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Publication
Journal: Communications Biology
October/17/2020
Abstract
Both biological and mechanical signals are known to influence cell proliferation. However, biological signals are mostly studied in two-dimensions (2D) and the interplay between these different pathways is largely unstudied. Here, we investigated the influence of the cell culture environment on the response to bFGF, a widely studied and important proliferation growth factor. We observed that human mesenchymal stromal cells (hMSCs), but not fibroblasts, lose the ability to respond to soluble or covalently bound bFGF when cultured on microfibrillar substrates. This behavior correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates. Inhibition of actomyosin or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 cells. To our knowledge, this is the first time FGFR1 expression is shown to be regulated through a mechanosensitive pathway in hMSCs. These results add to the sparse literature on FGFR1 regulation and potentially aid designing tissue engineering constructs that better control cell proliferation.
Publication
Journal: Nature Communications
October/17/2020
Abstract
Protein-DNA interactions are key to the functionality and stability of the genome. Identification and mapping of protein-DNA interaction interfaces and sites is crucial for understanding DNA-dependent processes. Here, we present a workflow that allows mass spectrometric (MS) identification of proteins in direct contact with DNA in reconstituted and native chromatin after cross-linking by ultraviolet (UV) light. Our approach enables the determination of contact interfaces at amino-acid level. With the example of chromatin-associated protein SCML2 we show that our technique allows differentiation of nucleosome-binding interfaces in distinct states. By UV cross-linking of isolated nuclei we determined the cross-linking sites of several factors including chromatin-modifying enzymes, demonstrating that our workflow is not restricted to reconstituted materials. As our approach can distinguish between protein-RNA and DNA interactions in one single experiment, we project that it will be possible to obtain insights into chromatin and its regulation in the future.
Publication
Journal: Neurology
October/17/2020
Abstract
Objective: To describe the respiratory trajectories and their correlation with motor function in an international paediatric cohort of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA).
Methods: Eight-year retrospective observational study of patients in the iSMAc natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC% predicted (FVC%P.), Non-Invasive ventilation (NIV) requirement. Hammersmith functional motor scale (HFMS) and Revised performance of upper limb (RULM) were correlated with respiratory function. We excluded patients in interventional clinical trials and on Nusinersen commercial therapy.
Results: There were 437 patients with SMA: 348 type 2, 89 non-ambulant type 3. Mean age at first visit was 6.9(±4.4) and 11.1(±4) years. In SMA type 2 FVC%P declined by 4.2%/year from 5 to 13 years, followed by a slower decline (1.0%/year). In type 3 FVC%P declined by 6.3%/year between 8 and 13 years, followed by a slower decline (0.9%/year). 39% SMA type 2 and 9% type 3 required NIV at median age 5.0(1.8-16.6) and 15.1(13.8-16.3) years. 84% SMA type 2 and 80% type 3 had scoliosis, 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM in both subtypes.
Conclusions: In SMA type 2 and non-ambulant type 3 lung function declines differently, with a common levelling after age 13 years. Lung and motor function correlated in both subtypes. Our data further defines the milder SMA phenotypes and provides novel information to benchmark the long-term efficacy of new treatments for SMA.
Publication
Journal: Science immunology
October/17/2020
Abstract
Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49a+CD16- NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16- NK cells when compared with conventional CD49a-CD16+ NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a+CD16- NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.
Publication
Journal: eNeuro
October/17/2020
Abstract
Impairment of axonal transport is an early pathological event that precedes neurotoxicity in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), a causative agent of AD, activate intracellular signaling cascades that trigger phosphorylation of many target proteins, including tau, resulting in microtubule destabilization and transport impairment. Here, we investigated how KIF1A, a kinesin-3 family motor protein required for the transport of neurotrophic factors, is impaired in mouse hippocampal neurons treated with AβOs. By live cell imaging, we observed that AβOs inhibit transport of KIF1A-GFP similarly in wildtype and tau knockout neurons, indicating that tau is not required for this effect. Pharmacological inhibition of glycogen synthase kinase 3β (GSK3β), a kinase overactivated in AD, prevented the transport defects. By mass spectrometry on KIF1A immunoprecipitated from transgenic AD mouse brain, we detected phosphorylation at Ser 402, which conforms to a highly conserved GSK3β consensus site, and confirmed that this site is phosphorylated by GSK3β in vitro Finally, we tested whether a phosphomimic of S402 could modulate KIF1A motility in control and AβO-treated mouse neurons and in a Golgi dispersion assay devoid of endogenous KIF1A. In both systems, transport driven by mutant motors was similar to that of wildtype motors. In conclusion, GSK3β impairs KIF1A transport but does not regulate motor motility at S402. Further studies are required to determine the specific phosphorylation sites on KIF1A that regulate its cargo binding and/or motility in physiological and disease states.SIGNIFICANCE STATEMENT Axonal transport of proteins and organelles is required for neuronal function and survival and is impaired in Alzheimer's disease (AD). Pathogenic mechanisms that directly impact motor protein motility prior to neuronal toxicity have not been widely investigated. Here, we show that KIF1A, the primary kinesin motor required for transport of neurotrophic factors, is impaired in mouse neurons treated with amyloid-β oligomers, a causative agent of AD. Inhibition of GSK3β, a kinase overactivated in AD, prevents these defects. We detected phosphorylation of S402, a highly conserved GSK3β consensus site, in KIF1A immunoprecipitated from AD mouse brain. However, a phosphomimic of S402 did not modulate KIF1A motility in cell-based assays. Thus, GSK3β impairs KIF1A transport but likely not through phosphorylation at S402.
Keywords: Alzheimer's disease; Amyloid beta oligomers; Axonal transport; Glycogen synthase kinase beta; Kinesin-3 (KIF1A); Motor protein phosphorylation.
Publication
Journal: British Journal of Ophthalmology
October/17/2020
Abstract
Background/aims: The SARS-CoV-2 pandemic has imposed barriers to retinal care delivery worldwide. In this context, retinal services are exploring novel ways to ensure access to healthcare.
Methods: We conducted a worldwide survey among retinal specialists between March 31, 2020 and April 12, 2020. The expert survey was developed on the basis of focus group discussions involving retinal specialists and literature searches. It included 44 questions on alternative ways of care provision including digital health domains such as teleophthalmology, home monitoring or decentralised patient care.
Results: 214 retinal experts participated in the survey, of which 120 (56.1%) had more than 15 years of experience in ophthalmology. Most participants were clinicians (n=158, 73.9%) practising in Western Europe (n=159, 74%). In the majority of institutions, teleophthalmology, home monitoring and decentralised patient care have not been implemented before the pandemic (n=46, 21.8.1%; n=64, 29.9%; n=38, 19.1%). During the pandemic, the use of teleophthalmology and home monitoring increased significantly (n=105, p<0.001; n=90, p<0.001). In the subgroup of institutions reporting no teleophthalmology service before and implementing a service during the pandemic (34/70, 48.6%), reimbursement was the sole significant parameter (OR 9.62 (95% CI 2.42 to 38.16); p<0.001).
Conclusion: Digital health is taking the centre stage tackling unpreceded challenges of retinal care delivery during the SARS-CoV-2 pandemic and may sustainably change the way we practice ophthalmology.
Keywords: Retina; Telemedicine.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
October/17/2020
Abstract
Recent measurements of the elastic constants in lyotropic chromonic liquid crystals (LCLCs) have revealed an anomalously small twist elastic constant compared to the splay and bend constants. Interestingly, measurements of the elastic constants in the micellar lyotropic liquid crystals (LLCs) that are formed by surfactants, by far the most ubiquitous and studied class of LLCs, are extremely rare and report only the ratios of elastic constants and do not include the twist elastic constant. By means of light scattering, this study presents absolute values of the elastic constants and their corresponding viscosities for the nematic phase of a standard LLC composed of disk-shaped micelles. Very different elastic moduli are found. While the splay elastic constant is in the typical range of 1.5 pN as is true in general for thermotropic nematics, the twist elastic constant is found to be one order of magnitude smaller (0.30 pN) and almost two orders of magnitude smaller than the bend elastic constant (21 pN). These results demonstrate that a small twist elastic constant is not restricted to the special case of LCLCs, but is true for LLCs in general. The reason for this extremely small twist elastic constant very likely originates with the flexibility of the assemblies that are the building blocks of both micellar and chromonic lyotropic liquid crystals.
Keywords: chirality; elasticity; light scattering; lyotropic liquid crystals; nematic liquid crystals.
Publication
Journal: Journal of Nursing Measurement
October/17/2020
Abstract
Introduction and objective: The cold chain of immunobiological agent conservation occupies a strategic position in the immunization system and, therefore, needs to be evaluated. This study psychometrically evaluated the Immunobiological Agent Conservation Assessment Scale (Escala de Avaliação da Conservação de Imunobiológicos-EACI).
Methods: Methodological study carried out in Minas Gerais, Brazil, including 275 immunization rooms, divided into three stages: (a) pilot study; (b) internal consistency and temporal reproducibility; (c) criterion validity and structural validity.
Results: The EACI items were analyzed for comprehension and clarity; presenting internally consistency (Cronbach's alpha: 0.72 [95% CI: 0.666-0.763]) and temporal reproducibility (ICC: 0.948 [95% CI: 0.911-0.981]), in addition to explaining 72% of the variance and discriminating the groups criteria (p = .0025).
Conclusion: The EACI is psychometrically reliable and valid and is the first assessment instrument available for this construct.
Keywords: immunization; nursing; psychometrics; refrigeration; vaccines; validation studies.
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Publication
Journal: Hospital pediatrics
October/17/2020
Abstract
Objectives: Hospitalization provides an opportunity to address sexual health needs of adolescents who may not otherwise receive regular medical care. We investigated documentation of a sexual health discussion with adolescents hospitalized at our medical center to determine if previous primary care physician (PCP) visits in the same health system were associated with sexual health documentation during the hospital admission.
Methods: We retrospectively identified adolescents aged 13 to 17 years discharged from the pediatric general ward. Documented discussion of sexual health was reviewed in the electronic medical record. Previous PCP visits were identified from the affiliated primary care clinics within 12 months before hospitalization. We also queried follow-up PCP visits within 90 days of discharge to determine if a sexual health discussion during hospitalization was followed-up in the outpatient setting.
Results: We analyzed 394 patients (49% girls; median age 15 years), of whom 122 (31%) had documentation of a sexual health discussion while hospitalized and 75 (19%) had previous PCP visits in our health system. On multivariable analysis, older age (P < .001), female sex (P = .016), admission from the emergency department (P < .001), and a genitourinary primary problem at admission (P = .007), but not previous PCP visits, were associated with increased likelihood of sexual health documentation.
Conclusions: Although discussion of sexual health was uncommon overall for hospitalized adolescents, we noted that nearly 4 in 5 adolescents for whom this was documented had not recently visited a PCP in our health system. These findings highlight hospitalization as a unique opportunity for sexual health intervention among adolescents who may not regularly see a PCP.
Publication
Journal: Journal of Nursing Measurement
October/17/2020
Abstract
Background and purpose: Deep vein thrombosis (DVT) is a serious condition resulting in poor patient outcomes. Therefore, methods to improve nurses' use of preventive measures for DVT are paramount. The purpose of this study was to develop and validate an instrument that captured nurses' intentions to use DVT preventive measures.
Methods: Instrument development occurred in several stages stemming from the recommended formatted structure associated with theory of planned behavior (TPB). Content validity was established with a panel of experts, then the instrument was pilot tested with a sample of intensive care unit (ICU) nurses.
Results: The final instrument consisted of four subscales, each subscale was tested with four items by content validity index (CVI) ranging between 0.8 and 1.0, and an overall S-CVI/Ave of 0.93.
Conclusions: The instrument demonstrated high content validity. Future research will test the instrument for psychometric properties.
Keywords: DVT; DVT prevention; DVT preventive measures; critically ill patients; instrument development; theory of planned behavior.
Publication
Journal: Journal of Nursing Measurement
October/17/2020
Abstract
Background and purpose: Nurses experienced compassion fatigue (CF), depression, burnout (BO), and even signs of post-traumatic stress disorder. This study aimed to evaluate the psychometric properties of the Professional Quality of Life Scale (ProQOL) among nurses in the Southeast Asia context.
Methods: Psychometric testing of interitem correlations and reliability, and both convergent and discriminant validity, as well as construct validity analyses was conducted among 1,338 nurses from two academic centers in Singapore.
Results: Findings demonstrated significant interconstruct correlations among the three subscales of ProQOL, namely compassion satisfaction (CS), BO, and secondary traumatic stress (STS). ProQOL displayed satisfactory internal consistency and discriminant validity.
Conclusions: Psychometric properties of the CS component were found to be satisfactory. ProQOL may be integrated into strategies in supporting and improving nurses' QoL which could focus to lessen BO and CF at work, as well as improving individual satisfaction in the care of patients.
Keywords: nurses; professional quality of life.
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Publication
Journal: Journal of Biological Chemistry
October/17/2020
Abstract
Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal 4th PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre-mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic 4th PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help understand significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.
Keywords: Hey1; Notch signaling; cardiovascular disease; development; embryo; endothelial cell; gene knockout; great vessel morphogenesis; pharyngeal arch artery; transcription regulation.
Publication
Journal: Heart
October/17/2020
Abstract
Objective: People's socioeconomic status (SES) has a major impact on the risk of atherosclerotic cardiovascular disease (ASCVD) in primary prevention. In patients with existing ASCVD these associations are less documented. Here, we evaluate to what extent SES is still associated with patients' risk profile in secondary prevention.
Methods: Based on results from a large sample of patients with coronary heart disease from the European Action on Secondary and Primary Prevention through Intervention to Reduce Events study, the relationship between SES and cardiovascular risk was examined. A SES summary score was empirically constructed from the patients' educational level, self-perceived income, living situation and perception of loneliness.
Results: Analyses are based on observations in 8261 patients with coronary heart disease from 27 countries. Multivariate logistic regression analyses demonstrate that a low SES is associated (OR, 95% CI) with lifestyles such as smoking in men (1.63, 1.37 to 1.95), physical activity in men (1.51, 1.28 to 1.78) and women (1.77, 1.32 to 2.37) and obesity in men 1.28 (1.11 to 1.49) and women 1.65 (1.30 to 2.10). Patients with a low SES have more raised blood pressure in men (1.24, 1.07 to 1.43) and women (1.31, 1.03 to 1.67), used less statins and were less adherent to them. Cardiac rehabilitation programmes were less advised and attended by patients with a low SES. Access to statins in middle-income countries was suboptimal leaving about 80% of patients not reaching the low-density lipoprotein cholesterol target of <1.8 mmol/L. Patients' socioeconomic level was also strongly associated with markers of well-being.
Conclusion: These results illustrate the complexity of the associations between SES, well-being and secondary prevention in patients with ASCVD. They emphasise the need for integrating innovative policies in programmes of cardiac rehabilitation and secondary prevention.
Keywords: cardiac risk factors and prevention.
Publication
Journal: PDA Journal of Pharmaceutical Science and Technology
October/17/2020
Abstract
Background: Flow Cytometry is a complex measurement characterisation technique, utilised within the manufacture, measurement and release of Cell and Gene Therapy products for rapid, high content and multiplexed discriminatory cell analysis. A number of factors influence the variability in the measurement reported including, but not limited to, biological variation, reagent variation, laser and optical configurations and data analysis methods. This research focuses on understanding the contribution of manual operator variability within the data analysis phase.
Methods: 38 participants completed a questionnaire providing information about experience and motivational factors, before completing a simple gating study. Results were analysed using Gauge Repeatability & Reproducibility techniques to quantify participant uncertainty. The various stages of the gating sequence were combined through summation in quadrature and expanded to give each participant a representative uncertainty value.
Results: 85 % of participants surveyed preferred manual gating to automated data analysis, with primary reasons being legacy (″it's always been done that way″) and accuracy, not in the metrological sense, but in clear definition of the correct target population. The median expanded uncertainty was calculated as 3.6 % for the population studied, with no significant difference between more or less experienced users.
Discussion: Operator subjectivity can be quantified to include within measurement uncertainty budgets, required for various standards and qualifications. An emphasis on biomanufacturing measurement terminology is needed to help understand future and potential solutions, possibly looking at translational clinical models to engage and enhance better training and protocols within industrial and research settings.
Keywords: Flow Cytometry; Gauge R&R; Measurement Uncertainty; Operators; Uncertainties; Variation.
Publication
Journal: Gut
October/17/2020
Abstract
The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time.
Keywords: ascites; cirrhosis.
Publication
Journal: Heart
October/17/2020
Abstract
Objective: Ethnic differences in cardiovascular disease incidence, but not cardiovascular disease recurrence, are reported. We characterised long-term risk of major adverse cardiovascular event (MACE) and mortality following a non-fatal cardiovascular event in a British cohort of South Asians, African Caribbeans and Europeans.
Methods: We identified index and recurrent cardiovascular events and mortality between 1988 and 2017 using hospital records and death registry. Using multivariable hazards models, we separately calculated the adjusted HR of MACE and death following index event, adjusting for demographics, vascular and lifestyle risk factors. Using interaction terms, we evaluated if decade of index event modified the association between ethnicity and outcomes.
Results: South Asians were younger at the index event (median age 66 years, n=396) than Europeans (69 years, n=335) and African Caribbeans (70 years, n=70). During 4228 person-years, of the 801 patients, 537 developed MACE and 338 died, with the highest crude rate of MACE in South Asians. On adjustment of baseline factors, compared with the Europeans, the higher risk of MACE (HR 0.97, 95% CI 0.77 to 1.21) and the lower risk of mortality (HR 0.95, 95% CI 0.72 to 1.26) in South Asians was eliminated. African Caribbeans had similar outcomes to Europeans (HR MACE 1.04, 95% CI 0.74 to 1.47; and HR death 1.07, 95% CI 0.70 to 1.64). Long-term survival following an index event improved in South Asians (ptrend 0.02) and African Caribbeans (ptrend 0.07) compared with Europeans.
Conclusions: Baseline vascular risk factors explained the observed ethnic variation in cardiovascular disease recurrence and long-term mortality, with a relative improvement in survival of minority ethnic groups over time.
Keywords: cardiac risk factors and prevention; epidemiology; quality and outcomes of care.
Publication
Journal: G3: Genes, Genomes, Genetics
October/17/2020
Abstract
Genomic selection (GS) is a breeding approach which exploits genome-wide information and whose unprecedented success has shaped several animal and plant breeding schemes through delivering their genetic progress. This is the first study assessing the potential of GS in apricot (Prunus armeniaca) to enhance postharvest fruit quality attributes. Genomic predictions were based on a F1 pseudo-testcross population, comprising 153 individuals with contrasting fruit quality traits. They were phenotyped for physical and biochemical fruit metrics in contrasting climatic conditions over two years. Prediction accuracy (PA) varied from 0.31 for glucose content with the Bayesian LASSO (BL) to 0.78 for ethylene production with RR-BLUP, which yielded the most accurate predictions in comparison to Bayesian models and only 10% out of 61,030 SNPs were sufficient to reach accurate predictions. Useful insights were provided on the genetic architecture of apricot fruit quality whose integration in prediction models improved their performance, notably for traits governed by major QTLs. Furthermore, multivariate modeling yielded promising outcomes in terms of PA within training partitions partially phenotyped for target traits. This provides a useful framework for the implementation of indirect selection based on easy-to-measure traits. Thus, we highlighted the main levers to take into account for the implementation of GS for fruit quality in apricot, but also to improve the genetic gain in perennial species.
Keywords: Prunus armeniaca; accuracy; genetic architecture; genomic; multivariate modeling; prediction.
Publication
Journal: Journal of Biological Chemistry
October/17/2020
Abstract
Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low to higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar, but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.
Keywords: IDP; Protein binding; coupled binding and folding; intrinsically disordered protein; pre-steady-state kinetics; protein complex; protein evolution; protein folding; transition state.
Publication
Journal: Hospital pediatrics
October/17/2020
Publication
Journal: Research
October/17/2020
Publication
Journal: Cancer Research
October/17/2020
Abstract
Although B cell acute lymphoblastic leukemia (ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients: while the majority of peaks remained stable between diagnosis and relapse, yet a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific super-enhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse.
Publication
Journal: Diabetes Care
October/17/2020
Abstract
Objective: In recent years, a growing number of people with type 1 diabetes have gained access to real-time continuous glucose monitoring (rtCGM). Long-term benefits of rtCGM are unclear because of a lack of large studies of long duration. We evaluated whether real-world rtCGM use up to 24 months offered benefits, particularly in those living with impaired awareness of hypoglycemia (IAH).
Research design and methods: This 24-month, prospective, observational, cohort study followed 441 adults with insulin pumps receiving full reimbursement for rtCGM. Forty-two percent had IAH. The primary end point was evolution of HbA1c, with secondary end points change in acute hypoglycemia complications, diabetes-related work absenteeism, and quality of life scores. Additionally, we evaluated whether people could achieve glycemic consensus targets during follow-up.
Results: After 24 months, HbA1c remained significantly lower compared with baseline (7.64% [60 mmol/mol] vs. 7.37% [57 mmol/mol], P < 0.0001). Sustained benefits were also observed for the score on the hypoglycemia fear survey and hypoglycemia-related acute complications irrespective of hypoglycemia awareness level. People with IAH had the strongest improvement, especially for severe hypoglycemia (862 events in the year before vs. 119 events per 100 patient-years in the 2nd year, P < 0.0001). Over 24 months, more people were able to meet hypoglycemia consensus targets at the expense of slightly fewer people achieving hyperglycemia consensus targets. Furthermore, the number of people with HbA1c <7% (<53 mmol/mol) without severe hypoglycemia events more than doubled (11.0% vs. 25.4%, P < 0.0001).
Conclusions: Use of rtCGM led to sustained improvements in hypoglycemia-related glucose control over 24 months. Lower fear of hypoglycemia, less acute hypoglycemia-related events, and diabetes-related days off from work were observed, particularly in those with IAH.
Publication
Journal: Journal of Cell Science
October/17/2020
Abstract
Cytoskeleton-associated protein 4 (CKAP4) is palmitoylated type II transmembrane protein localized to the endoplasmic reticulum (ER). Knockout (KO) of CKAP4 in HeLaS3 cells induced the alterations of mitochondrial structures and increased the number of ER-mitochondria contact sites. To understand the involvement of CKAP4 in mitochondrial functions, the binding proteins of CKAP4 were explored, enabling identification of the mitochondrial porin voltage-dependent anion-selective channel protein 2 (VDAC2), which is localized to the outer mitochondrial membrane. Palmitoylation at Cys100 of CKAP4 was required for the binding of CKAP4 and VDAC2. In CKAP4 KO cells, the binding of inositol trisphosphate receptor (IP3R) and VDAC2 was enhanced, the intramitochondrial Ca2+ concentration increased, and the mitochondrial membrane potential decreased. In addition, CKAP4 KO decreased the oxidative consumption rate, in vitro cancer cell proliferation under low-glucose conditions, and in vivo xenograft tumor formation. The phenotypes were not rescued by a palmitoylation-deficient CKAP4 mutant. These results suggest that CKAP4 plays a role in maintaining mitochondrial functions through the binding to VDAC2 at ER-mitochondria contact sites and that palmitoylation is required for this novel function of CKAP4.
Keywords: CKAP4; ER; MAM; Mitochondria; Palmitoylation; VDAC2.
Publication
Journal: Cancer Prevention Research
October/17/2020
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed too late for effective therapy. The classic strategy for early detection biomarker advancement consists of initial retrospective phases of discovery and validation with tissue samples taken from individuals diagnosed with disease, compared to controls. Using this approach, we previously reported the discovery of a blood biomarker panel consisting of thrombospondin-2 (THBS2) and CA19-9 that together could discriminate resectable stage I and IIa PDAC as well as stages III and IV PDAC, with c-statistic values in the range of 0.96-0.97 in two Phase 2 studies. We now report that in two studies of blood samples prospectively collected from one to fifteen years prior to a PDAC diagnosis (Mayo Clinic and PLCO cohorts), THBS2 and/or CA19-9 failed to discriminate cases from healthy controls at the AUC=0.8 needed. We conclude that PDAC progression may be heterogeneous and for some individuals can be more rapid than generally appreciated. It is important that PDAC early detection studies incorporate high-risk, prospective pre-diagnostic cohorts into discovery and validation studies.
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