation of function was described. Phylogenetically informed model testing led to an evolutionary scenario in which the GliT-based resistance mechanism is ancestral and RglT-mediated regulation of GliT occurred subsequently. In conclusion, this work describes the function of a previously uncharacterised TF in oxidative stress resistance, GT biosynthesis and self-protection in both GT-producing and non-producing Aspergillus species.
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http://dx.doi.org/10.1371/journal.ppat.1008645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384679PMC
July 2020

Aspergillus fumigatus Transcription Factors Involved in the Caspofungin Paradoxical Effect.

mBio 2020 06 16;11(3). Epub 2020 Jun 16.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Ribeirão Preto, Ribeirão Preto, Brazil

is the leading cause of pulmonary fungal diseases. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, in the last 10 years there have been several reports of azole resistance in and new strategies are needed to combat invasive aspergillosis. Caspofungin is effective against other human-pathogenic fungal species, but it is fungistatic only against Resistance to caspofungin in has been linked to mutations in the gene that encodes the target enzyme of the drug β-1,3-glucan synthase. However, tolerance of high caspofungin concentrations, a phenomenon known as the aspofungin aradoxical ffect (CPE), is also important for subsequent adaptation and drug resistance evolution. Here, we identified and characterized the transcription factors involved in the response to CPE by screening an library of 484 null transcription factors (TFs) in CPE drug concentrations. We identified 11 TFs that had reduced CPE and that encoded proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism, and cell wall remodeling. One of these TFs, FhdA, was important for mitochondrial respiratory function and iron metabolism. The Δ mutant showed decreased growth when exposed to Congo red or to high temperature. Transcriptome sequencing (RNA-seq) analysis and further experimental validation indicated that the Δ mutant showed diminished respiratory capacity, probably affecting several pathways related to the caspofungin tolerance and resistance. Our results provide the foundation to understand signaling pathways that are important for caspofungin tolerance and resistance., one of the most important human-pathogenic fungal species, is able to cause aspergillosis, a heterogeneous group of diseases that presents a wide range of clinical manifestations. Invasive pulmonary aspergillosis is the most serious pathology in terms of patient outcome and treatment, with a high mortality rate ranging from 50% to 95% primarily affecting immunocompromised patients. Azoles have been used for many years as the main antifungal agents to treat and prevent invasive aspergillosis. However, there were several reports of evolution of clinical azole resistance in the last decade. Caspofungin, a noncompetitive β-1,3-glucan synthase inhibitor, has been used against , but it is fungistatic and is recommended as second-line therapy for invasive aspergillosis. More information about caspofungin tolerance and resistance is necessary in order to refine antifungal strategies that target the fungal cell wall. Here, we screened a transcription factor (TF) deletion library for TFs that can mediate caspofungin tolerance and resistance. We have identified 11 TFs that are important for caspofungin sensitivity and/or for the aspofungin aradoxical ffect (CPE). These TFs encode proteins involved in the basal modulation of the RNA polymerase II initiation sites, calcium metabolism or cell wall remodeling, and mitochondrial respiratory function. The study of those genes regulated by TFs identified in this work will provide a better understanding of the signaling pathways that are important for caspofungin tolerance and resistance.
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http://dx.doi.org/10.1128/mBio.00816-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298710PMC
June 2020

Evaluation of the immune response to hepatitis B vaccine in patients on biological therapy: results of the RIER cohort study.

Clin Rheumatol 2020 Sep 4;39(9):2751-2756. Epub 2020 Apr 4.

Rheumatology Unit, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain.

To evaluate the response to hepatitis B virus (HBV) vaccine in patients on biological therapy. Adults with autoimmune inflammatory diseases on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included. Hepatitis B surface antibody (anti-HBs) was measured by ELISA before and after vaccination. Seroconversion was considered when an anti-HBs titer > 10 mIU/mL was achieved. The effect of treatment on the immunoprotective state was studied. The response was compared with that obtained in patients on synthetic disease modifying anti-rheumatic drugs (DMARDs) and healthy controls. A total of 187 patients on biologicals, 48 on synthetic DMARDs, and 49 on healthy controls were analyzed. More than 80% of patients on biologics responded to the vaccine but required more boosters and second vaccine series. Patients who achieved seroconversion were younger than those who did not (47.10 ± 12.99 vs. 53.18 ± 10.54 years, p = 0.012). Being on etanercept or golimumab was associated with seroconversion, while being on rituximab was not. Seroconversion was achieved in 93.75% of patients on synthetic DMARDs and 97.96% of healthy controls. The seroconversion rate in the biologics group was lower than in the synthetic DMARD group (p = 0.043) and tended to be lower than in the healthy group (p = 0.056). In patients on biological therapy, a high rate of HBV vaccine response can be achieved when a complete vaccination schedule is administered. Vaccination while not on biological agents reduces the requirement for boosters and revaccination. Key points: • Patients on biological therapy can achieve high rates of immune response to HBV vaccine when complete vaccination schedules are administered. • However, to achieve such a high seroconversion rate, more boosters and second vaccination series are required. • This supports the proposal already made to provide HBV vaccination to all patients with an autoimmune inflammatory disease after the diagnosis is made and not when the use of a biological treatment is under consideration.
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http://dx.doi.org/10.1007/s10067-020-05042-2DOI Listing
September 2020

Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing.

United European Gastroenterol J 2020 03 7;8(2):148-156. Epub 2020 Jan 7.

Trinity Translational Medicine Institute and Department of Clinical Medicine, Trinity Centre for Health Science, St James's Hospital, Dublin, Ireland.

Background: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. : To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years.

Methods: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time.

Results: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time.

Conclusions: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.
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http://dx.doi.org/10.1177/2050640619899225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079276PMC
March 2020

Oncolytic Adenovirus Armed with BiTE, Cytokine, and Checkpoint Inhibitor Enables CAR T Cells to Control the Growth of Heterogeneous Tumors.

Mol Ther 2020 05 24;28(5):1251-1262. Epub 2020 Feb 24.

Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA. Electronic address:

No single cancer immunotherapy will likely defeat all evasion mechanisms of solid tumors, including plasticity of tumor antigen expression and active immune suppression by the tumor environment. In this study, we increase the breadth, potency, and duration of anti-tumor activity of chimeric antigen receptor (CAR) T cells using an oncolytic virus (OV) that produces cytokine, checkpoint blockade, and a bispecific tumor-targeted T cell engager (BiTE) molecule. First, we constructed a BiTE molecule specific for CD44 variant 6 (CD44v6), since CD44v6 is widely expressed on tumor but not normal tissue, and a CD44v6 antibody has been safely administered to cancer patients. We then incorporated this BiTE sequence into an oncolytic-helper binary adenovirus (CAdDuo) encoding an immunostimulatory cytokine (interleukin [IL]-12) and an immune checkpoint blocker (PD-L1Ab) to form CAdTrio. CD44v6 BiTE from CAdTrio enabled HER2-specific CAR T cells to kill multiple CD44v6 cancer cell lines and to produce more rapid and sustained disease control of orthotopic HER2 and HER2 CD44v6 tumors than any component alone. Thus, the combination of CAdTrio with HER2.CAR T cells ensures dual targeting of two tumor antigens by engagement of distinct classes of receptor (CAR and native T cell receptor [TCR]), and significantly improves tumor control and survival.
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http://dx.doi.org/10.1016/j.ymthe.2020.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210703PMC
May 2020

The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance.

mBio 2020 02 4;11(1). Epub 2020 Feb 4.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

The filamentous fungus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the Δ, Δ, and Δ Δ mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in Δ, Δ, and Δ Δ mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the Δ and Δ and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.
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http://dx.doi.org/10.1128/mBio.02962-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002344PMC
February 2020

Pathophysiological dissociation of the interaction between time pressure and trait anxiety during spatial orientation judgments.

Eur J Neurosci 2020 Aug 27;52(4):3215-3222. Epub 2020 Jan 27.

Division of Brain Sciences, Academic Department of Neuro-otology, Imperial College London, Charing Cross Hospital, London, UK.

Spatial orientation is achieved by integrating visual, vestibular and proprioceptive cues. Individuals that rely strongly upon visual cues to facilitate spatial orientation are termed visually dependent. Heightened visual reliance commonly occurs in patients following vestibular dysfunction and can influence clinical outcome. Additionally, psychological factors, including anxiety, are associated with poorer clinical outcome following vestibular dysfunction. Given that visual dependency measures are affected by psychological and contextual influences, such as time pressure, we investigated the interaction between time pressure and anxiety upon visual dependency in healthy controls and vestibular migraine patients. Visual dependency was assessed using a "Rod and Disk" task at baseline and under time pressure (3 s to complete the task). Non-situational (trait) and situational (state) anxiety levels were quantified using the Spielberg State-Trait Anxiety Inventory. We calculated the change in visual dependency (VD) [∆VD = VD  - VD ] and correlated it with participants' trait anxiety scores. We observed a significant negative correlation between trait anxiety and the change in VD (R  = .393, p < .001) in healthy controls and a positive correlation in dizzy patients (R  = .317, p < .001). That is, healthy individuals that were more anxious became less visually dependent under time pressure (i.e., more accurate), whereas less anxious individuals became more visually dependent. The reverse was observed in vestibular migraine patients. Our results illustrate that anxiety can differentially modulate task performance during spatial orientation judgements under time pressure in healthy individuals and dizzy patients. These findings have potential implications for individualised patient rehabilitation therapies.
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http://dx.doi.org/10.1111/ejn.14680DOI Listing
August 2020

Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance.

PLoS Genet 2019 12 30;15(12):e1008551. Epub 2019 Dec 30.

Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.

Aspergillus fumigatus causes invasive aspergillosis, the most common life-threatening fungal disease of immuno-compromised humans. The treatment of disseminated infections with antifungal drugs, including echinocandin cell wall biosynthesis inhibitors, is increasingly challenging due to the rise of drug-resistant pathogens. The fungal calcium responsive calcineurin-CrzA pathway influences cell morphology, cell wall composition, virulence, and echinocandin resistance. A screen of 395 A. fumigatus transcription factor mutants identified nine transcription factors important to calcium stress tolerance, including CrzA and ZipD. Here, comparative transcriptomics revealed CrzA and ZipD regulated the expression of shared and unique gene networks, suggesting they participate in both converged and distinct stress response mechanisms. CrzA and ZipD additively promoted calcium stress tolerance. However, ZipD also regulated cell wall organization, osmotic stress tolerance and echinocandin resistance. The absence of ZipD in A. fumigatus caused a significant virulence reduction in immunodeficient and immunocompetent mice. The ΔzipD mutant displayed altered cell wall organization and composition, while being more susceptible to macrophage killing and eliciting an increased pro-inflammatory cytokine response. A higher number of neutrophils, macrophages and activated macrophages were found in ΔzipD infected mice lungs. Collectively, this shows that ZipD-mediated regulation of the fungal cell wall contributes to the evasion of pro-inflammatory responses and tolerance of echinocandin antifungals, and in turn promoting virulence and complicating treatment options.
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http://dx.doi.org/10.1371/journal.pgen.1008551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948819PMC
December 2019

Candidate genes expression profiling during wilting in chickpea caused by Fusarium oxysporum f. sp. ciceris race 5.

PLoS One 2019 23;14(10):e0224212. Epub 2019 Oct 23.

Department of Genetics - ETSIAM, University of Córdoba, Campus de Rabanales, Córdoba, Spain.

Chickpea production may be seriously threatened by Fusarium wilt, a disease caused by the soil-borne fungus Fusarium oxysporum f. sp. ciceris. F. oxysporum race 5 is the most important race in the Mediterranean basin. Recently, the region responsible for resistance race 5 has been delimited within a region on chromosome 2 that spans 820 kb. To gain a better understanding of this genomic region, we used a transcriptomic approach based on quantitative real-time PCR to analyze the expression profiles of 22 selected candidate genes. We used a pair of near-isogenic lines (NILs) differing in their sensitivity to Fusarium race 5 (resistant vs susceptible) to monitor the transcriptional changes over a time-course experiment (24, 48, and 72 hours post inoculation, hpi). Qualitative differences occurred during the timing of regulation. A cluster of 12 genes were induced by the resistant NIL at 24 hpi, whereas a second cluster contained 9 genes induced by the susceptible NIL at 48 hpi. Their possible functions in the molecular defence of chickpea is discussed. Our study provides new insight into the molecular defence against Fusarium race 5 and demonstrates that development of NILs is a rich resource to facilitate the detection of candidate genes. The new genes regulated here may be useful against other Fusarium races.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224212PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808423PMC
March 2020

The Aspergillus fumigatus Mismatch Repair Homolog Is Important for Virulence and Azole Resistance.

mSphere 2019 08 7;4(4). Epub 2019 Aug 7.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

The genetic stability of every living organism depends on accurate DNA replication and repair systems. Here, we investigated the mismatch repair (MMR) gene MshA and how it impacts virulence and the evolution of azole resistance. We examined gene variation in 62 environmental and clinical strains. We have observed 12 strains with variants (18.2%), and 8 strains among them showed missense variants. We demonstrated that null mutants are haploid and have conserved karyotypes with discrete gross chromosomal rearrangements. The Δ strains are not sensitive to several DNA-damaging agents. The lack of caused a significant reduction of virulence of in a neutropenic murine model of invasive pulmonary aspergillosis and in the invertebrate alternative model Wild-type and Δ populations did not show any significant changes in drug resistance acquisition after they were transferred 10 times in minimal medium in the absence of any stress. However, these populations rapidly acquired virulence in the Δ background and high levels of resistance to posaconazole in the presence of this drug (at least 200-fold-higher levels of resistance than those derived from the wild-type strain). Taken together, these results suggest that genetic instability caused by Δ mutations can confer an adaptive advantage, mainly increasing posaconazole resistance and virulence acquisition. Invasive aspergillosis (IA) has emerged as one of the most common life-threatening fungal diseases in immunocompromised patients, with mortality rates as high as 90%. Systemic fungal infections such as IA are usually treated with triazoles; however, epidemiological research has shown that the prevalence of azole-resistant isolates has increased significantly over the last decade. There is very little information about the importance of genomic stability for population structure, azole resistance, and virulence. Here, we decided to investigate whether the mismatch repair system could influence azole resistance and virulence, focusing on one of the components of this system, Although the mutation frequency of (the homologue) is low in environmental and clinical isolates, our results indicate that loss of function can provide increased azole resistance and virulence when selected for. These results demonstrate the importance of genetic instability in as a possible mechanism of evolving azole resistance and establishing fitness in the host.
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http://dx.doi.org/10.1128/mSphere.00416-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686229PMC
August 2019

DNA methylation patterns in bladder tumors of African American patients point to distinct alterations in xenobiotic metabolism.

Carcinogenesis 2019 11;40(11):1332-1340

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Racial/ethnic disparities have a significant impact on bladder cancer outcomes with African American patients demonstrating inferior survival over European-American patients. We hypothesized that epigenetic difference in methylation of tumor DNA is an underlying cause of this survival health disparity. We analyzed bladder tumors from African American and European-American patients using reduced representation bisulfite sequencing (RRBS) to annotate differentially methylated DNA regions. Liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics and flux studies were performed to examine metabolic pathways that showed significant association to the discovered DNA methylation patterns. RRBS analysis showed frequent hypermethylated CpG islands in African American patients. Further analysis showed that these hypermethylated CpG islands in patients are commonly located in the promoter regions of xenobiotic enzymes that are involved in bladder cancer progression. On follow-up, LC-MS/MS revealed accumulation of glucuronic acid, S-adenosylhomocysteine, and a decrease in S-adenosylmethionine, corroborating findings from the RRBS and mRNA expression analysis indicating increased glucuronidation and methylation capacities in African American patients. Flux analysis experiments with 13C-labeled glucose in cultured African American bladder cancer cells confirmed these findings. Collectively, our studies revealed robust differences in methylation-related metabolism and expression of enzymes regulating xenobiotic metabolism in African American patients indicate that race/ethnic differences in tumor biology may exist in bladder cancer.
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http://dx.doi.org/10.1093/carcin/bgz128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875901PMC
November 2019

Saccadic Direction Errors are Associated with Impulsive Compulsive Behaviours in Parkinson's Disease Patients.

J Parkinsons Dis 2019 ;9(3):625-630

Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology, University College London, London, UK.

Fifteen individuals with Parkinson's disease (PD) and impulsive compulsive behaviours (PD+ICB) were compared to 15 PD patients without ICBs (PD-ICB) and 15 healthy controls (HC) on a pro-saccades and an anti-saccades task to assess if ICBs are associated with distinct saccadic abnormalities. PD+ICB made shorter saccades than HC and more direction errors in the anti-saccades task than PD-ICB and HC, suggesting that patients with ICBs have greater difficulty in suppressing automatic saccades towards a given target. Saccadic assessment has the potential to evolve into a marker to guide therapeutic decisions in patients at risk of developing ICBs.
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http://dx.doi.org/10.3233/JPD-181460DOI Listing
June 2020

Nutritional Heterogeneity Among Strains Has Consequences for Virulence in a Strain- and Host-Dependent Manner.

Front Microbiol 2019 24;10:854. Epub 2019 Apr 24.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.

Acquisition and subsequent metabolism of different carbon and nitrogen sources have been shown to play an important role in virulence attributes of the fungal pathogen , such as the secretion of host tissue-damaging proteases and fungal cell wall integrity. We examined the relationship between the metabolic processes of carbon catabolite repression (CCR), nitrogen catabolite repression (NCR) and virulence in a variety of clinical isolates. A considerable amount of heterogeneity with respect to the degree of CCR and NCR was observed and a positive correlation between NCR and virulence in a neutropenic mouse model of pulmonary aspergillosis (PA) was found. Isolate Afs35 was selected for further analysis and compared to the reference strain A1163, with both strains presenting the same degree of virulence in a neutropenic mouse model of PA. Afs35 metabolome analysis in physiological-relevant carbon sources indicated an accumulation of intracellular sugars that also serve as cell wall polysaccharide precursors. Genome analysis showed an accumulation of missense substitutions in the regulator of protease secretion and in genes encoding enzymes required for cell wall sugar metabolism. Based on these results, the virulence of strains Afs35 and A1163 was assessed in a triamcinolone murine model of PA and found to be significantly different, confirming the known importance of using different mouse models to assess strain-specific pathogenicity. These results highlight the importance of nitrogen metabolism for virulence and provide a detailed example of the heterogeneity that exists between isolates with consequences for virulence in a strain-specific and host-dependent manner.
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http://dx.doi.org/10.3389/fmicb.2019.00854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492530PMC
April 2019

Body sway during postural perturbations is mediated by the degree of vestibulo-cortical dominance.

Brain Stimul 2019 Jul - Aug;12(4):1098-1100. Epub 2019 May 9.

Academic Department of Neuro-Otology, Division of Brain Sciences, Department of Medicine, Charing Cross Hospital Campus, Imperial College London, London, W6 8RF, UK; Department of Neuroscience, Psychology and Behaviour, University of Leicester, University Road, Leicester, LE1 7RH, UK. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2019.05.008DOI Listing
May 2019

JNK represses Lkb-deficiency-induced lung squamous cell carcinoma progression.

Nat Commun 2019 05 14;10(1):2148. Epub 2019 May 14.

Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA.

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.
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http://dx.doi.org/10.1038/s41467-019-09843-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517592PMC
May 2019

Antibody responses to influenza vaccine in patients on biological therapy: Results of RIER cohort study.

Med Clin (Barc) 2019 11 4;153(10):380-386. Epub 2019 May 4.

Rheumatology Department, Infanta Sofía University Hospital, Paseo de Europa 34, San Sebastián de los Reyes, 28702 Madrid, Spain.

Background And Objectives: Influenza vaccine is recommended for patients with autoimmune inflammatory rheumatic diseases who receive biological therapy. To evaluate if biological therapy impairs immunization after seasonal influenza vaccine.

Material And Methods: Patients with inflammatory arthopathies, psoriasis, inflammatory bowel disease or connective tissue diseases who were receiving or were going to initiate biological therapy were included and vaccinated during 2014-2015 influenza season. ELISA was used to measure influenza antigen A and B antibodies, before and after vaccination. Demographic parameters, diagnosis and kind of treatment were recorded and their influence on the final serological status against influenza was studied.

Results: 253 subjects were analyzed. After vaccination, 77% of participants presented detectable antibodies against antigen A and 50.6% of them had detectable antibodies against antigen B. Final seropositivity rate against antigen B antibodies increased from baseline (50.6% vs 43.5%, p<0.001). Anti-TNF drugs were associated with better response and rituximab with the worst (79.2% vs 55.0% for final seropositivity against antigen A, p=0.020). Vaccine response in the rituximab group tended to improve when the interval between the drug administration and the vaccination was at least 12 weeks (seropositivity rate 80.0% in those with the longer interval vs 25.0% in the other group, p=0.054).

Conclusions: Among the patients on biological therapy vaccinated against influenza, anti-TNF therapy was identified as a predictive factor of final seropositivity. Rituximab presented a lower rate of final seropositivity, which could be increased with an accurate administration schedule.
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http://dx.doi.org/10.1016/j.medcli.2019.02.003DOI Listing
November 2019

High frequency of non-classical congenital adrenal hyperplasia form among children with persistently elevated levels of 17-hydroxyprogesterone after newborn screening.

J Pediatr Endocrinol Metab 2019 May;32(5):499-504

Department of Pediatrics, Faculdade de Medicina, Hospital das Clinicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.

Background Early diagnosis after newborn screening (NBS) for congenital adrenal hyperplasia (CAH) allows proper treatment, reducing mortality rates and preventing development of hyperandrogenic manifestations and incorrect sex assignment at birth. Despite the high NBS sensitivity to detect CAH classical forms, one of the main issues is identifying asymptomatic children who remained with increased 17-hydroxyprogesterone (17-OHP) levels. In this study, we aimed to contribute to understanding the diagnosis of these children. Methods Children with increased serum 17-OHP levels, and without disease-related clinical features during follow-up, underwent the entire CYP21A2 gene sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis (SALSA MLPA P050B CAH). Patients' genotypes were subsequently sorted as compatible with CAH disease, and children were evaluated to determine the clinical status. Results During the study period, 106,476 newborns underwent CAH NBS. During follow-up, 328 children (0.3%) were identified as having false-positive tests and 295 were discharged after presenting with 17-OHP levels within reference values. Thirty-three remained asymptomatic and with increased serum 17-OHP levels after a mean follow-up of 3.4 years, and were subjected to molecular analysis. Seventeen out of the 33 children carried mutations: seven in the heterozygous state, nine carried non-classical genotypes and the remaining child carried a classical genotype. Conclusions We found a high frequency of non-classical CAH (NCCAH) diagnosis among children with persistent elevation of 17-OHP levels. Our findings support molecular study as decisive for elucidating diagnosis in these asymptomatic children. Molecular analysis as a confirmatory test is relevant to guide their follow-up, allows genetic counseling and avoids over treating NCCAH form.
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http://dx.doi.org/10.1515/jpem-2018-0398DOI Listing
May 2019

ERR1 and PGC1α associated mitochondrial alterations correlate with pan-cancer disparity in African Americans.

J Clin Invest 2019 03 28;129(6):2351-2356. Epub 2019 Mar 28.

Department of Molecular and Cellular Biology.

Background: African American (AA) patients have higher cancer mortality rates and shorter survival times compared to European American (EA) patients. Despite a significant focus on socioeconomic factors, recent findings strongly argue the existence of biological factors driving this disparity. Most of these factors have been described in a cancer-type specific context rather than a pan-cancer setting.

Methods: A novel in silico approach based on Gene Set Enrichment Analysis (GSEA) coupled to Transcription Factor enrichment was carried out to identify common biological drivers of pan-cancer racial disparity using The Cancer Genome Atlas (TCGA) dataset. Mitochondrial content in patient tissues was examined using a multi-cancer tissue microarray approach (TMA).

Results: Mitochondrial oxidative phosphorylation was uniquely enriched in AA tumors compared to EA tumors across various cancer types. AA tumors also showed strong enrichment for the ERR1-PGC1α-mediated transcriptional program, which has been implicated in mitochondrial biogenesis. TMA analysis revealed that AA cancers harbor significantly more mitochondria compared to their EA counterparts.

Conclusions: These findings highlight changes in mitochondria as a common distinguishing feature between AA and EA tumors in a pan-cancer setting, and provide the rationale for the repurposing of mitochondrial inhibitors to treat AA cancers.
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http://dx.doi.org/10.1172/JCI127579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546480PMC
March 2019

Probiotic Lactobacilli Precautions.

Front Microbiol 2019 12;10:375. Epub 2019 Mar 12.

European Forum for Primary Care (EFPC), Utrecht, Netherlands.

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http://dx.doi.org/10.3389/fmicb.2019.00375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423001PMC
March 2019

A systematic scoping review of interventions to improve appropriate prescribing of oral nutritional supplements in primary care.

Clin Nutr 2020 03 14;39(3):654-663. Epub 2019 Mar 14.

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland.

Background & Aims: Oral nutritional supplements (ONS) are commonly used to treat malnutrition. Many patients are prescribed ONS without assessment of nutritional status. This conflicts with prescribing guidelines and has considerable cost implications. This scoping review aimed to provide an overview of interventions to improve appropriate ONS prescribing in primary care.

Methods: A systematic scoping review was undertaken. PubMed, EMBASE and CINAHL were searched from inception to September 2018. Studies meeting inclusion criteria had to: evaluate interventions targeting ONS prescribing in primary care; use a comparative evaluation; be published in English. Two reviewers independently screened abstracts and extracted data relating to study design, intervention characteristics, outcome assessments and key findings. Extracted data were collated using figures, tables and accompanying descriptive summaries.

Results: 10 studies met inclusion criteria. All studies involved uncontrolled before-and-after designs. Interventions ranged from dietitian-led reviews of patients prescribed ONS to transfer of ONS prescribing privileges from general practitioners to dietitians. Post-intervention results showed improvements in ONS prescribing based on study-specific assessments of prescribing appropriateness and absolute reductions in prescribing, as well as potential cost-savings.

Conclusions: This review provides a detailed overview of interventions aimed at improving appropriate ONS prescribing in primary care. Interventions evaluated to date most commonly involved dietitians. However, use of controlled experimental design was lacking. Lack of consistency in defining appropriate ONS prescribing and assessment outcomes was apparent. Future research should attend to rigour during intervention development, evaluation and reporting in order to generate findings which could inform relevant policy and practice.
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http://dx.doi.org/10.1016/j.clnu.2019.03.003DOI Listing
March 2020

Subjective stability perception is related to postural anxiety in older subjects.

Gait Posture 2019 02 2;68:538-544. Epub 2019 Jan 2.

Neuro-otology Unit, Division of Brain Sciences, Charing Cross Hospital Campus, Imperial College London, London, UK. Electronic address:

Background: Under static conditions, the objective and subjective measures of postural stability correlate well. However, age-related changes in postural control and task-related anxiety may modify the relationship between these subjective and objective measures. Ultimately, patients' symptoms represent subjective reports, thus understanding this relationship has clinical implications.

Aims: This study investigates the relationship between subjective-objective measures of postural stability in dynamic conditions and whether this relationship is influenced by age or task-related anxiety.

Methods: 50 healthy participants (aged 18-83 years) stood on a platform oscillating at variable amplitudes, with-without a fall-preventing harness to modulate task-related anxiety. Trunk sway path, hip velocity and foot lifts (objective measures) and subjective scores of instability and task-related anxiety were recorded.

Results: The subjective perception of stability accurately matched objective body sway, following a logarithmic function profile (r = 0.72, p < 0.001). This function did not change significantly with age, harness or task presentation order. A strong relationship was observed between subjective measures of stability and task-related anxiety for all subjects (r = 0.81, p < 0.001). Task repetition reduced anxiety in the young, uncoupling anxiety changes from subjective instability, but not in the elderly who retained higher anxiety levels in line with subjective unsteadiness.

Discussion: Subjects accurately rate their own instability during dynamic postural challenges, irrespective of age and actual fall risk. However, anxiety may selectively modulate the perception of instability in older subjects. The perception of stability relies upon the integration of sensory afferents but also recruits emotional-cognitive processes, particularly in older individuals. The use of a safety harness has no influence on subjective or objective postural stability.
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http://dx.doi.org/10.1016/j.gaitpost.2018.12.043DOI Listing
February 2019

Viewing Target Distance Influences the Vestibulo-Ocular Reflex Gain when Assessed Using the Video Head Impulse Test.

Audiol Neurootol 2018 11;23(5):285-289. Epub 2018 Dec 11.

Neuro-Otology Unit, Division of Brain Sciences, Charing Cross Hospital Campus, Imperial College London, London, United Kingdom,

Gaze stabilization during head movements is provided by the vestibulo-ocular reflex (VOR). Clinical assessment of this reflex is performed using the video Head Impulse Test (vHIT). To date, the influence of different fixation distances on VOR gain using the vHIT has not been explored. We assessed the effect of target proximity on the horizontal VOR using the vHIT. Firstly, we assessed the VOR gain in 18 healthy subjects with 5 viewing target distances (150, 40, 30, 20, and 10 cm). The gain increased significantly as the viewing target distance decreased. A second experiment on 10 subjects was performed in darkness whilst the subjects were imagining targets at different distances. There were significant inverse relationships between gain and distance for both the real and the imaginary targets. There was a statistically significant difference between light and dark gains for the 20- and 40-cm distances, but not for the 150-cm distance. Theoretical VOR gains for different target distances were calculated and compared with those found in light and darkness. The increase in gain observed for near targets was lower than predicted by geometrical calculations, implying a physiological ceiling effect on the VOR. The VOR gain in the dark, as assessed with the vHIT, demonstrates an enhancement associated with a reduced target distance.
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http://dx.doi.org/10.1159/000493845DOI Listing
September 2019