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Clinical Research
Anti-CD47 Antibody As a Targeted Therapeutic Agent for Human Lung Cancer and Cancer Stem Cells
May 09, 2017   Frontiers In Immunology
Liu L, Zhang L, Yang L, Li H, Li R,   . . . . . .   , Yang F, Jin H, Wang J, Wang SE, Ren X
Anti-CD47 Antibody As a Targeted Therapeutic Agent for Human Lung Cancer and Cancer Stem Cells
May 09, 2017
Frontiers In Immunology
Accumulating evidence indicates that a small subset of cancer cells, termed the tumor-initiating cells or cancer stem cells (CSCs), construct a reservoir of self-sustaining cancer cells with the characteristic ability to self-renew and maintain the tumor mass. The CSCs play an important role in the tumor initiation, development, relapse, metastasis, and the ineffectiveness of conventional cancer therapies. CD47 is a ligand for signal-regulatory protein-α expressed on phagocytic cells and functions to inhibit phagocytosis. This study was to explore if the expression of CD47 is the mechanism used by lung cancer cells, especially CSCs, to escape phagocytosis in vitro and in vivo. Here, we selected CD133 as the marker for lung CSCs according to previous reports. We analyzed lung cancer and matched adjacent normal (non-tumor) tissue and revealed that CD47 is overexpressed on lung cancer cells, especially on lung CSCs. The mRNA expression levels of CD47 and CD133 correlated with a decreased probability of survival for multiple types of lung cancer. Blocking CD47 function with anti-CD47 antibodies enabled macrophage phagocytosis of lung cancer cells and lung CSCs. Anti-CD47 antibodies inhibited tumor growth in immunodeficient mouse xenotransplantation models established with lung cancer cells or lung CSCs and improved survival in tumor-bearing animals. These data indicate that CD47 is a valid target for cancer therapies, especially for anti-CSC therapies.
Global health: Boost multinational clinical research
May 18, 2017   Nature Add nature.com free-link Cancel
Demotes-Mainard J
Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients with Hypertension: The Systolic Blood Pressure Intervention (SPRINT) Trial
May 17, 2017   Circulation
Soliman EZ, Ambrosius WT, Cushman WC, Zhang ZM, Bates JT,   . . . . . .   , Shapiro BP, He J, Fine LJ, Lewis CE, SPRINT Research Study Group
Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients with Hypertension: The Systolic Blood Pressure Intervention (SPRINT) Trial
May 17, 2017
Circulation
Background -It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of Left ventricular hypertrophy (LVH) in patients with hypertension, and whether reducing the risk of LVH explains the reported cardiovascular disease (CVD) benefits of intensive BP lowering in this population. Methods -This analysis included 8,164 participants (mean age 67.9 years, 35.3% women, 31.2% blacks) with hypertension but no diabetes from the Systolic Blood Pressure Intervention (SPRINT) Trial; 4,086 randomly assigned to intensive BP lowering (target systolic BP
HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells
May 15, 2017   Nature Biotechnology Add nature.com free-link Cancel
Gornalusse GG, Hirata RK, Funk SE, Riolobos L, Lopes VS, Manske G, Prunkard D, Colunga AG, Hanafi LA, Clegg DO, Turtle C, Russell DW
HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells
May 15, 2017
Nature Biotechnology
Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8+ T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.
Resistance to malaria through structural variation of red blood cell invasion receptors
May 19, 2017   Science (New York, N.Y.)
Leffler EM, Band G, Busby GBJ, Kivinen K, Le QS,   . . . . . .   , Rowlands K, Rockett KA, Spencer CCA, Kwiatkowski DP, Malaria Genomic Epidemiology Network
Resistance to malaria through structural variation of red blood cell invasion receptors
May 19, 2017
Science (New York, N.Y.)
The malaria parasite Plasmodium falciparum invades human red blood cells via interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy number variants affecting the host invasion receptor genes GYPA and GYPB We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently risen in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria. Copyright © 2017, American Association for the Advancement of Science.
Effect of Canal Anastomosis on Periapical Fluid Pressure Build-up during Needle Irrigation in Single Roots with Double Canals using a Polycarbonate Model
May 09, 2017   Scientific Reports
Huang Q, Barnes JB, Schoeffel GJ, Fan B, Tay C, Bergeron BE, Susin LF, Ling JQ, Niu LN, Tay FR
Effect of Canal Anastomosis on Periapical Fluid Pressure Build-up during Needle Irrigation in Single Roots with Double Canals using a Polycarbonate Model
May 09, 2017
Scientific Reports
Sodium hypochlorite is an effective irrigant for chemical debridement of root canals. However, increasing the intracanal pressure during irrigant delivery may result in irrigant extrusion into the bone and soft tissues surrounding the tooth. Because clinicians often encounter teeth with intracanal communications, the objective of the present study was to examine the effects of canal anastomosis on the generation of periapical fluid pressure at different fluid flow rates and insertion depths. Two similar polycarbonate models were used to simulate a single root with double canals, one containing, and the other without communicating channels between the canals. For both models, periapical pressure increased with increasing irrigant flow rates and insertion depths of a 30-gauge side-venting needle. In the presence of communicating channels, the magnitude of pressure build-up decreased by almost 90% irrespective of the fluid flow rate or needle insertion depth. Pressure reduction in anastomoses-containing roots provides an explanation why pressure generation in single roots is considerably higher. Nevertheless, it is still possible in teeth with canal anastomoses for pressure exceeding the intraosseous pressure to be generated when the fluid flow rate is sufficiently high and when the needle tip is close to the apical terminus.
In situ printing of mesenchymal stromal cells, by laser-assisted bioprinting, for in vivo bone regeneration applications
May 12, 2017   Scientific Reports
Keriquel V, Oliveira H, Rémy M, Ziane S, Delmond S, Rousseau B, Rey S, Catros S, Amédée J, Guillemot F, Fricain JC
In situ printing of mesenchymal stromal cells, by laser-assisted bioprinting, for in vivo bone regeneration applications
May 12, 2017
Scientific Reports
Bioprinting has emerged as a novel technological approach with the potential to address unsolved questions in the field of tissue engineering. We have recently shown that Laser Assisted Bioprinting (LAB), due to its unprecedented cell printing resolution and precision, is an attractive tool for the in situ printing of a bone substitute. Here, we show that LAB can be used for the in situ printing of mesenchymal stromal cells, associated with collagen and nano-hydroxyapatite, in order to favor bone regeneration, in a calvaria defect model in mice. Also, by testing different cell printing geometries, we show that different cellular arrangements impact on bone tissue regeneration. This work opens new avenues on the development of novel strategies, using in situ bioprinting, for the building of tissues, from the ground up.
Protective effects of APOE e2 against disease progression in subcortical vascular mild cognitive impairment patients: A three-year longitudinal study
May 16, 2017   Scientific Reports
Kim YJ, Seo SW, Park SB, Yang JJ, Lee JS, Lee J, Jang YK, Kim ST, Lee KH, Lee JM, Lee JH, Kim JS, Na DL, Kim HJ
Protective effects of APOE e2 against disease progression in subcortical vascular mild cognitive impairment patients: A three-year longitudinal study
May 16, 2017
Scientific Reports
Although the association between apolipoprotein E (APOE) genotype and disease progression is well characterized in patients with Alzheimer's disease, such a relationship is unknown in patients with subcortical vascular cognitive impairment. We evaluated whether APOE genotype is associated with disease progression in subcortical vascular mild cognitive impairment (svMCI) patients. We prospectively recruited 72 svMCI patients (19 APOE4 carriers, 42 APOE3 homozygotes, and 11 APOE2 carriers). Patients were annually followed-up with brain MRI and neuropsychological tests for three years and underwent a second Pittsburgh compound B (PiB)-PET at a mean interval of 32.3 months. Amyloid-ß burden was quantified by PiB standardized uptake value ratio (SUVR), and the amount of small vessel disease was quantified by number of lacune and small vessel disease score on MRI. We also measured cortical thickness. During the three years of follow-up, compared to the APOE3 homozygotes, there was less increase in PiB SUVR among APOE2 carriers (p = 0.023), while the APOE genotype did not show significant effects on small vessel disease progression. APOE2 carriers also showed less cortical thinning (p = 0.023) and a slower rate of cognitive decline (p = 0.009) compared to those with APOE3 homozygotes. Our findings suggest that, in svMCI patients, APOE2 has protective effects against amyloid-ß accumulation, cortical thinning, and cognitive decline.
The antifungal effects and mechanical properties of silver bromide/cationic polymer nano-composite-modified Poly-methyl methacrylate-based dental resin
May 09, 2017   Scientific Reports
Zhang Y, Chen YY, Huang L, Chai ZG, Shen LJ, Xiao YH
The antifungal effects and mechanical properties of silver bromide/cationic polymer nano-composite-modified Poly-methyl methacrylate-based dental resin
May 09, 2017
Scientific Reports
Poly-methyl methacrylate (PMMA)-based dental resins with strong and long-lasting antifungal properties are critical for the prevention of denture stomatitis. This study evaluated the antifungal effects on Candida albicans ATCC90028, the cytotoxicity toward human dental pulp cells (HDPCs), and the mechanical properties of a silver bromide/cationic polymer nano-composite (AgBr/NPVP)-modified PMMA-based dental resin. AgBr/NPVP was added to the PMMA resin at 0.1, 0.2, and 0.3 wt%, and PMMA resin without AgBr/NPVP served as the control. Fungal growth was inhibited on the AgBr/NPVP-modified PMMA resin compared to the control (P  0.05) between the experimental and control groups. These data indicate that the incorporation of AgBr/NPVP conferred strong and long-lasting antifungal effects against Candida albicans to the PMMA resin, and it has low toxicity toward HDPCs, and its mechanical properties were not significantly affected.
Efficacy and safety of thiazolidinediones in diabetes patients with renal impairment: a systematic review and meta-analysis
May 12, 2017   Scientific Reports
Wang W, Zhou X, Kwong JSW, Li L, Li Y, Sun X
Efficacy and safety of thiazolidinediones in diabetes patients with renal impairment: a systematic review and meta-analysis
May 12, 2017
Scientific Reports
We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of TZDs in treatment of diabetes mellitus patients with renal impairment. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials. Randomized controlled trials (RCTs), cohort studies, and case-control studies that investigated the effects of TZDs in patients with diabetes and renal impairment were eligible. Outcomes included glycosylated hemoglobin, fasting plasma glucose, serum lipids, and patient-important outcomes (i.e. hypoglycemia, weight, edema, cardiovascular events and mortality). 19 RCTs and 3 cohort studies involving 21,803 patients with diabetes and renal impairment were included. Meta-analysis of RCTs showed that TZDs could significantly reduce HbA1c (MD -0.64, 95%CI -0.93 to -0.35), FPG (MD -26.27, 95%CI -44.90 to -7.64) and increase HDL levels (MD 3.70, 95%CI 1.10, 6.29). TZDs could increase weight (MD 3.23, 95% CI 2.29 to 4.16) and risk of edema (RR 2.96, 95% CI 1.22 to 7.20). Their effects on risk of hypoglycemia (RR 1.46, 95% CI 0.65 to 3.29), heart failure (RR 0.64, 95% CI 0.15 to 2.66), angina (RR 1.45, 95% CI 0.23 to 8.95) and all-cause mortality (RR 0.40, 95% CI 0.08 to 2.01) are uncertain. Results from cohort studies were similar to RCTs.
Precision Radiology: Predicting longevity using feature engineering and deep learning methods in a radiomics framework
May 11, 2017   Scientific Reports
Oakden-Rayner L, Carneiro G, Bessen T, Nascimento JC, Bradley AP, Palmer LJ
Precision Radiology: Predicting longevity using feature engineering and deep learning methods in a radiomics framework
May 11, 2017
Scientific Reports
Precision medicine approaches rely on obtaining precise knowledge of the true state of health of an individual patient, which results from a combination of their genetic risks and environmental exposures. This approach is currently limited by the lack of effective and efficient non-invasive medical tests to define the full range of phenotypic variation associated with individual health. Such knowledge is critical for improved early intervention, for better treatment decisions, and for ameliorating the steadily worsening epidemic of chronic disease. We present proof-of-concept experiments to demonstrate how routinely acquired cross-sectional CT imaging may be used to predict patient longevity as a proxy for overall individual health and disease status using computer image analysis techniques. Despite the limitations of a modest dataset and the use of off-the-shelf machine learning methods, our results are comparable to previous 'manual' clinical methods for longevity prediction. This work demonstrates that radiomics techniques can be used to extract biomarkers relevant to one of the most widely used outcomes in epidemiological and clinical research - mortality, and that deep learning with convolutional neural networks can be usefully applied to radiomics research. Computer image analysis applied to routinely collected medical images offers substantial potential to enhance precision medicine initiatives.
Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines
May 10, 2017   Scientific Reports
Mao X, Li K, Tang B, Luo Y, Ding D,   . . . . . .   , Xia K, Yan X, Jiang H, Lu S, Guo J
Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines
May 10, 2017
Scientific Reports
Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of "Epilepsy", which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.
Age-related penetrance of the C9orf72 repeat expansion
May 19, 2017   Scientific Reports
Murphy NA, Arthur KC, Tienari PJ, Houlden H, Chiò A, Traynor BJ
Age-related penetrance of the C9orf72 repeat expansion
May 19, 2017
Scientific Reports
A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
Blocking of stromal interaction molecule 1 expression influence cell proliferation and promote cell apoptosis in vitro and inhibit tumor growth in vivo in head and neck squamous cell carcinoma
May 11, 2017   PloS One
Li P, Bian XY, Chen Q, Yao XF, Wang XD, Zhang WC, Tao YJ, Jin R, Zhang L
Blocking of stromal interaction molecule 1 expression influence cell proliferation and promote cell apoptosis in vitro and inhibit tumor growth in vivo in head and neck squamous cell carcinoma
May 11, 2017
PloS One
Calcium signal plays an important role in a variety of cancer cell metabolism, but knowledge on its role in head and neck squamous cell carcinoma (HNSCC) is limited. Store-operated calcium entry (SOCE) is the principal Ca2+ entry mechanism that maintains calcium concentration and produces calcium signal in non-excitable cells. SOCE is triggered by stromal interaction molecule 1 (STIM1), which is located in endoplasmic reticulum (ER) as Ca2+ sensor. Although, many studies demonstrated that STIM1 and SOCE play important functions in the regulation of many cancer progressions, their clinical relevance in HNSCC remains unclear. In this study, STIM1 expression levels notably increased in 89% HNSCC tissues compared with those in adjacent normal tissues. Meanwhile, this overexpression was close associated with tumor size but not with neck lymph node metastasis. Thus, this study mainly focuses on STIM1 function in HNSCC tumor growth. Three HNSCC cell lines, namely, TSCCA (oral cancer cell line) and Hep2 (laryngeal cell line) with high STIM1 expression levels and Tb3.1 (oral cancer cell line) with STIM1 expression level lower than previous two cell lines, were selected for in vitro study. Downregulated STIM1 expression levels in TSCCA and Hep2 arrested cells in G0/G1 stages, promoted cell apoptosis, and inhibited cell proliferation. By contrast, upregulated STIM1 expression in Tb3.1 inhibited cell apoptosis and promoted cell proliferation. Induced by thapsigargin (TG), ER stress was amplified when STIM1 expression was downregulated but was attenuated as STIM1 expression was upregulated. Furthermore, TSCCA cell xenograft models confirmed that STIM1 could promote HNSCC tumor growth in vivo. The present study provides new insight into HNSCC molecular mechanism and potential therapeutic target through targeting SOCE-dependent process. However, whether STIM1 participates in HNSCC metastasis requires further study.
Gender bias in clinical case reports: A cross-sectional study of the "big five" medical journals
May 11, 2017   PloS One
Allotey P, Allotey-Reidpath C, Reidpath DD
Gender bias in clinical case reports: A cross-sectional study of the "big five" medical journals
May 11, 2017
PloS One
Gender bias in medical journals can affect the science and the benefit to patients. It has never been investigated in clinical case reports. The oversight is important because of the role clinical case reports play in hypothesis generation and medical education. We investigated contemporary gender bias in case reports for the highest ranked journals in general and internal medicine. PubMed case reports data from 2011 to 2016 were extracted for the Annals of Internal Medicine, British Medical Journal, the Journal of the American Medical Association, The Lancet, and New England Journal of Medicine. The gender of the patients were identified and a text analysis of the Medical Subject Headings conducted. A total of 2,742 case reports were downloaded and 2,582 (95.6%) reports contributed to the final analysis. A pooled analysis showed a statistically significant gender bias against female case reports (0.45; 95%CI: 0.43-0.47). The Annals of Internal Medicine was the only journal with a point estimate (non significant) in the direction of a bias against male patients. The text analysis identified no substantive difference in the focus of the case reports and no obvious explanation for the bias. Gender bias, previously identified in clinical research and in clinical authorship, extends into the patients presented in clinical case reports. Whether it is driven by authors or editors is not clear, but it likely contributes to and supports an overall male bias of clinical medicine.
Open lung approach versus standard protective strategies: Effects on driving pressure and ventilatory efficiency during anesthesia - A pilot, randomized controlled trial
May 11, 2017   PloS One
Ferrando C, Suarez-Sipmann F, Tusman G, León I, Romero E, Gracia E, Mugarra A, Arocas B, Pozo N, Soro M, Belda FJ
Open lung approach versus standard protective strategies: Effects on driving pressure and ventilatory efficiency during anesthesia - A pilot, randomized controlled trial
May 11, 2017
PloS One
Low tidal volume (VT) during anesthesia minimizes lung injury but may be associated to a decrease in functional lung volume impairing lung mechanics and efficiency. Lung recruitment (RM) can restore lung volume but this may critically depend on the post-RM selected PEEP. This study was a randomized, two parallel arm, open study whose primary outcome was to compare the effects on driving pressure of adding a RM to low-VT ventilation, with or without an individualized post-RM PEEP in patients without known previous lung disease during anesthesia. Consecutive patients scheduled for major abdominal surgery were submitted to low-VT ventilation (6 ml·kg-1) and standard PEEP of 5 cmH2O (pre-RM, n = 36). After 30 min estabilization all patients received a RM and were randomly allocated to either continue with the same PEEP (RM-5 group, n = 18) or to an individualized open-lung PEEP (OL-PEEP) (Open Lung Approach, OLA group, n = 18) defined as the level resulting in maximal Cdyn during a decremental PEEP trial. We compared the effects on driving pressure and lung efficiency measured by volumetric capnography. OL-PEEP was found at 8±2 cmH2O. 36 patients were included in the final analysis. When compared with pre-RM, OLA resulted in a 22% increase in compliance and a 28% decrease in driving pressure when compared to pre-RM. These parameters did not improve in the RM-5. The trend of the DP was significantly different between the OLA and RM-5 groups (p = 0.002). VDalv/VTalv was significantly lower in the OLA group after the RM (p = 0.035). Lung recruitment applied during low-VT ventilation improves driving pressure and lung efficiency only when applied as an open-lung strategy with an individualized PEEP in patients without lung diseases undergoing major abdominal surgery. ClinicalTrials.gov NCT02798133.
Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis
May 12, 2017   PloS One
Atassi N, Xu M, Triantafyllou C, Keil B, Lawson R, Cernasov P, Ratti E, Long CJ, Paganoni S, Murphy A, Salibi N, Seethamraju R, Rosen B, Ratai EM
Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis
May 12, 2017
PloS One
The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.
Asymptomatic carotid artery stenosis and retinal nerve fiber layer thickness. A community-based, observational study
May 11, 2017   PloS One
Wang D, Li Y, Zhou Y, Jin C, Zhao Q, Wang A, Wu S, Wei WB, Zhao X, Jonas JB
Asymptomatic carotid artery stenosis and retinal nerve fiber layer thickness. A community-based, observational study
May 11, 2017
PloS One
To examine whether an abnormally thin retinal nerve fiber layer (RNFL) is associated with cerebrovascular insufficiency. Community-based study. The Asymptomatic Polyvascular Abnormalities in Community Study included Chinese aged 40+ years and without histories of cerebrovascular incidents or coronary heart disease. Using transcranial Doppler and carotid duplex ultrasound examination, we assessed presence and degree of an intracranial arterial stenosis (ICAS) and extracranial carotid arterial stenosis (ECAS) and we measured the RNFL thickness by spectral-domain optical coherence tomography. The study included 3,376 participants with a mean age of 54.3±10.3 years. Thinner RNFL was significantly correlated with a higher prevalence of ECAS (P = 0.035; standardized regression coefficient beta:-0.04; non-standardized regression coefficient B:-0.99; 95% confidence intervals(CI):-1.90,-0.07), after adjusting for age (P
Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan
May 15, 2017   PloS One
Koga T, Okada A, Fukuda T, Hidaka T, Ishii T,   . . . . . .   , Nakamura H, Aoyagi K, Eguchi K, Kawakami A, Japanese RA Patients with RRP Study Group
Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan
May 15, 2017
PloS One
To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) achieving remission or low disease activity (LDA) in clinical practice. Using data from a nationwide, multicenter, prospective study in Japan, we evaluated 198 biological disease-modifying antirheumatic drug (bDMARD)-naïve RA patients who were in remission or had LDA at study entry after being treated with conventional synthetic DMARDs (csDMARDs). CRRP was defined as the yearly progression of modified total Sharp score (mTSS) >3.0 U. We performed a multiple logistic regression analysis to explore the factors to predict CRRP at 1 year. We used receiver operating characteristic (ROC) curve to estimate the performance of relevant variables for predicting CRRP. The mean Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) was 2.32 ± 0.58 at study entry. During the 1-year observation, remission or LDA persisted in 72% of the patients. CRRP was observed in 7.6% of the patients. The multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: anti-citrullinated peptide antibodies (ACPA) positivity at baseline (OR = 15.2, 95%CI 2.64-299), time-integrated DAS28-ESR during the 1 year post-baseline (7.85-unit increase, OR = 1.83, 95%CI 1.03-3.45), and the mTSS at baseline (13-unit increase, OR = 1.22, 95%CI 1.06-1.42). ACPA positivity was the strongest independent predictor of CRRP in patients with RA in remission or LDA. Physicians should recognize ACPA as a poor-prognosis factor regarding the radiographic outcome of RA, even among patients showing a clinically favorable response to DMARDs.
Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma
May 15, 2017   PloS One
Boyé P, Serres F, Marescaux L, Hordeaux J, Bouchaert E, Gomes B, Tierny D
Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma
May 15, 2017
PloS One
Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans' solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas.
Stress and salivary cortisol in emergency medical dispatchers: A randomized shifts control trial
May 15, 2017   PloS One
Bedini S, Braun F, Weibel L, Aussedat M, Pereira B, Dutheil F
Stress and salivary cortisol in emergency medical dispatchers: A randomized shifts control trial
May 15, 2017
PloS One
Stress at work is a public health concern. Phone operators in emergency medical dispatch centers are particularly at risk. We aimed to demonstrate that the most stressful time for emergency medical dispatchers is the shift when they receive emergency incoming calls, with cortisol as a biomarker of stress. For each emergency medical dispatcher, we measured outcomes over a control day and during three types of shift: Incoming emergency call, Dispatch and Re-assessment. The pattern of shifts was randomized. Saliva was sampled every 15 minutes for 2 hours, i.e. 6 consecutive times, starting 15 minutes after the first life-and-death incoming emergency call between 2 and 5 pm during three types of shift. We measured saliva cortisol every 2 hours over a control day, from 7am to 9pm. Perceived stress was assessed by a visual analog scale. We recruited 22 phone operators aged 36.4+/-10.8 years old (14 women and 8 men). Cortisol values were higher during the Incoming emergency call shift than during the Dispatch (p = .04) and Re-assessment (p = .04) shifts. The increase in cortisol levels was greater in men than in women (p = .009). There were no differences between control values and those of the three shifts. The kinetics of cortisol increased with greater perceived stress overall (p < .001) and for each type of shift (Incoming emergency call, p = .02; Dispatch p = .03; Re-assessment: p < .001). The kinetics of cortisol in response to incoming emergency calls was greater when the call was an absolute emergency (p = .03), and also tended to further increase when a subsequent absolute incoming emergency call was received (p = 0.07). In conclusion, the incoming emergency call shift carries particular risk for dispatchers, who have greater perceived stress and a greater increase in cortisol levels.
The impact of HCV therapy in a high HIV-HCV prevalence population: A modeling study on people who inject drugs in Ho Chi Minh City, Vietnam
May 11, 2017   PloS One
Birger RB, Le T, Kouyos RD, Grenfell BT, Hallett TB
The impact of HCV therapy in a high HIV-HCV prevalence population: A modeling study on people who inject drugs in Ho Chi Minh City, Vietnam
May 11, 2017
PloS One
Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection is a major global health problem especially among people who inject drugs (PWID), with significant clinical implications. Mathematical models have been used to great effect to shape HIV care, but few have been proposed for HIV/HCV. We constructed a deterministic compartmental ODE model that incorporated layers for HIV disease progression, HCV disease progression and PWID demography. Antiretroviral therapy (ART) and Methadone Maintenance Therapy (MMT) scale-ups were modeled as from 2016 and projected forward 10 years. HCV treatment roll-out was modeled beginning in 2026, after a variety of MMT scale-up scenarios, and projected forward 10 years. Our results indicate that scale-up of ART has a major impact on HIV though not on HCV burden. MMT scale-up has an impact on incidence of both infections. HCV treatment roll-out has a measurable impact on reductions of deaths, increasing multifold the mortality reductions afforded by just ART/MMT scale-ups. HCV treatment roll-out can have major and long-lasting effects on averting PWID deaths on top of those averted by ART/MMT scale-up. Efficient intervention scale-up of HCV alongside HIV interventions is critical in Vietnam.
OCT-angiography: A qualitative and quantitative comparison of 4 OCT-A devices
May 10, 2017   PloS One
Munk MR, Giannakaki-Zimmermann H, Berger L, Huf W, Ebneter A, Wolf S, Zinkernagel MS
OCT-angiography: A qualitative and quantitative comparison of 4 OCT-A devices
May 10, 2017
PloS One
To compare the quality of four OCT-angiography(OCT-A) modules. The retina of nineteen healthy volunteers were scanned with four OCT-devices (Topcon DRI-OCT Triton Swept-source OCT, Optovue RTVue-XR, a prototype Spectralis OCT2, Heidelberg-Engineering and Zeiss Cirrus 5000-HD-OCT). The device-software generated en-face OCT-A images of the superficial (SCP) and deep capillary plexuses (DCP) were evaluated and scored by 3 independent retinal imaging experts. The SCP vessel density was assessed using Angiotool-software. After the inter-grader reliability assessment, a consensus grading was performed and the modules were ranked based on their scoring. There was no significant difference in the vessel density among the modules (Zeiss 48.7±4%, Optovue 47.9±3%, Topcon 48.3±2%, Heidelberg 46.5±4%, p = 0.2). The numbers of discernible vessel-bifurcations differed significantly on each module (Zeiss 2±0.9 bifurcations, Optovue 2.5±1.2, Topcon 1.3±0.7 and Heidelberg 0.5±0.6, p≤0.001). The ranking of each module differed depending on the evaluated parameter. In the overall ranking, the Zeiss module was superior and in 90% better than the median (Bonferroni corrected p-value = 0.04). Optovue was better than the median in 60%, Topcon in 40% and Heidelberg module in 10%, however these differences were not statistically significant. Each of the four evaluated OCT-A modules had particular strengths, which differentiated it from their competitors.
Optimal method for assessment of respiratory muscle strength in neuromuscular disorders using sniff nasal inspiratory pressure (SNIP)
May 18, 2017   PloS One
Kaminska M, Noel F, Petrof BJ
Optimal method for assessment of respiratory muscle strength in neuromuscular disorders using sniff nasal inspiratory pressure (SNIP)
May 18, 2017
PloS One
The ability to accurately determine respiratory muscle strength is vitally important in patients with neuromuscular disorders (NMD). Sniff nasal inspiratory pressure (SNIP), a test of inspiratory muscle strength, is easier to perform for many NMD patients than the more commonly used determination of maximum inspiratory pressure measured at the mouth (MIP). However, due to an inconsistent approach in the literature, the optimal technique to perform the SNIP maneuver is unclear. Therefore, we systematically evaluated the impact of performing the maneuver with nostril contralateral to the pressure-sensing probe open (SNIPOP) versus closed (SNIPCL), on determination of inspiratory muscle strength in NMD patients as well as control subjects with normal respiratory muscle function. NMD patients (n = 52) and control subjects without respiratory dysfunction (n = 52) were studied. SNIPOP, SNIPCL, and MIP were measured during the same session and compared using ANOVA. Agreement and bias were assessed with intraclass correlation coefficients (ICC) and Bland-Altman plots. Mean MIP values were 58.2 and 94.0 cmH2O in NMD and control subjects, respectively (p
Metabolic profiling by gas chromatography-mass spectrometry of energy metabolism in high-fat diet-fed obese mice
May 18, 2017   PloS One
Patel DP, Krausz KW, Xie C, Beyoğlu D, Gonzalez FJ, Idle JR
Metabolic profiling by gas chromatography-mass spectrometry of energy metabolism in high-fat diet-fed obese mice
May 18, 2017
PloS One
A novel, selective and sensitive single-ion monitoring (SIM) gas chromatography-mass spectrometry (GCMS) method was developed and validated for the determination of energy metabolites related to glycolysis, the tricarboxylic acid (TCA) cycle, glutaminolysis, and fatty acid β-oxidation. This assay used N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA) containing 1% tert-butyldimethylchlorosilane (TBDMCS) as derivatizing reagent and was highly reproducible, sensitive, specific and robust. The assay was used to analyze liver tissue and serum from C57BL/6N obese mice fed a high-fat diet (HFD) and C57BL/6N mice fed normal chow for 8 weeks. HFD-fed mice serum displayed statistically significantly reduced concentrations of pyruvate, citrate, succinate, fumarate, and 2-oxoglutarate, with an elevated concentration of pantothenic acid. In liver tissue, HFD-fed mice exhibited depressed levels of glycolysis end-products pyruvate and lactate, glutamate, and the TCA cycle intermediates citrate, succinate, fumarate, malate, and oxaloacetate. Pantothenate levels were 3-fold elevated accompanied by a modest increased gene expression of Scl5a6 that encodes the pantothenate transporter SLC5A6. Since both glucose and fatty acids inhibit coenzyme A synthesis from pantothenate, it was concluded that these data were consistent with downregulated fatty acid β-oxidation, glutaminolysis, glycolysis, and TCA cycle activity, due to impaired anaplerosis. The novel SIM GCMS assay provided new insights into metabolic effects of HFD in mice.

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