A paradigm for restenosis after angioplasty: clues for the development of new preventive therapies

Restenosis after intravascular intervention is one of the most important unsolved clinical and economic problems in the management of cardiovascular disease. Although neither its pathogenesis nor its prevention are yet defined, the early and late histologic appearance of the angioplasty state are known. Immediately after angioplasty, the atheroma has fissures, and the normal segment of the vessel circumference is stretched. There is substantial evidence of intimal injury. When restenosis develops at 1-4 months the histologic appearance of the restenotic lesion is intimal hyperplasia. Given this endpoint, we may theorize that the proximate cause of this response is denuding and stretching vascular injury. Since the healing response to tissue injury has been studied extensively, we can hypothesize the major milestones in the temporal sequence of restenosis are platelet aggregation, inflammatory cell infiltration, release of growth factors, medial smooth muscle cell modulation and proliferation, proteoglycan synthesis and extracellular matrix remodeling. At each of these steps, there are potential inhibitors. The resolution of the problem of restenosis may require both removal of atheroma mass and appropriate timing and effective delivery of inhibitors of intimal hyperplasia to the injury site in adequate concentration.Biomedical Reviews 1992; 1: 13-24

Promoting physical activity in patients with colon adenomas: a randomized pilot intervention trial

BACKGROUND: Physical activity decreases risk of colon polyps and colon cancer and might reduce risk of colon cancer recurrence. Focusing on recent calls for translation of epidemiologic evidence into clinical care, our pilot study delivered an evidence-based physical activity intervention in adults with polyps, who are thus at elevated risk of developing colon cancer. The objective was to evaluate change in physical activity, measured by steps per day and minutes of moderate/vigorous physical activity. METHODS: Sixteen adults with adenomas detected and removed at screening colonoscopy were recruited to a 12-week physical activity intervention. Participants were randomized to receive a standard (30 minutes/day) or high (60 minutes/day) walking program. Physical activity was measured via blinded pedometer and accelerometer at baseline and follow-up. Intervention messages focused on self-monitoring using pedometers and overcoming barriers to engaging in physical activity. RESULTS: Participants in both arms significantly increased objectively measured minutes of moderate/vigorous physical activity over the course of the intervention. Both arms exceeded the intervention goal, but there was not a significant difference between arms at follow-up. Results were similar for pedometer measured physical activity, with a significant overall increase in steps/day from baseline to follow-up, but no between arm difference in change. CONCLUSION: Simple interventions of minimal contact time focusing on walking can significantly increase physical activity in individuals at increased risk of developing colon cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT0147663

LenSiam: Self-Supervised Learning on Strong Gravitational Lens Images

Self-supervised learning has been known for learning good representations from data without the need for annotated labels. We explore the simple siamese (SimSiam) architecture for representation learning on strong gravitational lens images. Commonly used image augmentations tend to change lens properties; for example, zoom-in would affect the Einstein radius. To create image pairs representing the same underlying lens model, we introduce a lens augmentation method to preserve lens properties by fixing the lens model while varying the source galaxies. Our research demonstrates this lens augmentation works well with SimSiam for learning the lens image representation without labels, so we name it LenSiam. We also show that a pre-trained LenSiam model can benefit downstream tasks. We open-source our code and datasets at https://github.com/kuanweih/LenSiam .Comment: 5 pages, 2 figures. Accepted by NeurIPS 2023 AI for Science Worksho

Latent Stochastic Differential Equations for Modeling Quasar Variability and Inferring Black Hole Properties

Active galactic nuclei (AGN) are believed to be powered by the accretion of matter around supermassive black holes at the centers of galaxies. The variability of an AGN's brightness over time can reveal important information about the physical properties of the underlying black hole. The temporal variability is believed to follow a stochastic process, often represented as a damped random walk described by a stochastic differential equation (SDE). With upcoming wide-field surveys set to observe 100 million AGN in multiple bandpass filters, there is a need for efficient and automated modeling techniques that can handle the large volume of data. Latent SDEs are well-suited for modeling AGN time series data, as they can explicitly capture the underlying stochastic dynamics. In this work, we modify latent SDEs to jointly reconstruct the unobserved portions of multivariate AGN light curves and infer their physical properties such as the black hole mass. Our model is trained on a realistic physics-based simulation of ten-year AGN light curves, and we demonstrate its ability to fit AGN light curves even in the presence of long seasonal gaps and irregular sampling across different bands, outperforming a multi-output Gaussian process regression baseline.Comment: 10 pages, 5 figures, accepted at the ICLR 2023 Workshop on Physics for Machine Learnin

Microsomal prostaglandin E2 synthase-1 is induced by conditional expression of RET/PTC in thyroid PCCL3 cells through the activation of the MEK-ERK pathway

RET/PTC rearrangements are believed to be tumor-initiating events in papillary thyroid carcinomas. We identified microsomal prostaglandin E2 synthase-1 (mPGES-1) as a RET/PTC-inducible gene through subtraction hybridization cloning and expression profiling with custom microarrays. The inducible prostaglandin E2 (PGE2) biosynthetic enzymes cyclooxygenase-2 (COX-2) and mPGES-1 are up-regulated in many cancers. COX-2 is overexpressed in thyroid malignancies compared with benign nodules and normal thyroid tissues. Eicosanoids may promote tumorigenesis through effects on tumor cell growth, immune surveillance, and angiogenesis. Conditional RET/PTC1 or RET/PTC3 expression in PCCL3 thyroid cells markedly induced mPGES-1 and COX-2. PGE2 was the principal prostanoid and up-regulated (by approximately 60-fold), whereas hydroxyeicosatetraenoic acid metabolites were decreased, consistent with shunting of prostanoid biosynthesis toward PGE2 by coactivation of the two enzymes. RET/PTC activated mPGES-1 gene transcription. Based on experiments with kinase inhibitors, with PCCL3 cell lines with doxycycline-inducible expression of RET/PTC mutants with substitutions of critical tyrosine residues in the kinase domain, and lines with inducible expression of activated mutants of H-RAS and MEK1, RET/PTC was found to regulate mPGES-1 through Shc-RAS-MEK-ERK. These data show a direct relationship between activation of a tyrosine kinase receptor oncogene and regulation of PGE2 biosynthesis. As enzymes involved in prostanoid biosynthesis can be targeted with pharmacological inhibitors, these findings may have therapeutic implications

Refinement Modal Logic

In this paper we present {\em refinement modal logic}. A refinement is like a bisimulation, except that from the three relational requirements only `atoms' and `back' need to be satisfied. Our logic contains a new operator 'all' in addition to the standard modalities 'box' for each agent. The operator 'all' acts as a quantifier over the set of all refinements of a given model. As a variation on a bisimulation quantifier, this refinement operator or refinement quantifier 'all' can be seen as quantifying over a variable not occurring in the formula bound by it. The logic combines the simplicity of multi-agent modal logic with some powers of monadic second-order quantification. We present a sound and complete axiomatization of multi-agent refinement modal logic. We also present an extension of the logic to the modal mu-calculus, and an axiomatization for the single-agent version of this logic. Examples and applications are also discussed: to software verification and design (the set of agents can also be seen as a set of actions), and to dynamic epistemic logic. We further give detailed results on the complexity of satisfiability, and on succinctness

Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth

Insulin-like growth factor I (IGF-I) potently stimulates intestinal growth. Insulinreceptorsubstrate-1(IRS-1)mediates proliferative and antiapoptotic actions of IGF-I in cell lines, but its in vivo relevance in intestine is not defined. This study tested the hypothesis that there is cell type-specific dependence on IRS-1 as a mediator of IGF-I action. Length, mass, crypt cell proliferation, and apoptosis were measured in small intestine and colon of IRS-1-null mice and wild-type (WT) littermates and in colon of IRS-1-null or WT mice expressing IGF-I transgenes. Expression of IGF-I receptor and signaling intermediates was examined in intestine of WT and IRS-1-null mice, cultured intestinal epithelial cells, and myofibroblasts. Absolute IRS-1 deficiency reduced mucosal mass in jejunum and colon, but effects were more pronounced in colon. Muscularis mass was decreased in both segments. In IGF-I transgenics, IRS-1 deficiency significantly attenuated IGF-I-stimulated growth of colonic mucosa and abolished antiapoptotic but not mitogenic effects of IGF-I transgene on crypt cells. IGF-I-induced muscularis growth was unaffected by IRS-1 deficiency. In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. We conclude that the intestinal epithelium but not the muscularis requires IRS-1 for normal trophic actions of IGF-I and that IRS-1 is required for antiapoptotic but not mitogenic effects of IGF-I in the intestinal crypts in vivo

Evaluating the quality of interaction between medical students and nurses in a large teaching hospital

BACKGROUND: Effective health care depends on multidisciplinary collaboration and teamwork, yet little is known about how well medical students and nurses interact in the hospital environment, where physicians-in-training acquire their first experiences as members of the health care team. The objective of this study was to evaluate the quality of interaction between third-year medical students and nurses during clinical rotations. METHODS: We surveyed 268 Indiana University medical students and 175 nurses who worked at Indiana University Hospital, the School's chief clinical training site. The students had just completed their third year of training. The survey instrument consisted of 7 items that measured "relational coordination" among members of the health care team, and 9 items that measured psychological distress. RESULTS: Sixty-eight medical students (25.4%) and 99 nurses (56.6%) completed the survey. The relational coordination score (ranked 1 to 5, low to high), which provides an overall measure of interaction quality, showed that medical students interacted with residents the best (4.16) and with nurses the worst (2.98; p < 0.01). Conversely, nurses interacted with other nurses the best (4.36) and with medical students the worst (2.68; p < 0.01). Regarding measures of psychological distress (ranked 0 to 4, low to high), the interpersonal sensitivity score of medical students (1.56) was significantly greater than that of nurses (1.03; p < 0.01), whereas the hostility score of nurses (0.59) was significantly greater than that of medical students (0.39; p < 0.01). CONCLUSION: The quality of interaction between medical students and nurses during third-year clinical rotations is poor, which suggests that medical students are not receiving the sorts of educational experiences that promote optimal physician-nurse collaboration. Medical students and nurses experience different levels of psychological distress, which may adversely impact the quality of their interaction

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments