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Cell-type Specific Molecular Expression Levels by Restricted-Dimensional Cytometry
Get PDFBackground: Cytometric analysis has been commonly used to delineate distinct cell subpopulations among peripheral blood mononuclear cells by the differential expression of surface receptors. This capability has reached its apogee with high-dimensional approaches such as mass cytometry and spectral cytometry that include simultaneous assessment of 20–50 analytes. Unfortunately, this approach also engenders significant complexity with analytical and interpretational pitfalls. Methods: Here, we demonstrate a complementary approach with restricted-dimensionality to assess cell-type specific intracellular molecular expression levels at exceptional levels of precision. The expression of five analytes was individually assessed in four mononuclear cell-types from peripheral blood. Results: Distinctions in expression levels were seen between cell-types and between samples from different donor groups. Mononuclear cell-type specific molecular expression levels distinguished pregnant from nonpregnant women and G-CSF-treated from untreated persons. Additionally, the precision of our analysis was sufficient to quantify a novel relationship between two molecules—Rel A and translocator protein—by correlational analysis. Conclusions: Restricted-dimensional cytometry can provide a complementary approach to define characteristics of cell-type specific intracellular protein and phosphoantigen expression in mononuclear cells
Dose Tapering and Discontinuation of Biologic DMARDs in Axial Spondyloarthritis: A Narrative Review (2023 SPARTAN Annual Meeting Proceedings)
Get PDFPurpose of Review: Limited data is available for tapering or discontinuation of biologic therapy in patients with axSpA who are in disease remission. The current review concentrates on published studies regarding dose tapering or withdrawal of biologics in axSpA. Recent Findings: Recent evidence in light of randomized controlled trials suggests that tapering of b-DMARDs is a feasible strategy to maintain remission or low disease activity in axSpA patients. TNF inhibitors were the studied biologics in most of these trials. The disease flare rates were comparable to those maintained on standard dose in most of these studies, although with variable tapering strategies and follow-up. Additionally, the duration of disease in remission prior to tapering, studied primary outcome, and flare definitions were heterogeneous. Female sex, HLA-B*27 negativity, high physician global score, and high CRP were negative predictors of successful tapering, but not consistently reported in all the trials. Although designed to address efficacy, there were no safety concerns with b-DMARD tapering. Withdrawal or complete discontinuation of biologics met with increased risk of flares compared to standard dosing. Summary: Tapering of TNF inhibitors may be feasible in certain axSpA patients with an acceptable disease state; however, discontinuation is not currently recommended owing to increased risk of flare. Future studies with axSpA patients with longer remission duration prior to taper and different doses and types of b-DMARDs may provide more guidance
Is Postnatal Acetaminophen Therapy Problematic for Preterm Infants?
Get PDFIn this issue, Srajer et al. report on the neurodevelopmental outcomes at 18–21 months of preterm infants treated with acetaminophen in the NICU.1 Their study shows no evidence of neurological harm from acetaminophen, after adjusting for known risk factors for neurodevelopmental impairment (NDI). Temporal trends in both pain and patent ductus arteriosus (PDA) management have led to an increase in acetaminophen use in the NICU in recent years, resulting in a crucial need for long-term safety data in this vulnerable population
Kindlin-2 Regulates the Oncogenic Activities of Integrins and TGF-β in Triple-Negative Breast Cancer Progression and Metastasis
Get PDFKindlin-2, an adapter protein, is dysregulated in various human cancers, including triple-negative breast cancer (TNBC), where it drives tumor progression and metastasis by influencing several cancer hallmarks. One well-established role of Kindlin-2 involves the regulation of integrin signaling, achieved by directly binding to the cytoplasmic tail of the integrin β subunit. In this study, we present novel insights into Kindlin-2’s involvement in stabilizing the β1-Integrin:TGF-β type 1 receptor (TβRI) complexes, acting as a physical bridge that links β1-Integrin to TβRI. Loss of Kindlin-2 results in the degradation of this protein complex, leading to the inhibition of downstream oncogenic pathways. We used a diverse range of in vitro assays, including CRISPR/Cas9 gene editing, cell migration, 3D-tumorsphere formation and invasion, solid binding, co-immunoprecipitation, cell adhesion and spreading assays, as well as western blot and flow cytometry analyses, utilizing MDA-MB-231 and 4T1 TNBC cell lines. Additionally, preclinical in vivo mouse models of TNBC tumor progression and metastasis were employed to substantiate our findings. Our studies established the direct interaction between Kindlin-2 and β1-Integrin and between Kindlin-2 and TβRI. Disruption of these interactions, via CRISPR/Cas9-mediated knockout of Kindlin-2, led to the degradation of β1-Integrin and TβRI, resulting in the inhibition of oncogenic pathways downstream of both proteins, subsequently hindering tumor growth and metastasis. Treatment of Kindlin-2-deficient cells with the proteasome inhibitor MG-132 restored the expression of both β1-Integrin and TβRI. Furthermore, the rescue of Kindlin-2 expression reinstated their oncogenic activities in vitro and in vivo, while Kindlin-2 lacking domains involved in the interaction of Kindlin-2 with β1-Integrin or TβRI did not. This study identifies a novel function of Kindlin-2 in stabilizing the β1-Integrin:TβRI complexes and regulating their downstream oncogenic signaling. The translational implications of these findings are substantial, potentially unveiling new therapeutically targeted pathways crucial for the treatment of TNBC tumors
Pathogenicity Prediction of GABAA Receptor Missense Variants
Get PDFVariants in the genes encoding gamma-aminobutyric acid type A (GABAA) receptor subunits are associated with epilepsy. To date, over 1000 clinical variants have been identified in these genes. However, the majority of these variants lack functional studies and their clinical significance is uncertain although accumulating evidence indicates that proteostasis deficiency is the major disease-causing mechanism. Here, we apply two state-of-the-art modeling tools, namely AlphaMissense and Rhapsody to predict the pathogenicity of saturating missense variants in genes that encode the major subunits of GABAA receptors in the central nervous system, including GABRA1, GABRB2, GABRB3, and GABRG2. We demonstrate that the predicted pathogenicity correlates well between AlphaMissense and Rhapsody. In addition, AlphaMissense pathogenicity score correlates modestly with plasma membrane expression, peak current amplitude, and GABA potency of the variants that have available experimental data. Furthermore, almost all annotated pathogenic variants in the ClinVar database are successfully identified from the prediction, whereas uncertain variants from ClinVar partially due to the lack of experimental data are differentiated into different pathogenicity groups. The pathogenicity prediction of GABAA receptor missense variants provides a resource to the community as well as guidance for future experimental and clinical investigations
Postnatal Corticosteroid Therapy in Bronchopulmonary Dysplasia - Why Animal Studies Disagree with Clinical Trials?
Get PDFAbstract: The systematic review and meta-analysis of newborn animal models by Irene Lok et al. is the first to extensively summarize the literature regarding postnatal systemic corticosteroid use on lung development of newborn rodent models. The meta-analysis showed that the use of postnatal corticosteroids resulted in a reduction in body weight along with persistent alveolar simplification. The most frequently used corticosteroid was dexamethasone. Corticosteroids have been extensively used in clinical trials in preterm newborns. Trials using early systemic administration of corticosteroids reduced the rate of BPD or mortality with no increase in the rates of cerebral palsy. Use of late systemic corticosteroids (administered \u3e7 days after birth) also reduced the rate of BPD, mortality, and combined outcome of mortality or BPD. Late systemic corticosteroids showed no impact on the rates of neurodevelopmental outcomes in later childhood. It is important to note that later stages of inflammation leading to a more severe form of BPD continues to be a problem with no clear therapy in sight. The authors made a critical point in their paper – the negative effects of steroids were greater in the normal lung control animals than in the injured. This conveys caution in using steroids in a prophylactic manner. Impact: Use of systemic corticosteroids in clinical trials have shown good response in preterm neonates evidenced by reduced rate of bronchopulmonary dysplasia. Rodent models have not shown a similar beneficial response. Use of systemic corticosteroids have caused greater arrest of lung development in rodent models with normal lungs compared to those with lung damage
ASO Author Reflections: Comparison of Hospital Volume and Risk-Standardized Mortality Rate as a Proxy for Hospital Quality in Complex Oncologic Hepatopancreatobiliary Surgery
Get PDFMelanism in Polymorphic Terrestrial Snakes: A Meta-Analysis and Systematic Review
Get PDFBackground and Aim: Colour polymorphic populations constitute excellent model systems for testing ecological and evolutionary hypotheses, as alternate colourations are associated with differences in various biological, behavioural and life-history traits. Melanism is the most common and most obvious form of polymorphism. In reptiles in general (and snakes in particular), thermal melanism has been a popular hypothesis used to explain the appearance of black individuals. It suggests that a trade-off exists between superior thermoregulation and reduced protection through the loss of crypsis. Surprisingly, despite the growing body of literature available, to date, there are only two qualitative reviews on the evolutionary significance of melanism in reptiles and no quantitative synthesis. We conducted the first systematic review and meta-analysis summarising the current knowledge on melanism in polymorphic terrestrial snakes and synthesised the evidence for an adaptive advantage of the melanistic morph. Location: Northern Hemisphere. Taxon: Polymorphic terrestrial snakes. Results: Mean prevalence of melanism is 31% with no significant differences between species. Annual precipitation was a significant moderator of melanism prevalence. Our results revealed no significant differences in odds ratios of melanism between sexes or in mean body size. Main Conclusions: Environmental plasticity can be considered the primary cause of melanism, possibly as a result of seasonal climatic variations, a result corroborated by the formal meta-analysis conducted. Conclusions from the meta-analysis are that melanism in snakes follows Gloger\u27s rule, as is the case in birds and mammals, and as opposed to the thermal melanism hypothesis. Further, our findings do not lend support for other predictions from the thermal melanism hypothesis, such as skewed frequency of melanistics in favour of males or females, or larger body sizes in black individuals. Our results hold implications for the future diversity of animal populations, as climate change is predicted to decrease the degree of colour variation
Continuing Benefits of the Montreal Protocol and Protection of the Stratospheric Ozone Layer for Human Health and the Environment
Get PDFThe protection of Earth’s stratospheric ozone (O3) is an ongoing process under the auspices of the universally ratified Montreal Protocol and its Amendments and adjustments. A critical part of this process is the assessment of the environmental issues related to changes in O3. The United Nations Environment Programme’s Environmental Effects Assessment Panel provides annual scientific evaluations of some of the key issues arising in the recent collective knowledge base. This current update includes a comprehensive assessment of the incidence rates of skin cancer, cataract and other skin and eye diseases observed worldwide; the effects of UV radiation on tropospheric oxidants, and air and water quality; trends in breakdown products of fluorinated chemicals and recent information of their toxicity; and recent technological innovations of building materials for greater resistance to UV radiation. These issues span a wide range of topics, including both harmful and beneficial effects of exposure to UV radiation, and complex interactions with climate change. While the Montreal Protocol has succeeded in preventing large reductions in stratospheric O3, future changes may occur due to a number of natural and anthropogenic factors. Thus, frequent assessments of potential environmental impacts are essential to ensure that policies remain based on the best available scientific knowledge. Graphical abstract: (Figure presented.
Image-Based Fracture Surface Defect Characterization Methods for Additively Manufactured Ti-6Al-4V Tested in Fatigue
Get PDFFatigue initiation in additively manufactured samples/parts often occurs at processed-induced defects such as lack-of-fusion (LoF), keyhole, or other morphological/microstructural defects that have unique characteristics and measurable qualities. Attempts at identifying and minimizing such defects have utilized optimized processing conditions along with in situ and ex situ characterization that includes metallography and/or X-ray computed tomography (XCT). This paper highlights the benefits of using fracture surface analyses to detect and quantify defects that may not be detected by metallography/XCT due to sectioning and resolution limits. In addition to using manual quantification of fatigue initiating LoF and keyhole defects on fracture surfaces, image-based machine learning using convolutional neural networks such as U-Net were also used to automate the process. Statistical analyses were used to identify the extreme cases of defects that initiated and accelerated fatigue and to model the distribution of defect size and shape characteristics to distinguish the type of defect. Initial results show agreement between trained machine learning models and ground truth data in defect segmentation, and the distributions of defect characteristics are distinguishable to particular process-induced defect types. This article was updated to correct Arafath Nifar to Arafath Nihar in the author list
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