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PubMed2003

Microdialysis of dopamine interpreted with quantitative model incorporating probe implantation trauma.

Although microdialysis is widely used to sample endogenous and exogenous substances in vivo, interpretation of the results obtained by this technique remains controversial. The goal of the present study was to examine recent criticism of microdialysis in the specific case of dopamine (DA) measurements in the brain extracellular microenvironment. The apparent steady-state basal extracellular concentration and extraction fraction of DA were determined in anesthetized rat striatum by the concentration difference (no-net-flux) microdialysis technique. A rate constant for extracellular clearance of DA calculated from the extraction fraction was smaller than the previously determined estimate by fast-scan cyclic voltammetry for cellular uptake of DA. Because the relatively small size of the voltammetric microsensor produces little tissue damage, the discrepancy between the uptake rate constants may be a consequence of trauma from microdialysis probe implantation. The trauma layer has previously been identified by histology and proposed to distort measurements of extracellular DA levels by the no-net-flux method. To address this issue, an existing quantitative mathematical model for microdialysis was modified to incorporate a traumatized tissue layer interposed between the probe and surrounding normal tissue. The tissue layers are hypothesized to differ in their rates of neurotransmitter release and uptake. A post-implantation traumatized layer with reduced uptake and no release can reconcile the discrepancy between DA uptake measured by microdialysis and voltammetry. The model predicts that this trauma layer would cause the DA extraction fraction obtained from microdialysis in vivo calibration techniques, such as no-net-flux, to differ from the DA relative recovery and lead to an underestimation of the DA extracellular concentration in the surrounding normal tissue.

Animals↗
PubMed2000

Adoptive transfer of nuclear factor-kappaB-inactive macrophages to the glomerulus.

BACKGROUND: Macrophages have been regarded as "blackguards" in the generation of glomerular injury. However, it is still unclear what kind of cellular machinery is responsible for their pathogenic actions. To explore this issue, this investigation aims at developing a novel strategy using adoptive transfer of "loss-of-function" macrophages to the glomerulus. As a prototypal investigation, this study examines a role for nuclear factor-kappaB (NF-kappaB) in effector actions of macrophages within the glomerular microenvironment. METHODS: NF-kappaB-inactive macrophages, NIKMACNR, were created by transduction of NR8383 rat macrophages with retrovirus encoding a super-repressor mutant of IkappaBalpha, IkappaBalphaM. The effector functions of NIKMACNR cells on resident cells were evaluated by coculture, cross-feeding, and in vivo macrophage transfer. RESULTS: Rat mesangial cells cocultured with control macrophages showed abundant expression of activation markers, including monocyte chemoattractant protein-1, stromelysin, and gelatinase B. In contrast, coculture with NIKMACNR macrophages induced only modest gene expression. Similarly, culture medium conditioned by activated, control macrophages triggered mesangial cells and isolated glomeruli to express the activation markers, whereas the stimulatory effect was not observed in medium conditioned by NIKMACNR macrophages. To evaluate effector actions of NIKMACNR macrophages in the glomerulus, control macrophages and NIKMACNR cells were transferred into normal rat glomeruli via renal artery injection. After the transfer of control macrophages, substantial induction of the activation marker stromelysin was observed in resident glomerular cells. This induction was dramatically diminished in the glomeruli transferred with NIKMACNR macrophages. CONCLUSIONS: Inactivation of NF-kappaB in macrophages effectively disrupted paracrine, stimulatory loops from macrophages to resident glomerular cells. A combination of "loss-of-function" strategies with the technique for adoptive cell transfer is thus useful to explore pathophysiologic roles for certain machinery of macrophages within the glomerulus.

Animals↗
PubMed1996

Regulation of bone formation by bone morphogenetic proteins and other growth factors.

Bone formation in adult humans is a complex and closely regulated process. It usually occurs at sites of previous osteoclastic bone resorption. It also may occur in the growing long bones during endochondral bone formation, and appositional bone formation also can appear during growth and adolescence without prior local resorption, particularly on periosteal surfaces. The cellular events involved in bone formation include chemotaxis of osteoblast precursors; proliferation of committed osteoblast precursors; differentiation, including expression of growth regulatory factors and the structural proteins of bone, such as osteocalcin, osteopontin, and Type I collagen; and mineralization. It is clear that these cellular events must be under very tight regulatory control. They may all be modulated by systemic hormones, including the calciotropic hormones, parathyroid hormone and 1,25 dihydroxyvitamin D and other systemic hormones, such as the pituitary and thyroid hormones and sex steroids, but probably are modulated predominantly by local factors or cytokines generated in the bone cell microenvironment.

Animals↗
PubMed2005

Imaging molecular interactions in living cells.

Hormones integrate the activities of their target cells through receptor-modulated cascades of protein interactions that ultimately lead to changes in cellular function. Understanding how the cell assembles these signaling protein complexes is critically important to unraveling disease processes, and to the design of therapeutic strategies. Recent advances in live-cell imaging technologies, combined with the use of genetically encoded fluorescent proteins, now allow the assembly of these signaling protein complexes to be tracked within the organized microenvironment of the living cell. Here, we review some of the recent developments in the application of imaging techniques to measure the dynamic behavior, colocalization, and spatial relationships between proteins in living cells. Where possible, we discuss the application of these different approaches in the context of hormone regulation of nuclear receptor localization, mobility, and interactions in different subcellular compartments. We discuss measurements that define the spatial relationships and dynamics between proteins in living cells including fluorescence colocalization, fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy. These live-cell imaging tools provide an important complement to biochemical and structural biology studies, extending the analysis of protein-protein interactions, protein conformational changes, and the behavior of signaling molecules to their natural environment within the intact cell.

Animals↗
PubMed2006

CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12.

BACKGROUND: Hematopoietic cells home to bone by means of chemo-attraction to marrow chemokines, and interaction of chemokines with their receptors leads to the expression/activation of adhesion molecules and proteases. Recent evidence suggests that similar mechanisms may be active in cancer metastasis. Previously, we showed that metalloproteases (MMPs), and in particular MMP-9, play a role in prostate cancer (PC) expansion in bone. METHODS: We used a variety of methods including RT-PCR, immunohistochemistry, ELISA, gelatin zymography, cellular motility and invasion, and subcellular fractionation of PC cells applied to in vivo and in vitro models. RESULTS: Here we showed that (a) CXCL12/CXCR4 axis is expressed in PC bone metastasis; (b) exogenous CXCL12 induced MMP-9 expression by PC cells; (c) bone stromal cells and bone tissue conditioned media induced the migration of PC cells in a CXCR4-dependent manner; (d) pharmacological inhibition of PI3 kinase and MAP kinase pathways abrogated CXCL12-induced MMP-9 expression and invasion of PC cells; (e) exogenous CXCL12 induced Akt1 phosphorylation is indispensable for proMMP-9 secretion, migration, and invasion of PC cells; (f) CXCR4 was localized to lipid rafts in PC cells and initiated Akt phosphorylation. CONCLUSIONS: These data suggest that chemoattractive mechanisms involve migration of cancer cells towards bone tissue, and that cell signaling induced by binding of the chemokine to its receptor leads to the activation of multiple signaling pathways and subsequent secretion of MMP-9 into the local environment. These findings provide a link between chemoattractive mechanisms, growth of tumor cells in bone, and tumor-enhanced bone matrix turnover.

Animals↗
PubMed1998

Macrophages, estrogen and the microenvironment of breast cancer.

Estrogen is a major mitogenic stimulus to established breast cancer. Estrogen sources include ovarian, extraglandular sites and breast tissue. Which source primarily maintains benign and breast cancer tissue estrogen concentrations remains unclear. While macrophages may comprise up to 50% of the mass of breast carcinomas, previous studies neglected to study them as possible sources of estrogen. We present evidence that breast macrophages constitute an in situ source of estradiol and that the amount produced is sufficient to mediate cellular proliferation. We utilized immunohistochemistry and RT-PCR to study cell-specific aromatase expression in (i) 29 breast biopsies, (ii) human monocytes/macrophages and (iii) a myeloid cell line (THP-1) capable of differentiating into macrophages. Use of a breast cancer cell line (MCF-7) provided biologic confirmation of the role of aromatization in cell proliferation. We demonstrated considerable amounts of immunoreactive-aromatase (irARO) in breast tissue macrophages and a positive correlation between the proportion of irARO present in macrophages and lesion severity. Using in vitro techniques, we demonstrated that monocytes and THP-1 cells require differentiation into macrophages to produce aromatase in amounts approaching placental levels. The amount of estrogen produced by THP-1 cells stimulated MCF-7 cells to proliferate, an effect blocked by aromatase inhibitors. Estrogen production by macrophages in breast tissue appears sufficient to stimulate the proliferation of adjacent epithelial cells and to autoregulate cytokine production. These findings represent a new dimension of cellular regulation in breast tissue with major biologic implications, amenable to pharmacological manipulation.

Antineoplastic Agents↗
PubMed2006

Molecular networks orchestrating GALT development.

During evolution, the development of secondary lymphoid organs has evolved as a strategy to promote adaptive immune responses at sites of antigen sequestration. Mesenteric lymph nodes (LNs) and Peyer's patches (PPs) are localized in proximity to mucosal surfaces, and their development is coordinated by a series of temporally and spatially regulated molecular events involving the collaboration between hematopoietic, mesenchymal, and, for PPs, epithelial cells. Transcriptional control of cellular differentiation, production of cytokines as well as adhesion molecules are mandatory for organogenesis, recruitment of mature leukocytes, and lymphoid tissue organization. Similar to fetal and neonatal organogenesis, lymphoid tissue neoformation can occur in adult individuals at sites of chronic stimulation via cytokines and TNF-family member molecules. These molecules represent new therapeutic targets to manipulate the microenvironment during autoimmune diseases.

Animals↗
PubMed1986

Role of mucus in the repair of gastric epithelial damage in the rat. Inhibition of epithelial recovery by mucolytic agents.

A role for mucus in providing a microenvironment over sites of gastric damage, which is conducive to reepithelialization, has been proposed. We tested this hypothesis by examining the effects of disruption of such mucus on the recovery of epithelial integrity after damage induced by 50% ethanol. Exposure of an ex vivo chambered gastric mucosa to topically applied 50% ethanol resulted in copious release of mucus, cellular debris, and plasma, which formed a continuous cap over the mucosal surface. Ethanol-induced gastric damage was accompanied by extensive surface epithelial cell damage and a marked decrease in transmucosal potential difference. During the 30 min after ethanol was removed from the chamber, the epithelium became reestablished and the potential difference gradually recovered to 94% of the level before ethanol treatment. However, if the mucolytic agents N-acetylcysteine (5%) or pepsin (0.5%) were added to the bathing solutions, the "mucoid cap" disintegrated and the recovery of potential difference was significantly retarded (recovering to only 51% and 52% of levels before ethanol treatment). Histologic evaluation confirmed that mucosae treated with either agent had significantly less (p less than 0.005) intact epithelium at the end of the experiment. Removal of the mucoid cap with forceps caused a similar inhibition of the repair of the epithelium and the recovery of potential difference. Both mechanical and chemical (N-acetylcysteine) disruption of the mucoid cap resulted in a significant increase in the mucosal leakage of albumin and hemoglobin, supporting previous histologic evidence that the mucoid cap traps blood components over the damaged mucosa. These studies support the hypothesis that mucus released in response to topical application of an irritant plays an important role in the repair of epithelial damage through the process of restitution.

Acetylcysteine↗
PubMed2002

Cell interactions with three-dimensional matrices.

Signaling and other cellular functions differ in three-dimensional compared with two-dimensional systems. Cell adhesion structures can evolve in vitro towards in-vivo-like adhesions with distinct biological activities. In this review, we examine recent advances in studies of interactions of fibroblasts with collagen gels and fibronectin-containing matrices that mimic in vivo three-dimensional microenvironments. These three-dimensional systems are illuminating mechanisms of cell-matrix interactions in living organisms.

Animals↗
PubMed1999

Pathogenesis of endometriosis: the role of peritoneal fluid.

Peritoneal fluid is a specific microenvironment. It originates mainly as an ovarian exudation product due to increased vascular permeability, and contains large amounts of macrophages and their secretion products, which include growth factors, cytokines and angiogenic factors. Similarly, within the ovary, there is also a specific microenvironment, best characterised by the follicular milieu with steroid hormone concentrations that are 1,000 times higher than in plasma. Since endometrial cells in peritoneal fluid and superficially implanted cells will be influenced by peritoneal fluid concentrations, any differences found between minimal endometriosis and eutopic endometrium could be the consequence of their different local environments, rather than inherent cellular differences. Superficial endometrial implants may be regulated by factors in peritoneal fluid, while deep endometriosis and cystic ovarian endometriosis may be under the influence of factors in blood and within the ovary, in which case minimal endometriosis may be physiologic only, while deep endometriosis and cystic ovarian endometriosis, both associated with pelvic pain and infertility, may be a pathological state. In conclusion, the local endocrine environment, that is, in blood, peritoneal fluid, and within the ovary, should be taken into account to explain the differences between superficial, deep and cystic ovarian endometriosis, together with inherent differences in the endometrial cells of women with and without endometriosis.

Animals↗
PubMed2000

Physiological and cell biological aspects of perfusion culture technique employed to generate differentiated tissues for long term biomaterial testing and tissue engineering.

Optimal results in biomaterial testing and tissue engineering under in vitro conditions can only be expected when the tissue generated resembles the original tissue as closely as possible. However, most of the presently used stagnant cell culture models do not produce the necessary degree of cellular differentiation, since important morphological, physiological, and biochemical characteristics disappear, while atypical features arise. To reach a high degree of cellular differentiation and to optimize the cellular environment, an advanced culture technology allowing the regulation of differentiation on different cellular levels was developed. By the use of tissue carriers, a variety of biomaterials or individually selected scaffolds could be tested for optimal tissue development. The tissue carriers are to be placed in perfusion culture containers, which are constantly supplied with fresh medium to avoid an accumulation of harmful metabolic products. The perfusion of medium creates a constant microenvironment with serum-containing or serum-free media. By this technique, tissues could be used for biomaterial or scaffold testing either in a proliferative or in a postmitotic phase, as is observed during natural development. The present paper summarizes technical developments, physiological parameters, cell biological reactions, and theoretical considerations for an optimal tissue development in the field of perfusion culture.

Animals↗
PubMed2003

[Autocrine stimulation of receptor-tyrosine kinases (RTK) in human tumor cell lines in vitro: therapeutic implications].

AIMS: The VEGF/VEGFR system is known to play an important role in the development of new blood vessels during tumor formation. There is evidence that VEGFRs are not only present on endothelial cells but also on tumor cells. Since VEGF is able to induce proliferation and migration via VEGFR-2 we have studied the expression of VEGFRs and related receptor tyrosine kinases (RTKs) in different tumor cell lines and the effect of growth factor stimulation. METHODS: RTK expression was investigated in 5 different human tumor cell lines on protein and mRNA levels. Tumor cell lines were exposed to growth factors such as VEGF and the phosphorylation of downstream molecules involved in proliferation, migration and apoptosis were assessed. Under comparable conditions proliferation and migration essays were performed. Endogenous production of VEGF and PDGF by the tumor cells was measured by ELISA of cell culture supernatants. RESULTS: Most tested cell lines expressed all known VEGFR's, PDGFR-beta on protein and mRNA levels to a varying extent. 3 out of 5 cell lines could be stimulated after addition of VEGF reflected by an increased phosphorylation of MAPK, AKT/PKB and to a lesser extent of p38. This was underlined by an increased cell number and reduced number of apoptotic cells. After stimulation with PDGF-BB a stronger induction of MAPK and AKT/PKB phosphorylation than for VEGF could be seen. In contrast, no effect on tumor cell migration was detectable in all examined cell lines. The investigation of cell culture supernatants revealed that most cell lines do not produce VEGF or PDGF. CONCLUSIONS: Tumor cell lines express RTKs and the receptor is stimulable after addition of growth factors such as VEGF. Thus, secretion of groth factors in the tumor microenvironment is not only able to stimulate proliferation and survival of endothelial cells but also tumor cells themselve. One cell line displayed high levels of endogenous VEGF which could explain the lack of an increased cell number after addition of VEGF. It remains obscure why another cell line could not be stimulated although receptors were present at the cellular surface. Further investigations should prove that RTK's could be influenced by therapeutic drugs in order to suppress cell proliferation and migration and induce apoptosis in tumor cell lines.

Cell Line, Tumor↗
PubMed2006

Murine mesenchymal stem cells transplanted to the central nervous system of neonatal versus adult mice exhibit distinct engraftment kinetics and express receptors that guide neuronal cell migration.

Mesenchymal stem cells (MSCs) have demonstrated efficacy as cellular vectors for treating a variety of nervous system disorders. Nevertheless, few studies have quantified MSC engraftment levels or explored the mechanisms that promote their survival and migration in nervous tissue. In this study, we compared the engraftment kinetics and anatomical distribution of murine, male MSCs injected intracranially into neonatal versus adult female mice using a real-time PCR assay that targets the mouse SRY gene. These analyses revealed that MSCs exhibited low but equivalent engraftment levels in the central nervous system (CNS) of neonatal and adult transplant recipients at 12 days post-injection. However, MSC engraftment levels were significantly greater at 60 and 150 days post-transplantation in neonates as compared to adults. Despite these differences, engrafted MSCs were widely distributed along the neuraxis of the CNS in both transplant groups. Collectively, these data indicate that proliferation, but not engraftment and migration, of MSCs in brain are regulated by the host microenvironment. Using a genomics approach, we also identified MSC subpopulations that express neural adhesion proteins and receptors that regulate neuronal cell migration in brain, including cadherin 2, neurexin 1, ninjurin 1, neogenin 1, neuropilin 2, and roundabout homolog 1 and 4. Functional studies indicate these proteins confer cell adhesion and migration of MSCs in response to the appropriate chemoattractant. On the basis of these findings, we conclude that the unique molecular composition of MSC subpopulations imparts to them an inherent capacity to engraft and migrate in brain. These subpopulations may represent more potent cellular vectors for treating CNS disorders.

Aging↗
PubMed1983

[Embryonal hematopoiesis in the intact human liver and in its organ culture].

Hepatic tissues in 58 human embryos, 5-12 week-old have been investigated. At that time hemopoiesis is mainly presented by erythropoiesis. Ultrastructure of the hepatic parenchymal cells and that of the hemopoietic cellular elements have been studied. The cultural system used makes it possible to maintain hemopoiesis in the explants for 3.5 weeks. Under the conditions of cultivation in the organic culture, certain changes in architectonics of the explants are observed. As the time of the cultivation increases, the ultrastructure of the hepatic parenchymal cells, which make the hemopoiesis-inducing microenvironment, undergo further changes. A gradual substitution of erythropoiesis for granulomonocytopoiesis takes place.

Hematopoiesis↗
PubMed1994

Retinoids (all-trans and 9-cis retinoic acid) stimulate production of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by human bone marrow stromal cells.

Retinoic acids (RAs) exert pleiotropic effects on cellular growth and differentiation. All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA), a stereoisomer of ATRA, induce differentiation of leukemic cell lines and cells from patients with acute myelogenous leukemia (AML) in vitro. Despite information on the effects of RAs on hematopoietic cells, little is known about how RAs act on the hematopoietic microenvironment, especially on bone marrow stromal cells. Based on recent observations that various cytokines produced mainly by bone marrow stromal cells regulate hematopoiesis, we analyzed the effects of RAs on cytokine production by these cells. ATRA or 9-cis RA treatment of human bone marrow stromal cell line KM101, which produces macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) constitutively, enhanced mRNA levels of both cytokines in a dose-dependent manner. Both RAs also stimulated M-CSF production from primary cultures of human bone marrow stromal cells. Both retinoic acid receptor (RAR)-alpha and retinoid X receptor (RXR)-alpha were expressed constitutively in KM101 cells. ATRA did not affect the expression of either receptor, whereas 9-cis RA increased RXR-alpha mRNA expression in a dose-dependent manner, but did not affect levels of RAR-alpha mRNA. These findings may have important biologic implications for both the role of RAs in hematopoiesis and the therapeutic effects of ATRA on the hematopoietic microenvironment in patients with acute promyelocytic leukemia (APL).

Bone Marrow Cells↗
PubMed1994

Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. I. Mechanism and evidence of functional significance.

Tenidap is a novel anti-inflammatory and antiarthritic agent that in clinical studies of rheumatoid arthritis patients, displays symptomatic efficacy superior to nonsteroidal anti-inflammatory drugs (NSAIDs) and equivalent to combinations of NSAIDs and second line agents. Clinical and preclinical biochemical studies have demonstrated that tenidap combines cytokine modulation with suppression of prostaglandin biosynthesis. To better understand tenidap's mechanism of action, in vitro studies of intracellular pH (pHi) were conducted. In cells loaded with the pH-sensitive fluorescence dye 2',7'-bis-(2-carboxyethyl)-5-(and -6) carboxyfluorescein, tenidap, but not NSAIDs, caused a rapid and sustained acidification of the cytoplasmic compartment. Tenidap did not act as a proton ionophore, as it did not dissipate the low pH within lysosomes. Mammalian cells regulate pHi through the concerted action of a number of specific transport proteins, including sodium-proton antiporters and chloride-bicarbonate exchangers. Tenidap did not alter pHi via inhibition of the sodium-proton antiporter, but inhibited activity of chloride-bicarbonate exchangers, as did UK5099, a known anion-transport inhibitor that also lowers pHi. This similar activity suggests that the pHi change is coupled to anion transport inhibition. As a result of the pHi change, tenidap affected pH-dependent cellular activities. Tenidap inhibited mannose 6-phosphate receptor-mediated endocytosis, inhibited protein synthesis, and stimulated accumulation of the amino acid leucine. Effects on these cellular processes rapidly reversed when tenidap was removed from the culture medium. Tenidap's in vitro activities were highly dependent on the medium composition; protein content, pH, and bicarbonate concentration all were important factors that influenced activity. These results indicate that tenidap is a potent anion-transport inhibitor and modulator of pHi. Within the appropriate cell or tissue microenvironment, these activities may contribute to tenidap's novel therapeutic profile.

Animals↗
PubMed1993

[The effect of fibronectin on hematopoiesis in long-term cultures of the bone marrow from patients with acute leukemias in the remission stage].

Hemopoietic effects in bone marrow long-term cultures (BMLTC) of healthy subjects and patients with acute myeloid leukemia (AML) in remission were studied due to fibronectin (FN) and glycoprotein of extracellular matrix of stromal microenvironment. Twelve AML patients and 6 healthy donors of allogenic transplant were examined. Blood formation in the BMLTC was assessed by weekly production of cells in nonadhesive BMLTC fraction and the content of granulocytic-macrophagal colony-forming cells in it. The response of hemopoietic stroma on FN sublayer was evaluated by weekly measurements of BMLTC adhesive layer cellularity. FN is demonstrated to stimulate the growth of BMLTC adhesive cell sublayer, the cellularity increase being the same in the above groups. FN sublayer had no influence on cellularity of the nonadhesive fraction and on the number of granulocytic-macrophagal colony-forming cells in healthy subjects, whereas it increased these values in AML patients in remission. This rise, however, was not significant. BMLTC is capable of defining a favorable effect of FN sublayer on hemopoiesis in AML patients in remission. This effect may arise from higher quality of the sublayer and survival of cells-precursors at initial stages of the cultivation.

Acute Disease↗
PubMed2026

Clinical evidence on non-viral CAR-T cell therapies for solid tumors: a scoping review.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy in solid tumors is hindered by the immunosuppressive tumor microenvironment and by toxicities associated with viral-vector manufacturing. Non-viral gene delivery platforms have emerged as a potential alternative, though clinical evidence remains fragmented. METHODS: Following an a priori protocol registered on the Open Science Framework (OSF; https://doi.org/10.17605/OSF.IO/2TPQS) and adhering to JBI/PRISMA-ScR guidelines, a systematic search was conducted across four databases from inception through May 15, 2026. Patient-level data were extracted to describe cellular persistence and clinical outcomes across strictly non-viral delivery platforms. RESULTS: Four early-phase studies met the inclusion criteria, encompassing 28 heavily pretreated patients with metastatic solid tumors. Two non-viral platforms were identified: mRNA electroporation (n=19; intravenous in 13, intratumoral in 6) and the piggyBac transposon system (n=9). Across both mRNA routes, transient CAR-T persistence (<7 days) was observed, with no objective responses (ORR 0%), though disease stabilization yielded a disease control rate (DCR) of 53%; cross-route comparison is limited by differing distribution profiles. The piggyBac system showed longer persistence (~28 days) and a DCR of 78%, including the only documented objective response (ORR 11%). No Grade &#x2265;3 cytokine release syndrome or neurotoxicity was reported in any of the 28 patients, and no tocilizumab or systemic corticosteroids were required. CONCLUSIONS: Within this limited early-phase evidence base, no severe toxicities attributable to non-viral platforms were reported, and the evidence identifies knowledge gaps warranting prospective investigation. mRNA platforms showed transient persistence and disease stabilization in 53% of patients. One partial response was documented with the piggyBac platform in a single patient; however, this outcome cannot be attributed to the delivery platform given simultaneous differences in target antigen, tumor histology, route of administration, and geographic setting. No firm conclusions regarding comparative platform performance can be drawn from this evidence base. SYSTEMATIC REVIEW REGISTRATION: https://doi.org/10.17605/OSF.IO/2TPQS, identifier OSF.IO/2TPQS.

Humans↗