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Lupus erythematosus (LE)-specific bullous lesions are often difficult to distinguish from other bullous diseases presenting in patients with systemic lupus erythematosus. Herein, we describe a 49-year-old woman with systemic lupus erythematosus with recurrent tense bullae on the forearms. Clinical, histopathologic, and serologic findings led to the diagnosis of LE-specific bullous lesions. We also summarize the diagnostic clues for distinguishing LE-specific bullous lesions, bullous systemic lupus erythematosus, and erythema multiforme-like lesions in LE (Rowell syndrome).
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Eritema Multiforme , Lupus Eritematoso Cutáneo , Lupus Eritematoso Sistémico , Enfermedades Cutáneas Vesiculoampollosas , Femenino , Humanos , Persona de Mediana Edad , Vesícula/diagnóstico , Vesícula/etiología , Vesícula/patología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/patología , Eritema Multiforme/diagnóstico , Eritema Multiforme/patología , Enfermedades Cutáneas Vesiculoampollosas/diagnóstico , Enfermedades Cutáneas Vesiculoampollosas/patología , Lupus Eritematoso Cutáneo/diagnóstico , Lupus Eritematoso Cutáneo/patologíaRESUMEN
Significance: Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim: This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach: Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion: Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.
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Técnicas Histológicas , Microscopía , Animales , Citometría de Flujo , Procesamiento de Imagen Asistido por ComputadorRESUMEN
OBJECTIVES: This systematic review of qualitative studies explored interventions to improve student nurses' knowledge, attitudes or willingness to work with older people. Student nurses are likely to encounter older people in all health and aged care settings, however, research demonstrates that few have career aspirations in gerontological nursing. METHODS: Qualitative systematic review method based on the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Search of Medline, Embase, PsycINFO, EBSCOhost and Scopus yielded 1841 articles which were screened to include primary research about educational interventions to improve student nurses' knowledge, attitudes and/or willingness to work with older people. Data extraction was performed on the 14 included studies, and data were analysed using directed content analysis. The Mixed Methods Appraisal Tool (MMAT) was used the assess the quality of the studies. CONCLUSIONS: Educational interventions included theory or practice courses, or a combination of theory and practice. While most interventions changed nursing students' negative attitudes towards older people, few increased their willingness to work with them. Practice courses had the most significant impact on willingness to work with older people. Quality assessment revealed methodical limitations. More research is needed to better understand the elements of practice interventions that enhance student nurses' knowledge, attitudes, and willingness to work with older people, so that they can be replicated.
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Geriatría , Enfermeras y Enfermeros , Estudiantes de Enfermería , Anciano , Humanos , Actitud del Personal de Salud , Competencia ClínicaRESUMEN
Although RAS was formerly considered undruggable, various agents that inhibit RAS or specific RAS oncoproteins have now been developed. Indeed, the importance of directly targeting RAS has recently been illustrated by the clinical success of mutant-selective KRAS inhibitors. Nevertheless, responses to these agents are typically incomplete and restricted to a subset of patients, highlighting the need to develop more effective treatments, which will likely require a combinatorial approach. Vertical strategies that target multiple nodes within the RAS pathway to achieve deeper suppression are being investigated and have precedence in other contexts. However, alternative strategies that co-target RAS and other therapeutic vulnerabilities have been identified, which may mitigate the requirement for profound pathway suppression. Regardless, the efficacy of any given approach will likely be dictated by genetic, epigenetic and tumour-specific variables. Here we discuss various combinatorial strategies to treat KRAS-driven cancers, highlighting mechanistic concepts that may extend to tumours harbouring other RAS mutations. Although many promising combinations have been identified, clinical responses will ultimately depend on whether a therapeutic window can be achieved and our ability to prospectively select responsive patients. Therefore, we must continue to develop and understand biologically diverse strategies to maximize our likelihood of success.
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Cells are equipped with asymmetrically localised and functionally specialised components, including cytoskeletal structures and organelles. Positioning these components to specific intracellular locations in an asymmetric manner is critical for their functionality and affects processes like immune responses, tissue maintenance, muscle functionality, and neurobiology. Here, we provide an overview of strategies to actively move, position, and anchor organelles to specific locations. By conceptualizing the cytoskeletal forces and the organelle-to-cytoskeleton connectivity, we present a framework of active positioning of both membrane-enclosed and membrane-less organelles. Using this framework, we discuss how different principles of force generation and organelle anchorage are utilised by different cells, such as mesenchymal and amoeboid cells, and how the microenvironment influences the plasticity of organelle positioning. Given that motile cells face the challenge of coordinating the positioning of their content with cellular motion, we particularly focus on principles of organelle positioning during migration. In this context, we discuss novel findings on organelle positioning by anchorage-independent mechanisms and their advantages and disadvantages in motile as well as stationary cells.
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DESIGN: Prospective diagnostic study. OBJECTIVES: Anatomical evaluation and graduation of the severity of spinal stenosis is essential in degenerative cervical spine disease. In clinical practice, this is subjectively categorized on cervical MRI lacking an objective and reliable classification. We implemented a fully-automated quantification of spinal canal compromise through 3D T2-weighted MRI segmentation. SETTING: Medical Center - University of Freiburg, Germany. METHODS: Evaluation of 202 participants receiving 3D T2-weighted MRI of the cervical spine. Segments C2/3 to C6/7 were analyzed for spinal cord and cerebrospinal fluid space volume through a fully-automated segmentation based on a trained deep convolutional neural network. Spinal canal narrowing was characterized by relative values, across sever segments as adapted Maximal Canal Compromise (aMCC), and within the index segment as adapted Spinal Cord Occupation Ratio (aSCOR). Additionally, all segments were subjectively categorized by three observers as "no", "relative" or "absolute" stenosis. Computed scores were applied on the subjective categorization. RESULTS: 798 (79.0%) segments were subjectively categorized as "no" stenosis, 85 (8.4%) as "relative" stenosis, and 127 (12.6%) as "absolute" stenosis. The calculated scores revealed significant differences between each category (p ≤ 0.001). Youden's Index analysis of ROC curves revealed optimal cut-offs to distinguish between "no" and "relative" stenosis for aMCC = 1.18 and aSCOR = 36.9%, and between "relative" and "absolute" stenosis for aMCC = 1.54 and aSCOR = 49.3%. CONCLUSION: The presented fully-automated segmentation algorithm provides high diagnostic accuracy and objective classification of cervical spinal stenosis. The calculated cut-offs can be used for convenient radiological quantification of the severity of spinal canal compromise in clinical routine.
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This paper aims to reduce friction pair erosion of the clutch in the case of continuous shift; the dynamic separation process of the friction pair is investigated. The temperature of the friction pair, friction torque, and separation speed in the separation process are taken as the research objects, and the dynamics simulation model and finite element thermal coupling simulation model of the clutch separation process are established. The nonlinear dynamic separation characteristics of the friction pair are investigated by comparing and analyzing the effects of control parameters such as rotational speed difference, damping ratio, and lubricant viscosity on the friction torque, friction pair separation speed, separation gap, and contact stress during the separation process. The gap recovery coefficient is proposed as a response indicator for observing the separation process in response to the inability to observe the nonlinear dynamic motion of the friction pair during the separation process and to measure the end time of the separation. Finally, the clutch was subjected to a separation test. The results show that the proposed gap recovery coefficient accurately describes the separation process. The simulation model can simulate the clutch's separation and predict the trend of separation parameters.
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In this study, a poor/imperfect interphase is assumed to express the effective interphase thickness, operative filler concentration, percolation onset and volume share of network in graphene-polymer systems. Additionally, a conventional model is advanced by the mentioned terms for conductivity of samples by the extent of conduction transference between graphene and polymer medium. The model predictions are linked to the experimented data. Likewise, the mentioned terms as well as the conductivity of nanocomposites are expressed at dissimilar ranges of various factors. The novel equations successfully predict the percolation onset and conductivity in the samples containing a poor/imperfect interphase. Thin and long nanosheets with high conduction transportation desirably govern the percolation onset and nanocomposite conductivity, but a bigger tunneling distance causes a lower conductivity.
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As one of the most prevalent anti-phage defense systems in prokaryotes, Gabija consists of a Gabija protein A (GajA) and a Gabija protein B (GajB). The assembly and function of the Gabija system remain unclear. Here we present cryo-EM structures of Bacillus cereus GajA and GajAB complex, revealing tetrameric and octameric assemblies, respectively. In the center of the complex, GajA assembles into a tetramer, which recruits two sets of GajB dimer at opposite sides of the complex, resulting in a 4:4 GajAB supramolecular complex for anti-phage defense. Further biochemical analysis showed that GajA alone is sufficient to cut double-stranded DNA and plasmid DNA, which can be inhibited by ATP. Unexpectedly, the GajAB displays enhanced activity for plasmid DNA, suggesting a role of substrate selection by GajB. Together, our study defines a framework for understanding anti-phage immune defense by the GajAB complex.
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The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER+ breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1, KLF4, YAP1, SNAI1, and MYC. Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML-depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Significantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer, and offer new insights into the unique roles of PML isoforms in breast cancer.
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The hypomethylating agent 5-azacytidine (AZA) is the first-line treatment for AML patients unfit for intensive chemotherapy. The effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, evidence supporting higher ERE MAPs presentation after AZA treatment is lacking. Therefore, using proteogenomics, we examined the impact of AZA on the repertoire of MAPs and their source transcripts. AZA-treated AML upregulated both CTA and ERE transcripts, but only CTA MAPs were presented at greater levels. Upregulated ERE transcripts triggered innate immune responses against double-stranded RNAs but were degraded by autophagy, and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2. Autophagy inhibition had an additive effect with AZA on AML cell proliferation and survival, increased ERE levels, increased pro-inflammatory responses, and generated immunogenic tumor-specific ERE-derived MAPs. Finally, autophagy was associated with a lower abundance of CD8+ T-cell markers in AML patients expressing high levels of EREs. This work demonstrates that AZA-induced EREs are degraded by autophagy and shows that inhibiting autophagy can improve the immune recognition of AML blasts in treated patients.
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BACKGROUND: Neurodevelopmental trajectories of preterm children may have changed due to changes in care and in society. We aimed to compare neurodevelopmental trajectories in early and moderately late preterm children, measured using the Developmental (D)-score, in two cohorts born 15 years apart. METHODS: We included early preterm and moderately late preterm children from two Dutch cohorts (LOLLIPOP, 2002-2003 and ePREM, 2016-2017). ePREM counterparts were matched to LOLLIPOP participants by gestational age and sex. D-score trajectories were summarized by a multilevel model with random intercepts and random slopes, and multigroup analyses were used to test if the intercepts and slopes differed across cohorts. RESULTS: We included 1686 preterm children (1071 moderately late preterm, 615 early preterm) from LOLLIPOP, and matched these with 1686 ePREM counterparts. The neurodevelopmental trajectories of the two cohorts were mostly similar. For early preterm children, we found no statistically significant differences. For moderately late preterm children, both the intercept (43.0 vs. 42.3, p < 0.001) and slope (23.5 vs. 23.9, p = 0.002) showed some, but only clinically minor, differences. CONCLUSION: Developmental trajectories, measured using the D-score, in the first four years of life are comparable and stable across a period of 15 years for both early and moderately late preterm children. IMPACT: Neurodevelopmental trajectories are similar for early and moderately late preterm children born 15 years apart and thus seem quite stable in time. The validated Developmental score visualizes these trajectories based on developmental milestone attainment Because of its stability over time, the Developmental score trajectory may aid clinicians in neurodevelopmental assessment of preterm children as this simplifies monitoring and interpretation, similar to a growth chart.
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OBJECTIVES: To determine, among neonates at-risk for hyperbilirubinemia, whether measuring end-tidal carbon monoxide concentration (ETCOc) twice before 48 hours could identify those who would develop hyperbilirubinemia and differentiate hemolytic vs. non-hemolytic causes. METHODS: Prospective study on neonates meeting criteria "at-risk for hyperbilirubinemia." Routine bilirubin measurements and 10-day follow-up were used to categorize neonates as; (1) normal (no hyperbilirubinemia, all bilirubins <95th percentile of Bhutani nomogram), (2) having hemolytic hyperbilirubinemia (bilirubin ≥95th percentile, DAT+, elevated retic, or G6PD+), or (3) having non-hemolytic hyperbilirubinemia. RESULTS: 386 neonates were enrolled. 321 (83%) did not develop hyperbilirubinemia and 65 (17%) did, of which 29 were judged hemolytic and 36 non-hemolytic. High ETCOc differentiated the hemolytic group (p < 0.001). First-day ETCOc correlated with bilirubin and with reticulocyte count (r = 0.896 and 0.878) and sensitivity and specificity for predicting hyperbilirubinemia were excellent (83% and 95%). CONCLUSIONS: ETCO measurement in the first 48 hours after birth predicts hemolytic hyperbilirubinemia.
