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PubMed2025

A Programmable Nanovaccine Platform Based on M13 Bacteriophage for Personalized Cancer Vaccine and Therapy.

Nanovaccines co-assemble antigens and adjuvants to elicit robust immune responses but often require complex synthesis and post-modification procedures. Here, a programmable nanovaccine platform based on the M13 bacteriophage is developed for the scalable production of vaccines and single-step modular engineering of adjuvanticity, length, and antigen density. By reprogramming the sequence and size of the noncoding phage genome, the Toll-like receptor 9 activation and the length of the phage are precisely controlled. With a novel molecular engineering approach, the antigen density is tuned from 13.6% to 70.3%. A systematic modulation reveals an optimal adjuvanticity at a constant antigen density for maximum anti-tumor CD8+ T cell response, and vice versa, using the model antigen SIINFEKL. The M13 phage-based nanovaccine induces durable memory immunity lasting over a year. In addition, a 24-fold increase in neoantigen-specific CD8+ T cell frequency is achieved when increasing both the adjuvanticity and antigen density. Furthermore, when combined with anti-PD-1 therapy, the M13 phage-based personalized vaccine eradicates established MC-38 tumors in 75% of treated animals and they develop 100% resistance against tumor invasion when challenged 5 months after treatment. These findings establish M13 phage as a powerful and versatile nanovaccine platform with transformative potential for personalized cancer immunotherapy.

Cancer Vaccines↗
PubMed2003

Vancomycin assembly: nature's way.

Antibiotics are precious resources in the fight to combat bacterial infections caused by pathogenic organisms. Vancomycin is one of the antibiotics of last resort in the treatment of life-threatening infections by gram-positive bacteria. The rules by which nature assembles the glycopeptide (vancomycin) and lipoglycopeptide (teicoplanin) antibiotics are becoming elucidated and verified: first amino acids are synthesized, then joined together and cross-linked. This knowledge opens up approaches for reprogramming strategies at the level of altered monomers, swapped assembly lines, and different post-assembly tailoring enzymes.

Anti-Bacterial Agents↗
PubMed2025

Immune Aging in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a life-long autoimmune disease caused by the confluence of genetic and environmental variables that lead to loss of self-tolerance and persistent joint inflammation. RA occurs at the highest incidence in individuals >65 years old, implicating the aging process in disease susceptibility. Transformative approaches in molecular immunology and in functional genomics have paved the way for pathway paradigms underlying the replacement of immune homeostasis with autodestructive immunity in affected patients, including the process of immune aging. Patients with RA have a signature of premature immune aging, best understood for CD4+ T cells, which function as pathogenic effectors in this HLA class II-associated disease. Premature immune aging is present in healthy HLA-DRB1*04+ individuals, placing accelerated immune aging before joint inflammation. Aging-related molecular abnormalities directly implicated in turning RA CD4+ T cells into proinflammatory effector cells are linked to malfunction of subcellular organelles, such as mitochondria, lysosomes, lipid droplets, and the endoplasmic reticulum. Resulting changes in T cell behavior include cellular hypermobility, tissue invasiveness, unopposed mammalian target of rapamycin complex (mTORC)1 activation, excessive release of tumor necrosis factor, lysosomal failure, clonal expansion, and immunogenic cell death. Aged and metabolically reprogrammed T cells in patients with RA are accompanied by age-associated B cells, which specialize in autoantibody production. Clonal hematopoiesis drives myeloid cell aging by producing aged monocytes and hypermetabolic macrophages, which sustain the process of inflammaging. Here, we synthesize insights into the relationship of RA risk and immune aging and discuss mechanisms through which immune aging can cause autoimmunity.

Humans↗
PubMed2005

Diethylstilbestrol exposure in utero: a paradigm for mechanisms leading to adult disease.

The synthetic estrogen diethylstilbestrol (DES) was administered to pregnant women between the 1940s and the mid-1970s and is believed to be responsible for numerous uterine/cervical/vaginal malformations and cancers that appeared after birth and in young adult life. This medical tragedy has served as one of the prototypical examples of a phenomenon known as "endocrine disruption," in which either environmental agents or other compounds disrupt normal hormonal signaling in the body. Whereas DES signals through estrogen receptors, the subsequent molecular targets were largely unknown. We had identified Wnt7a as a target in this pathway and have used genetic analyses of mutant mice to demonstrate that disruption of Wnt7a is the key event leading to the DES phenotypes and cancers. We find that Wnt7a expression is only transiently deregulated in response to DES exposure, leading to the conclusion that critical events during early reproductive tract development results in a permanent change or "reprogramming" in subsequent development.

Animals↗
PubMed2003

Cell-based therapies for birth defects: a role for adult stem cell plasticity?

Cell therapy can offer a reasonable approach to the treatment of specific birth defects, particularly those for which hematopoietic stem cells (HSCs) can be used to restore (even partially) the number of cells, protein levels, or enzyme activity. Relatively few clinical experiences have been published on this subject, but when a natural selective advantage exists for the cell graft, a degree of "rescue" is possible. Strategies have been developed to confer a selective advantage through genetic engineering of donor cells, and this approach may prove valuable in the treatment of birth defects, as it is in hematological malignancy. Stem cell (SC) plasticity, or transdifferentiation, may offer another route for delivery of cells to established or developing organs. A wide variety of studies support the concept that adult tissue-specific SCs can, if displaced from their normal niche to another, be reprogrammed to produce cell types appropriate to their new environment. Clinical observations reveal that persistent tissue microchimerism develops not only in blood lineages after transfusion, but also in thyroid follicular epithelium via transplacental exchange. In addition, hepatic and renal parenchyma also become chimeric following allografts or bone marrow transplantation (BMT). Experimental models indicate that a renal glomerulosclerosis phenotype can be transferred by grafting whole BM, and that a severe liver disorder in fah-/- mice can be overcome by grafting HSCs and then exerting a selection pressure. It may be possible in the future to exploit the ability of adult SCs to contribute to diverse tissues; however, our understanding of the processes involved is at a very early stage.

Adult↗
PubMed2005

DNA methylation in mammalian development and disease.

Epigenetic modification of the cytosine base of DNA by its methylation introduced the possibility that beyond the inherent information contained within the nucleotide sequence there was an additional layer of information added to the underlying genetic code. DNA methylation has been implicated in a wide range of biological functions, including an essential developmental role in the reprogramming of germ cells and early embryos, the repression of endogenous retrotransposons, and a generalized role in gene expression. Special functions of DNA methylation include the marking of one of the parental alleles of many imprinted genes, a group of genes essential for growth and development in mammals with a unique parent-of-origin expression pattern, a role in stabilizing X-chromosome inactivation, and centromere function. In this regard, it is not surprising that errors in establishing or maintaining patterns of methylation are associated with a diverse group of human diseases and syndromes.

Alleles↗
PubMed2005

Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate.

The goal of this review is to examine the fate of the hypertrophic chondrocyte in the epiphyseal growth plate and consider the impact of the cartilage microenvironment on cell survival and apoptosis. Early investigations pointed to a direct role of the hypertrophic chondrocyte in osteogenesis. The terminally differentiated cells were considered to undergo a dramatic change in shape, size, and phenotype, and assume the characteristics of an osteoblast. While some studies have supported the notion of transdifferentiation, much of the evidence in favor of reprogramming epiphyseal chondrocytes is circumstantial and based on microscopic evaluation of cells that are present at the chondro-osseous junction. Although these investigations provided a novel perspective on endochondral bone formation, they were flawed by the failure to consider the importance of stem cells in osseous tissue formation. Subsequent studies indicated that many, if not all, of the cells of the cartilage plate die through the induction of apoptosis. With respect to agents that mediate apoptosis, at the chondro-osseous junction, solubilization of mineral and hydrolysis of organic matrix constituents by septoclasts generates high local concentrations of ions, peptides, and glycans, and secreted matrix metalloproteins. Individually, and in combination, a number of these agents serve as potent chondrocyte apoptogens. We present a new concept: hypertrophic cells die through the induction of autophagy. In the cartilage microenvironment, combinations of local factors cause chondrocytes to express an initial survival phenotype and oxidize their own structural macromolecules to generate ATP. While delaying death, autophagy leads to a state in which cells are further sensitized to changes in the local microenvironment. One such change is similar to ischemia reperfusion injury, a condition that leads to tissue damage and cell death. In the growth cartilage, an immediate effect of this type of injury is sensitization to local apoptogens. These two concepts (type II programmed cell death and ischemia reperfusion injury) emphasize the importance of the local microenvironment, in particular pO(2), in directing chondrocyte survival and apoptosis.

Animals↗
PubMed2004

Turning back the clock on neural progenitors.

Drosophila neural progenitor cells, or neuroblasts, alter their transcriptional profile over time to produce different neural cell types. A recent paper by Pearson and Doe shows that older neuroblasts can be reprogrammed to behave like young neuroblasts, and to produce early neural cell types, simply by expressing the transcription factor, Hunchback. The authors show that competence to respond to Hunchback diminishes over time. Manipulating neural progenitors in this way may have important implications for therapeutic uses of neural stem cells.

Animals↗
PubMed2007

New insights into the nucleophosmin/nucleoplasmin family of nuclear chaperones.

Basic proteins and nucleic acids are assembled into complexes in a reaction that must be facilitated by nuclear chaperones in order to prevent protein aggregation and formation of non-specific nucleoprotein complexes. The nucleophosmin/nucleoplasmin (NPM) family of chaperones [NPM1 (nucleophosmin), NPM2 (nucleoplasmin) and NPM3] have diverse functions in the cell and are ubiquitously represented throughout the animal kingdom. The importance of this family in cellular processes such as chromatin remodeling, genome stability, ribosome biogenesis, DNA duplication and transcriptional regulation has led to the rapid growth of information available on their structure and function. The present review covers different aspects related to the structure, evolution and function of the NPM family. Emphasis is placed on the long-term evolutionary mechanisms leading to the functional diversification of the family members, their role as chaperones (particularly as it pertains to their ability to aid in the reprogramming of chromatin), and the importance of NPM2 as an essential component of the amphibian chromatin remodeling machinery during fertilization and early embryonic development.

Animals↗
PubMed2006

Ethical questions concerning research on human embryos, embryonic stem cells and chimeras.

Research using human embryos and embryonic stem cells is viewed as important for various reasons. Apart from questions concerning legal regulations, numerous ethical objections are raised pertaining to the use of surplus embryos from reproductive medicine as well as the creation of embryos and stem cells through cloning. In the hopes of avoiding ethical problems, alternatives have been proposed including the extraction of egg cells from "dead" embryos derived from in vitro fertilization procedures, the extraction of pluripotent stem cells from blastocysts, technologies such as "altered nuclear transfer" (ANT) and "oocyte-assisted reprogramming" (ANT-OAR) as well as parthenogenesis. Initial ethical assessments show that certain questions pertaining to such strategies have remained unanswered. Furthermore, with the help of new or more differentiated biotechnological procedures, it is possible to create chimeras and hybrids in which human and non-human cells are combined. Human-animal chimeras, in which gametes or embryonic tissue have been mixed with embryonic or adult stem cells, demonstrate a different "quality" and "degree of penetration" from those produced in previous experiments. Not only does this have consequences regarding questions of patentability, this situation also raises fundamental questions concerning the human being's self image, the concept of person, identity and species and the moral rights and duties that are connected with such concepts. There is a need for legal regulation, on the national as well as the international level.

Cloning, Organism↗
PubMed2026

Engineering the Vero Cell Lineage: Toward a Programmable Vaccine Manufacturing Platform.

Vero cells remain an indispensable continuous substrate for human viral vaccine manufacturing. Despite decades of empirical process optimization, intrinsic genomic instability, including segmental aneuploidy and dynamic chromatin rearrangements, continues to limit the durability of engineered phenotypes under sustained viral burden and bioreactor stress. Here, we review the expanding engineering toolkit for the Vero lineage across a three-layered functional framework: the membrane interface, cytoplasmic foundry, and nuclear blueprint, evaluating translational prospects at each level. Receptor transplantation and morphological reprogramming have broadened viral entry range and enabled suspension-adapted culture formats, while metabolic flux management and temporally controlled apoptosis modulation have addressed intracellular production bottlenecks, albeit often with trade-offs between productivity, biosafety, and long-term population stability. At the genomic level, targeted perturbations of transcriptional regulators and emerging epigenetic interventions offer more durable gains, yet expression drift, clonal heterogeneity, and karyotypic instability during extended passaging highlight the need for locus-level precision rather than constitutive trait installation. Looking forward, infection-responsive dynamic logic circuits and the systematic identification of Vero-specific genomic safe harbors could shift the paradigm toward a conditionally responsive manufacturing architecture. Collectively, these advances suggest a pathway for transitioning the Vero lineage from a passive, empirically optimized biological substrate into a conditionally responsive, genomically stable, and programmable platform for modern vaccine preparedness.

Vero cells↗
PubMed1989

Runaway pacemaker: a still existing complication and therapeutic guidelines.

Runaway pacemaker is a rare, but still existing potential lethal complication in permanent pacemakers. Within 4 1/2 years, we saw two cases of runaway pacemaker in patients with multiprogrammable, VVI pacemakers (Siemens-Elema, Model 668). In both cases a pacemaker-induced ventricular tachycardia (rate 240-260 beats/min) was documented. One patient died. Runaway pacemakers must be exchanged as soon as possible. Until this can be accomplished, different emergency maneuvers should be tried. As documented in the cases presented, placing a magnet over the pacemaker may result in a lower, more physiological pacing rate. Reprogramming the pulse generator to a lower output or the use of external chest wall overdrive stimulation may also be successful, but these procedures require the presence of an adequate escape rhythm. If this is not the case or the former maneuvers have failed, an external pacemaker may be connected to the permanent pacing lead. Thereafter, the lead can be safely cut. As an alternative, a temporary transvenous pacing lead may be established prior to disconnecting the permanent pacing lead.

Aged↗
PubMed1994

Termination of pacemaker-mediated tachycardia by adenosine.

A 30-year-old woman was referred for follow-up right- and left-heart catheterization 4 years after cardiac transplantation. She had an implanted epicardial pacemaker for bradycardia; this was programmed to the DDD mode. At the time of her catheterization, as a pigtail catheter was pulled back across the aortic valve, runs of premature ventricular complexes occurred and tachycardia with ventricular pacing spikes and ventricular capture was initiated at a rate of 126 beats/min. Adenosine 6 mg was given intravenously through a femoral venous sheath and within 20 s the tachycardia broke. The tachycardia was consistent with pacemaker-mediated tachycardia (PMT), a circus movement tachycardia occurring when ventricular pacing causes retrograde atrial depolarization followed by triggering of ventricular pacing. With reprogramming of the pacemaker to an AV delay of 160 ms and a postventricular atrial refractory period of 300 ms, no further episodes of PMT have occurred. This case illustrates that intravenous adenosine can effectively terminate PMT by causing ventriculoatrial block, thus interrupting the reentrant circuit by eliminating retrograde atrial activation.

Adenosine↗
PubMed1996

Interference of cellular phones with implanted permanent pacemakers.

BACKGROUND AND HYPOTHESIS: Occasional reports have suggested that cellular phones may interfere with permanent pacemakers. Our investigation sought to determine systematically the effects of commercially available cellular phones on the performances of different pacing modes and sensing lead configurations of permanent implanted pacemakers. METHODS: We conducted the study in 29 patients implanted with single- or dual-chamber bipolar rate-adaptive permanent pacemakers (a total of nine different models and six different sensors: minute ventilation, activity sensing using either accelerometer or piezoelectric crystal, QT and oxygen saturation sensing) from four different manufacturers. Three different cellular phones with analog or digital coding with maximum power from 0.6 to 2 W were used to assess the effect of pacemaker interference. Each cellular phone was positioned at (1) above the pacemaker pocket, (2) the ear level ipsilateral to the pacemaker pocket, and (3) the contralateral ear level. Surface electrocardiograms, intracardiac electrograms, and marker channels were recorded where possible during the following maneuvers at each position: (1) calls made by a stationary phone to cellular phone, and (2) calls made from the cellular phone to a stationary phone. A total of eight different pacing modes [DDD(R), VDD(R), AAI(R) and VVI(R)] in both unipolar and bipolar sensing configurations was tested. RESULTS: Interference was demonstrated during cellular phone operation in 74 of 2,418 (3.1%) episodes in eight patients. Three types of interference were observed: inhibition of pacing output, rapid ventricular tracking in DDD(R) or VDD(R) mode, and asynchronous pacing. All were observed only with the cellular phone positioned above the pacemaker pocket. Interference occurred prior to and after the termination of the ringing tone of the cellular phone in 57% of cases. Cellular phones with either digital or analog technology could cause interference. Unipolar atrial lead was most susceptible to interference (relative frequency of interference: unipolar 1.8%, bipolar 0.4%, p < 0.05; atrial 2.9%, ventricular 1%, p < 0.05). There was no sensor-driven rate acceleration during all tests. In all patients, reprogramming of the sensitivity level successfully prevented cellular phone interference. CONCLUSIONS: Commercially available cellular phones can cause reversible interference to implanted single- or dual-chamber permanent pacemakers. The effect is maximal with high atrial unipolar sensitivity, especially in single pass VDD(R) systems. Both digital and analog cellular phones can lead to interference. Pacemaker interference can occur prior to a warning sign (ringing tone) of the phone and may have significant implications in patient safety.

Adult↗
PubMed2006

6-alkylthio-4-[1-(2,6-difluorophenyl)alkyl]-1H-[1,3,5]triazin-2-ones (ADATs): novel regulators of cell differentiation and proliferation.

Novel triazine analogues of 5-alkyl-2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones (F(2)-DABOs), previously described by us as nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs), were tested for their antiproliferative and cytodifferentiating activity on the A-375 human melanoma cell line. Most of the tested derivatives were effective in decreasing cell proliferation, facilitating morphological differentiation, and reprogramming gene expression. All these effects were reversible upon withdrawal of RT inhibitors. Among the compounds tested, 3 f showed the highest antiproliferative effect, whereas compound 6 c, although not affecting cell proliferation, is endowed with a strong cytodifferentiating effect, which is probably related to a marked upregulation of the e-cad gene. These results support the potential of NNRTIs as valuable antitumor agents.

Cell Differentiation↗
PubMed2006

Discrete pulses of molting hormone, 20-hydroxyecdysone, during late larval development of Drosophila melanogaster: correlations with changes in gene activity.

Periodic pulses of the insect steroid molting hormone 20-hydroxyecdysone (20E), acting via its nuclear receptor complex (EcR/USP), control gene expression at many stages throughout Drosophila development. However, during the last larval instar of some lepidopteran insects, subtle changes in titers of ecdysteroids have been documented, including the so-called "commitment peak." This small elevation of 20E reprograms the larva for metamorphosis to the pupa. Similar periods of ecdysteroid immunoreactivity have been observed during the last larval instar of Drosophila. However, due to low amplitude and short duration, along with small body size and staging difficulties, their timing and ecdysteroid composition have remained uncertain. Employing a rigorous regimen of Drosophila culture and a salivary gland reporter gene, Sgs3-GFP, we used RP-HPLC and differential ecdysteroid RIA analysis to determine whole body titers of 20E during the last larval instar. Three small peaks of 20E were observed at 8, 20, and 28 hr following ecdysis, prior to the well-characterized large peak around the time of pupariation. The possible regulation of 20E levels by biosynthetic P450 enzymes and the roles of these early peaks in coordinating gene expression and late larval development are discussed.

Animals↗
PubMed2007

Differential gene expression patterns in porcine nuclear transfer embryos reconstructed with fetal fibroblasts and mesenchymal stem cells.

The present study compared the developmental ability and gene expression pattern at 4-cell, 8-cell, morula, and blastocyst stages of porcine nuclear transfer (NT) embryos from fetal fibroblasts (FFs) and mesenchymal stem cells (MSCs), in vitro fertilized (IVF), and in vivo derived embryos. MSC-NT embryos showed enhanced blastocyst formation, higher total cell number, and a low incidence of apoptosis compared to FF-NT embryos. Alterations in the expression pattern of genes implicated in transcription and pluripotency (Oct4, Stat3, Nanog), DNA methylation (Dnmt1, Dnmt3a), histone deacetylation (Hdac2), growth factor signaling, and imprinting (Igf2, Igf2r) and apoptosis (Bax, Bcl2) regulation were observed in NT embryos. The expression of transcripts in MSC-NT embryos more closely followed that of the in vivo derived embryos compared with FF-NT embryos. In conclusion, MSCs with a relatively undifferentiated genome might serve as suitable donors that could be more efficiently reprogrammed to re-activate expression of early embryonic genes in porcine NT.

Analysis of Variance↗
PubMed1994

Characterization and expression of C/EPB-like genes in the liver of Rana catesbeiana tadpoles during spontaneous and thyroid hormone-induced metamorphosis.

Tissue-specific changes in gene expression occur in the liver of Rana catesbeiana tadpoles undergoing metamorphosis. Many of these changes can be induced precociously by administration of thyroid hormone (TH) to a tadpole or to cultured tadpole liver. While the precise molecular means by which TH exerts a tissue-specific response is unknown, recent studies suggest that the expression of genes which are liver-specific and characteristic of the adult liver phenotype may rely on TH-induction of tissue-specific transcription factors, as well as the thyroid hormone receptor proteins. Guided by this notion, we screened our Rana catesbeiana liver cDNA library and isolated clones, RcC/EBP-1 and -2, encoding Rana homologues of a mammalian transcription factor, C/EBP (CCAAT/enhancer core binding protein), implicated in the expression of liver-specific genes and terminal differentiation of hepatocytes. Gel mobility shift assays demonstrate that the proteins synthesized from these cDNAs bind specifically to the consensus binding site for C/EBP-related proteins. Characterization of the amino acid sequence in the bZIP DNA-binding domains of these proteins suggests that RcC/EBP-1 and -2 encode Rana homologues of C/EBP alpha and delta, respectively. Hybridization analyses demonstrate that the amount of RcC/EBP-2 mRNAs in tadpole liver remains constant throughout metamorphosis, whereas RcC/EBP-1 mRNAs are up-regulated during both spontaneous and TH-induced metamorphosis. The TH-induced up-regulation of RcC/EBP-1 mRNAs precedes the up-regulation of liver-specific urea cycle enzyme mRNAs by 6 to 12 hours. These results, coupled with in situ hybridization studies, suggest that RcC/EBP-1 mRNAs encode a transcription factor which may play an early role(s) in the terminal differentiation and/or reprogramming of gene expression in this tadpole's liver cells during both spontaneous and TH-induced metamorphosis.

Amino Acid Sequence↗