Stage-specific reprogramming of globin gene expression.
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Animals↗
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Results for “reprogramming”
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Automated health services--reprogramming the doctor.
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Electronic Data Processing↗
DDD pacing mode survival in patients with a dual-chamber pacemaker.
Dual-chamber (DDD) pacing mode survival was assessed by reviewing 486 consecutive initial transvenous DDD pacemaker implantations between December 1981 and December 1988 inclusive, with a mean follow-up time of 33 months. The patients' mean age was 71.4 years and 55% were male; 38% had dominant sinoatrial and 62% had dominant atrioventricular (AV) node disease. Nineteen patients (4%) underwent secondary operative intervention for lead dislodgement (n = 11), lead or pulse generator malfunction (n = 6) or infection (n = 2). During follow-up, 87 patients (18%) had their device permanently reprogrammed out of the DDD mode and 10 others (2%) required temporary reprogramming out of this mode; 12 patients who required device reprogramming were managed in other dual-chamber or atrial pacing modes. Reasons for reprogramming included atrial fibrillation (n = 48; 10%); loss of atrial sensing (n = 26; 5%); recurrent "endless loop" tachycardia (n = 5; 1%); lead dislodgement without repositioning (n = 4; 1%); pulse generator malfunction (n = 1; 1%) and other (n = 5; 1%). The occurrence of atrial fibrillation was associated with dominant sinoatrial disease and a prior history of atrial fibrillation; 19% of atrial sensing loss was attributable to early or faulty pacemaker technology. The DDD mode survival rate at 1, 2, 3, 4 and 5 years was, respectively, 90%, 88%, 84%, 79% and 78%.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Clinical experience with a new multiprogrammable dual chamber pacemaker.
We evaluated the clinical performance of a new dual chamber pacemaker, ELA Chorus, in 35 patients. This device incorporates linear rate adaptive AV delay (AVDR), rate smoothing, fallback, impedance telemetry, pacemaker mediated tachycardia (PMT) recognition and reprogramming software, intracardiac electrogram displays, autothreshold testing, diagnostic data, battery depletion curves, and laptop computer programming. Mean patient age was 68 years; 18 patients had AV block, six had sinus node dysfunction (one with AV block), nine had carotid sinus hypersensitivity (three with AV block), and two had vagally mediated syncope. At hospital discharge, programming was DDD with a mean low rate of 60 (50-70) beats/min, mean high rate of 126 (120-154) beats/min; AVDR was ON in 21 patients, rate smoothing ON in six patients, fallback ON in six patients, and PMT reprogramming algorithm ON in 27 patients. Pacemaker follow-up involved 500 clinic visits over 14.3 months (1-36). Three patients developed atrial fibrillation, reprogrammed to DDI mode (two patients) or fallback (one patient). Fallback was used 617 times. PMT occurred 427 times in six patients; the PMT algorithm reprogrammed AV delay and postventricular atrial refractory period (PVARP) automatically, a function unique to the Chorus. Intracardiac electrograms and autothreshold testing improved follow-up efficiency. This new dual chamber pacemaker enhances programming flexibility and improves diagnostic accuracy at follow-up.
Aged↗
Cloning of embryos.
Nuclear transfer for the study of differentiation in amphibians has been used since the 1950s, but not until recently have the same procedures been applied successfully to some mammals. Nuclear transfer, as developed for the amphibian, is successful in sheep, cattle, rabbit, and pig, but not mouse embryos. This fact is discussed in relation to the species-specific timing of the activation of the zygotic genome. Nuclear transfer to an oocyte presumably results in a genomic reprogramming of the transferred nucleus. The limits of differentiation that can be reprogrammed have yet to be determined. Since the cells of early embryos are thought to have identical nuclear genomes, early embryos can be used as a source of donor nuclei; and, when combined with serial nuclear transfer, can theoretically produce an unlimited number of identical offspring. Cloning by splitting does not result in a reprogramming of the genome and is limited in the number of identical offspring that can result. Here we discuss some of the factors to consider concerning micromanipulation and nuclear reprogramming and how they relate to other embryo technologies.
Animals↗
Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin.
Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor β (TGF-β)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.
Animals↗
Transcription regulation of cell fate plasticity - from embryonic development to tissue regeneration.
Cell fate plasticity refers to the capacity of cells sharing the same genome to alter, reverse, or reconfigure their identity under physiological, pathological, or experimental conditions. This property underlies embryonic development, cellular reprogramming, and tissue regeneration, but becomes progressively restricted as lineage identity is stabilized. Embryonic development represents an intrinsic process of fate transitions, whereas reprogramming and regeneration reveal how differentiated cells can dedifferentiate or transdifferentiate under specific conditions. Across these contexts, plasticity is governed by multilayered regulatory networks involving transcription factors, epigenetic regulators, cofactors, and the core transcription machinery. Robust regulatory programs stabilize cell identity, whereas stochastic fluctuations in gene expression and chromatin state can prime cells for fate transitions, adding a tunable dimension to plasticity control. In this review, we synthesize recent advances in the regulation of cell fate plasticity across development, reprogramming, and regeneration, highlighting how transcription factors, epigenetic modifications, transcriptional cofactors, and core transcription machinery cooperate to control cell fate decisions and plasticity.
Animals↗
Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.
Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system-the major pathway for MGO detoxification-restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC.
Humans↗
Profiling the long noncoding RNA interaction network in the regulatory elements of target genes by chromatin in situ reverse transcription sequencing.
Long noncoding RNAs (lncRNAs) can regulate the activity of target genes by participating in the organization of chromatin architecture. We have devised a "chromatin-RNA in situ reverse transcription sequencing" (CRIST-seq) approach to profile the lncRNA interaction network in gene regulatory elements by combining the simplicity of RNA biotin labeling with the specificity of the CRISPR/Cas9 system. Using gene-specific gRNAs, we describe a pluripotency-specific lncRNA interacting network in the promoters of Sox2 and Pou5f1, two critical stem cell factors that are required for the maintenance of pluripotency. The promoter-interacting lncRNAs were specifically activated during reprogramming into pluripotency. Knockdown of these lncRNAs caused the stem cells to exit from pluripotency. In contrast, overexpression of the pluripotency-associated lncRNA activated the promoters of core stem cell factor genes and enhanced fibroblast reprogramming into pluripotency. These CRIST-seq data suggest that the Sox2 and Pou5f1 promoters are organized within a unique lncRNA interaction network that determines the fate of pluripotency during reprogramming. This CRIST approach may be broadly used to map lncRNA interaction networks at target loci across the genome.
Animals↗
Epigenetic reduction OF H3K9me3 and H3K27me3 by RK-701 and GSK 126 improves the developmental competence of bovine SCNT embryos.
Somatic cell nuclear transfer (SCNT) failure has largely been attributed to incomplete epigenetic reprogramming, particularly the dysregulation of repressive histone modifications such as H3K9me3 and H3K27me3. Reducing these repressive marks has been shown to improve reprogramming efficiency in SCNT embryos. Although histone demethylase mRNA injection has been used for this purpose, it is labor-intensive, technically demanding, and time-consuming. In this study, we investigated a simplified approach that combined RK-701 and GSK-126 to reduce H3K9me3 and H3K27me3 levels, respectively, in bovine SCNT embryos. Three experimental groups were established: IVF embryos (control), SCNT-control (SCNT-C) embryos, and inhibitor-treated SCNT embryos (SCNT-T). The IVF group was used as a reference standard. Fused one-cell SCNT embryos were treated with 2 μM RK-701 and 0.2 μM GSK-126 from the one-cell stage to the 16-cell stage. Gene expression analysis at the 16-cell stage revealed a significant reduction in histone methyltransferase (HMT) expression (p < 0.05), and immunofluorescence analysis confirmed marked decreases in H3K9me3 and H3K27me3 levels. In addition, the expression of genes associated with zygotic genome activation (ZGA) and pluripotency was significantly higher in SCNT-T embryos than in SCNT-C embryos. Assessment of blastocyst quality revealed reduced reactive oxygen species (ROS) levels, decreased expression of apoptosis-related genes, and improved mitochondrial membrane potential in the treated group, as indicated by JC1 staining. Overall, this approach effectively reduced repressive histone marks, enhanced epigenetic reprogramming, and improved ZGA, thereby increasing the developmental rate and adhesion potential of bovine SCNT embryos. These findings suggest that combined treatment with RK-701 and GSK-126 may provide a simple and practical strategy for improving the efficiency of bovine cloning.
Bovine embryos↗
Atrial arrhythmias in dual chamber pacing and their influence on long-term mortality.
A retrospective study of 252 patients who received a DDD pacemaker between October 1982 and December 1990 was performed. During a mean follow-up of 30 months, reprogramming to the VVI mode was necessary in 39 patients (15.5%). Technical problems causing downgrading occurred 15 times, of which 13 problems became permanent. A total number of 24 patients had sustained atrial arrhythmias, including 14 with atrial fibrillation and 10 with atrial flutter. In this group, conversion to sinus rhythm could be obtained in 38%. After 2 years, reliable DDD pacing was maintained in 86% of the surviving patients. The survival after 1 and 2 years was 94% and 89%, respectively, and was not influenced by arrhythmias or technical problems. We conclude that atrial arrhythmias including flutter are the most important reasons for reprogramming to the VVI mode, although in an important number of patients, predominantly those with flutter, restoration of AV synchrony can be obtained. The high number of patients with atrial flutter could imply some role for DDD devices offering the option of antitachycardia pacing. Reprogramming of the pacing mode did not influence mortality.
Arrhythmia, Sinus↗
Incidence and timing of activity parameter changes in activity responsive pacing systems.
The incidence and timing of rate response parameter reprogramming in activity responsive pacing systems during the year after implantation was evaluated in two groups of patients: 24 patients in whom a VVI,R system was implanted (Activitrax, Medtronic, Inc.), and 21 patients in whom a DDD,R system was implanted (Synchrony, Siemens Pacesetter, Inc.). Activity parameter changes in Activitrax patients were made based on the presence of symptoms, while in Synchrony patients, changes were based on objective data obtained using a sensor indicated rate histogram with a slow and fast walk protocol. No significant difference in the incidence of activity parameter reprogramming was noted at various time intervals during the first year in Activitrax patients; in Synchrony patients a greater incidence of reprogramming changes was noted at the 1-month follow-up visit compared to later follow-up visits (P less than 0.02). Further, the incidence of changes at 1 month was greater for Synchrony compared to Activitrax patients (P less than 0.001), while no difference was detected between groups at subsequent follow-up intervals. Use of the slow and fast walk protocol, by permitting serial evaluation of sensor response, demonstrated alterations in sensor drive rates with similar levels of activity over the initial 4 to 6 postimplant weeks. This may result from postoperative changes at the pacemaker insertion site. Based on this experience, predischarge programming may not predict long-term rate response requirements. We recommend evaluation of sensor function using an exercise protocol performed at 4 to 6 postimplant weeks in all rate responsive pacing systems that utilize a piezoelectric crystal.
Aged↗
Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation.
As obligatory intracellular parasites, viruses must rely on metabolic reprogramming of host cells to meet their replication needs. Baculovirus is an important biopesticide and a vector for the preparation of biological products. In addition, one of its representative species, Bombyx mori nucleopolyhedrovirus (BmNPV-Baculoviridae), also causes huge losses to the insect industry. In our previous study, amino acid metabolism has been found to play a crucial role in the BmNPV infection process. However, the mechanisms by which BmNPV reprograms host amino acid metabolism remains unclear. In fact, current insights in the importance of amino acid metabolism are limited to the impact of glutamine on viral infection. Therefore, unraveling the mechanism of amino acid metabolism reprogramming induced by baculovirus would advance this field of research to a great extent. In this study, targeted metabolomics revealed that the preferred amino acids of BmNPV budded virus (BV) include arginine, lysine, proline, isoleucine, histidine and others. In addition, most of the viral amino acids were found to be increased in the hemolymph of BmNPV infected silkworms at the later stage of infection, especially arginine, valine, phenylalanine and others. Furthermore, the importance of arginine for BmNPV proliferation was validated. Next, we confirmed that the expression of the arginine transporter Slc7a6 was strongly induced by BmNPV infection and that Slc7a6 could promote arginine uptake to support BmNPV proliferation in host cells. Moreover, using Slc7a6 knockout cells which eliminate extracellular arginine uptake, we confirmed that BmNPV could induce mitochondrial autophagy, thereby supplementing intracellular arginine and providing necessary amino acids for BmNPV proliferation. Overall, these findings support a model in which baculovirus (BmNPV) enhances the uptake of exogenous amino acids by inducing the expression of amino acid transporters and activating autophagy of organelles to maintain intracellular amino acid levels, thereby facilitating virus proliferation.
Animals↗
Physiologic pacing in the elderly. Effects on exercise capacity and exercise-induced arrhythmias.
It is not clear whether hemodynamic and other benefits from dual-chamber pacing also exist in elderly patients. We studied a group of 18 elderly patients (mean age 74 +/- 4 yrs) with exercise testing in DDD and VVI modes in a randomized way to compare the effects of these pacing modes on exercise capacity, atrial rate and exercise-induced arrhythmias. Patients were selected when complete heart block was present without clinical evidence of sinus node dysfunction. Significant differences were observed: atrial rate was lower during exercise in DDD-mode (p less than 0.01); exercise time and cumulative load increased (p less than 0.05); maximal oxygen uptake was improved (p less than 0.05). Some of these differences were less clear in a subgroup with replacement of a VVI-device by DDD-stimulation. No differences could be observed in severity of exercise-induced arrhythmias. No evidence of sinus node dysfunction was found during exercise. Reprogramming of atrial sensitivity was required in 3 patients, with reprogramming to DVI because of paroxysmal atrial fibrillation once. Two patients died within a mean follow-up period of 13 months. Sinus rhythm was present at the most recent evaluation in all patients, including the patient stimulated in the DVI mode. Physiologic stimulation is of value for elderly patients with an active life style and complete heart block. Reprogramming to another pacing mode is only seldom necessary.
Aged↗
Genome agnostic, multi-level non-oncogene addiction-based systems pharmacology for rescuing metastatic relapsed/refractory neoplasias.
Rescue therapies for relapsed/refractory (r/r) metastatic neoplasias present significant unmet needs. Tumor tissue editing regimen for 13 r/r tumor types, carcinomas, sarcomas and hematologic neoplasias, included in 15 phase I/II trials, nuclear/cytokine receptor agonists, pioglitazone, plus/minus dexamethasone or all-trans retinoic acid or interferon-α to counterbalance tumor tissue homeostasis and reprogramming of cancer hallmarks, stress response inhibitors, COX-2 inhibitor, everolimus, lenalidomide, or clarithromycin, and a stress response inducer, low-dose metronomic chemotherapy with treosulfan, trofosfamide, capecitabine, or azacitidine. CR in three, cCR in another five r/r neoplasias, as the best response occurred after transcriptional reprogramming of cancer hallmarks, inflammation control or differentiation induction. Receptor agonist combinations for cCR induction can be identical among quite different tumor types and diversified within the same tumor histology. Data reveal ubiquitous, differential transcriptional access to non-oncogene addiction (NOA) networks that cope with cancer hallmarks/stress responses and three levels of therapeutic NOA targeting. (1) Agonists of nuclear/cytokine receptor NOAs critically target tumor identity and viability, while (2) transcriptional reprogramming of NOA networks that contribute to tumor tissue addiction, thereby genome-agnostically counteracting oncogene addictions. (3) Targeting edited NOAs may improve long-term outcome with CR/cCR (everolimus, IMiD). Transcriptionally accessible NOA targets offer high specificity, modest toxicity profile, low cost of therapy and outpatient treatment, independent of comorbidities. Adaptive targeting of the transcriptomic landscapes of tumor cell compartments breaks tumor tissue addiction and overcomes M-CRAC, post-therapy metastasis, cancer cell recolonization, acquired resistance and genetic heterogeneity. Thus, editing approaches provide a template for controlling metastatic r/r tumors. In the future, diagnostics of NOA networks and transcription factors involved in tumor tissue addiction may be as valuable for therapy selection as histological/molecular genetic tumor typing for the establishment of personalized hematology/oncology.
Hodgkin’s lymphoma↗
Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma with context-dependent tumor-restraining and tumor-promoting functions, highlighting the need to selectively reprogram stromal states. Extravascular coagulation is a prominent feature of the PDAC tumor microenvironment, yet whether it functions as an upstream regulator of fibrotic stromal states, rather than merely a byproduct of tumor-associated vascular dysfunction, has remained unclear. Here, we identify extravascular coagulation as a tumor-amplified regulatory module that stabilizes pro-fibrotic stromal states via tumor-intrinsic protease-activated receptor-1 (PAR1) signaling. To interrogate this axis mechanistically, we integrated human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models that reconstruct tumor-stroma interactions under controlled coagulation exposure, followed by cross-scale validation in vivo. Analysis of The Cancer Genome Atlas (TCGA) revealed heterogeneous F2R (PAR1) expression across tumors, with elevated expression associated with fibrotic transcriptional programs and reduced survival. Consistently, thrombin induced coordinated pro-fibrotic programs in tumor cells and cancer-associated fibroblasts (CAFs), which were recapitulated in MPTS where tumor-intrinsic PAR1 was required for amplification of extracellular matrix deposition and CAF activation. Mechanistically, PAR1 signaling amplified tumor-stroma communication, in part through induction of TGF-β1-dependent pathways, establishing a reinforcing feedback loop that stabilizes fibrotic remodeling. Pharmacologic inhibition of PAR1 selectively suppressed the fibrotic transcriptional program within myofibroblastic CAFs while reducing the abundance of other CAF subtypes, reprogramming stromal states and attenuating tumor progression across MPTS and in vivo models. These findings establish a coagulation-PAR1 axis as an upstream organizer of PDAC stromal architecture and identify pharmacologic PAR1 inhibition as a mechanistically grounded strategy for selectively reprogramming the tumor-promoting stroma.
Journal Article↗
[Aging and limited capacity for division of normal, diploid amphibian fibroblasts in vitro in relation to cell nucleus transplantations in amphibia].
In many experiments Hayflick had proved the limited division capacity of lung fibroblasts derived from different mammalian species, chicken and tortoise. Gurdon transplanted the nuclei of differentiated Xenopus cells into enucleated eggs yielding a complete development of the hybrid individuals. These results arise the question about a reprogramming of cell nuclei concerning their division capacity. On the other hand, amphibian cells may not show any proliferative limit. Thus, primary cultures were established from tadpoles, recently metamorphosed frogs and adult animals, respectively. The latent period of the tissue explants proved to be dependent on donor age. The cell strain I401 showed the characteristic degeneration phenomena after six subcultivations and ceased to proliferate. These results lead to the conclusion that nuclear transplantation into an enucleated egg yields reprogramming of the nucleus, including the reprogramming of the division capacity as much as the biological age of the nucleus.
Animals↗
Proteomic signatures of adipocyte recruitment in breast cancer.
The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of breast cancer progression, with adipocytes functioning as active contributors rather than passive bystanders. Here, we investigated the proteomic and morphologic reprogramming of breast cancer-associated adipocytes (BrCAAs) in response to triple-negative breast cancer (TNBC). Using conditioned medium from HCC1143 cells, we established an in vitro BrCAA model and performed mass spectrometry-based proteomics. Comparative profiling revealed 256 differentially expressed proteins, enriched for pathways including fatty acid degradation, carbon metabolism, and glycogen turnover, consistent with a metabolic shift from energy storage to energy supply. Gene ontology and protein-protein interaction analyses further identified cytoskeletal remodeling, adhesion dynamics, and secretory pathway activation, supporting BrCAA-driven microenvironmental remodeling. In the MMTV-PyMT mouse model, morphometric analysis demonstrated progressive size reduction and increased contour irregularity of adipocytes adjacent to tumors, correlating with proteomic evidence of metabolic stress. Importantly, BrCAAs localized at tumor interfaces were associated with increased microvessel density and CD105+ endothelial activation compared to desmoplastic zones. Proteomic enrichment highlighted pro-angiogenic remodeling, with validation of basigin (BSG), integrin αV (ITGAV), and 2,4-dienoyl-CoA reductase 1 (DECR1). Collectively, our findings establish BrCAAs as metabolically and structurally reprogrammed stromal components that promote tumor metabolism and localized angiogenesis, representing potential therapeutic targets in aggressive breast cancer.
Female↗