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Biomedical subjects

J M Isner

Publications and source records attributed to J M Isner.

At least 163 records · Page 9Linked to original sources
PubMed1995

The changing profile of patient selection, procedural techniques, and outcomes in excimer laser coronary angioplasty. Participating Investigators of the Percutaneous Excimer Laser Coronary Angioplasty Registry.

During the course of development of excimer laser angioplasty, several changes in patient selection and technique have occurred. It is uncertain, however, whether these changes have been associated with improved procedural outcome. In this study, multivariable regression methods were used to identify the factors responsible for clinical success, major complications, and vessel perforation in 2,041 consecutive patients treated with excimer laser coronary angioplasty. The overall rates of clinical success were 89%, major complications 7.5%, and vessel perforation 2.1%. Clinical success was 86% in patients treated with prototype catheters, 89% with flexible catheters, 92% with extremely flexible catheters, and 95% in patients treated with directional eccentric catheters (P < 0.001). By multivariable analysis, clinical success increased with each subsequent catheter design (odds ratio [OR] = 1.4 per iteration [95% confidence interval 1.2, 1.6]), and with improved lesion selection. Major complications were reduced when operators had performed more than 25 cases (rate = 6.5%, OR = 0.7 [0.5, 0.9]), and the incidence of vessel perforation was decreased when the size of the target vessel was > 1.0 mm larger than the diameter of the laser catheter (rate = 1.1%, OR = 0.3 [0.2, 0.5]). In conclusion, during the course of clinical investigation with excimer laser angioplasty, procedural outcome has improved. These results emphasize the importance of careful patient selection and procedural technique to enhance the success of excimer laser angioplasty.

Aged↗
PubMed1995

Epidermal growth factor receptor-targeted cytotoxin inhibits neointimal hyperplasia in vivo. Results of local versus systemic administration.

Smooth muscle cell accumulation is a key feature of restenosis that may be inhibited by the delivery of receptor-targeted cytotoxins. DAB389EGF is a recombinant fusion protein in which the receptor-binding domain of diphtheria toxin has been replaced by human epidermal growth factor (EGF). We investigated the effectiveness of DAB389EGF to inhibit neointimal hyperplasia in the balloon-injured rat carotid artery. Incubation of rat carotid arteries with 125I-labeled EGF revealed extensive EGF binding sites in the neointima of balloon-injured arteries. Sixty rats subsequently received either saline or DAB389EGF (total dose, 0.15 mg) delivered immediately following balloon injury either systemically, via 14-day continuous osmotic pump infusion, or locally, via 30-minute intraluminal incubation. The effect of both treatment strategies was measured 2 weeks after injury by cross-sectional morphometric analysis of intimal area, the ratio of intimal/medial area (I/M), and the percent luminal narrowing (%LN). In addition, proliferative activity was assessed by immunostaining for the presence of the proliferating cell nuclear antigen (PCNA). Compared with controls, systemic delivery of fusion toxin significantly reduced intimal area, I/M, and %LN by 40%, 40%, and 29%, respectively. However, these rats exhibited 2% weight loss, indicating mild systemic toxicity. Local, intraluminal administration of DAB389EGF yielded a more pronounced reduction in intimal area, I/M, and %LN by 74%, 79%, and 72%, respectively. This inhibitory effect was preserved at 3 weeks postinjury, and PCNA immunostaining of locally treated arteries revealed a virtual absence of proliferative activity in the neointima and media at this timepoint. In contrast to systemically treated rats, rats receiving fusion toxin locally gained weight at a rate similar to controls, indicating avoidance of systemic toxicity. We conclude that DAB389EGF is a potent inhibitor of neointimal hyperplasia in vivo and that whereas an inhibitory effect may be achieved by systemic delivery, local delivery appears to be more potent, avoids systemic toxicity, and thus represents a feasible strategy to preempt restenosis.

Animals↗
PubMed1995

Low-efficiency of percutaneous adenovirus-mediated arterial gene transfer in the atherosclerotic rabbit.

Recombinant adenoviruses are the most efficient vectors with which to perform arterial gene transfer. Previous in vivo studies of adenovirus-mediated arterial transfection, however, have been performed using normal or endothelium-denuded arteries. It is unclear whether these results can be extended to atherosclerotic arteries. Accordingly, this study was designed to (a) assess the feasibility of adenovirus-mediated gene transfer to atherosclerotic lesions, and (b) compare the transfection efficiency, anatomic distribution of transfected cells, and duration of transgene expression achieved in normal versus atherosclerotic arteries. A recombinant adenovirus including a nuclear-targeted beta-galactosidase gene was percutaneously delivered to the iliac artery of normal (n = 25) and atherosclerotic (n = 25) rabbits. Transgene expression, assessed by morphometric as well as chemiluminescent analyses, was documented in all normal and atherosclerotic arteries between 3 and 14 d after gene transfer, but was undetectable at later time points. Transfected cells were identified as smooth muscle cells located in the media of normal arteries, and in the neointima and the vasa-vasora of atherosclerotic arteries. Two percent of medial cells, but only 0.2% of medial and neointimal cells expressed the transgene in normal and atherosclerotic arteries, respectively (P = 0.0001). Similarly, nuclear beta-galactosidase activity was higher in normal than in atherosclerotic arteries (3.2 vs. 0.8 mU/mg protein, P = 0.02). These findings indicate that atherosclerosis reduces the transfection efficiency which can be achieved with adenoviral vectors, and thus constitutes a potential limitation to adenovirus-based, arterial gene therapy.

Adenoviruses, Human↗
PubMed1995

Time course of increased cellular proliferation in collateral arteries after administration of vascular endothelial growth factor in a rabbit model of lower limb vascular insufficiency.

Proliferation of vascular cells has been previously shown to contribute to spontaneous development of coronary collaterals. Recent studies from several laboratories have established that collateral artery growth in both the heart and limb can be enhanced by administration of angiogenic growth factors, or therapeutic angiogenesis. In this study, we sought (1) to define the extent and time course of endothelial cell (EC) and smooth muscle cell (SMC) proliferation accompanying spontaneous collateral development during limb ischemia and (2) to determine the extent to which proliferative activity of ECs and SMCs is augmented during therapeutic angiogenesis with vascular endothelial growth factor (VEGF), a heparin-binding EC-specific mitogen. Ten days after induction of limb ischemia by surgically excising the femoral artery of rabbits, either VEGF (500 to 1000 micrograms) or saline was administered as a bolus into the iliac artery of the ischemic limb. Cellular proliferation was evaluated by bromodeoxyuridine labeling for 24 hours at day 0 (immediately before VEGF administration) and at days 3, 5, and 7 after VEGF, EC proliferation in the midzone collaterals of VEGF-treated animals increased 2.8-fold at day 5 (P < 0.05 versus control), and returned to baseline levels by day 7. SMC proliferation in midzone collaterals also increased 2.7-fold in response to VEGF (P < 0.05). No significant increase in EC or SMC proliferation was observed in either the stem or re-entry collaterals of VEGF-treated animals compared with untreated ischemic control animals. Reduction of hemodynamic deficit in the ischemic limb measured by lower limb blood pressure was documented at day 7 after VEGF (P < 0.01 versus untreated, ischemic control). These data thus (1) establish the contribution of cellular proliferation to collateral vessel development in limb ischemia and (2) support the concept that augmented cellular proliferation contributes to the enhanced formation of collateral vessels after therapeutic angiogenesis with VEGF.

Animals↗
PubMed1994

Predictors of outcome of percutaneous excimer laser coronary angioplasty of saphenous vein bypass graft lesions. The Percutaneous Excimer Laser Coronary Angioplasty Registry.

A total of 495 patients underwent treatment with excimer laser angioplasty for 545 saphenous vein graft stenoses. Clinical success was achieved in 455 of 495 patients (92%), as indicated by < or = 50% residual stenosis at every target lesion and no complication during hospitalization. At least 1 in-hospital complication occurred in 30 of 495 patients (6.1%): death (1.0%), bypass surgery (0.6%), and Q-wave (2.4%) or non-Q-wave (2.2%) myocardial infarction. Relative risk analysis showed that ostial lesions (n = 65) tended to have higher clinical success (success rate = 95%, adjusted odds ratio [OR] = 2.1 [95% confidence interval (CI) 0.62, 6.88]; p = 0.24) and lower complications (complication rate = 0%, OR = 0.10 [CI 0.01, 0.79]; p = 0.03) than lesions in the body of the vein graft. Lesions > 10 mm (n = 131) had lower success (success rate = 84%, OR = 0.30 [CI 0.16, 0.56]; p = 0.001) and higher complications (complication rate = 12%, OR = 3.3 [CI 1.6, 6.6]; p = 0.004) than discrete lesions. Lesions in small vein grafts < 3.0 mm (n = 76) tended to have increased success (success rate = 94%, OR = 1.55 [CI 0.70, 3.44]; p = 0.39) and lower complications (complication rate = 2.2%, OR = 0.31 [CI 0.10, 0.94]; p = 0.03). Thus, excimer laser-facilitated angioplasty has the most favorable outcome for discrete lesions located at the ostium of all grafts and in the body of smaller saphenous vein grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Prospects for site-specific delivery of pharmacologic and molecular therapies.

The local delivery of therapeutic agents to the arterial wall represents a new strategy for the treatment of vascular diseases, including restenosis. Approaches for local, intravascular, site-specific delivery include 1) direct deposition of therapeutic agents into the vessel wall through an intravascular delivery system; 2) systemic administration of inactive agents followed by local activation; and 3) systemic administration of fusion toxins that have a specific affinity to proliferating smooth muscle cells at the angioplasty site. In addition to conventional drugs, new therapeutic agents based on molecular mechanisms, including recombinant genes and antisense oligonucleotides, are now under investigation. Although development of intravascular drug delivery devices, including those tailored to accommodate novel therapeutic agents, offers new treatment options for restenosis and other vascular diseases, certain issues that currently limit the safety and efficacy of these approaches remain to be addressed.

Blood Vessels↗
PubMed1994

Physiological assessment of augmented vascularity induced by VEGF in ischemic rabbit hindlimb.

This study was designed to assess the physiological consequences of augmented vascularity induced by administration of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, in a rabbit model of hindlimb ischemia. Ten days after excision of the common and superficial femoral arteries from one hindlimb of 24 New Zealand White rabbits, VEGF (n = 15) or saline (control; n = 9) was selectively injected into the ipsilateral internal iliac artery. Limb perfusion was evaluated immediately pre-VEGF (baseline) and again at days 10 and 30. A Doppler guide wire was advanced to the internal iliac artery to record flow velocity at rest and at maximum flow velocity provoked by intra-arterial injection of papaverine. At baseline and at day 10, no differences in flow parameters were observed between the control and the VEGF-treated animals. By day 30, however, flow at rest (P < 0.05), maximum flow velocity (P < 0.001), and maximum blood flow (P < 0.001) were all significantly higher in the VEGF-treated group. These physiological findings complement previous-anatomic studies by providing evidence that a single intra-arterial bolus of VEGF augments flow, particularly maximum flow, in the rabbit ischemic hindlimb. These data thus support the notion that VEGF administration represents a potential treatment strategy for certain patients with lower extremity ischemia.

Animals↗
PubMed1994

Liposome-mediated gene transfer into human vascular smooth muscle cells.

BACKGROUND: Complexing recombinant DNA with cationic liposomes is a convenient means of introducing foreign genes into cells (lipofection) and could potentially form the basis for genetically modifying diseased blood vessels in patients. The mechanism of lipofection is incompletely understood, but it is recognized that the degree of successful gene transfer is highly dependent on cell type. To date, there has been no reported experience with lipofection of human vascular smooth muscle cells. METHODS AND RESULTS: Primary cultures of human vascular smooth muscle cells were transfected under optimized conditions with a plasmid expressing either firefly luciferase (Luc) or nuclear-localized beta-galactosidase (NL-beta-gal). Cells were derived from either normal human internal mammary arteries (n = 6), fragments of primary atherosclerotic plaque (n = 4), or fragments of restenotic lesions (n = 5). Concurrent lipofection of rabbit vascular smooth muscle cells and NIH 3T3 cells was performed as well. Cultures derived from 15 patients all demonstrated positive expression of the reporter gene. Compared with NIH 3T3 cells, however, expression in human vascular smooth muscle cells was markedly reduced: in cells derived from internal mammary artery, Luc expression, normalized for protein content, was 123-fold lower than in NIH 3T3 cells, whereas the proportion of cells expressing NL-beta-gal was 30-fold lower. Luc expression in cells derived from restenotic tissue was significantly greater than from cells derived from primary plaque (P < .03). Within a given population of cells, the mitotic index of cells expressing the recombinant gene was significantly higher than the mitotic index for the total population of cells (P < .05). Finally, cotransfection experiments, in which lipofection of smooth muscle cells was performed using genes for NL-beta-gal and for human growth hormone, showed that among positive transfects, a high proportion of cells (23% to 36%) coexpressed both genes. CONCLUSIONS: The efficiency of successful lipofection in human vascular smooth muscle cells in vitro is low. Transfection appears to be preferentially facilitated in cells derived from restenotic tissue, and specific properties of smooth muscle cells, including growth rates, appear to be critical for successful transfection. Further elucidation of cell properties that promote transfection is required to augment the efficiency of liposome-mediated gene transfer in human vascular cells.

3T3 Cells↗
PubMed1994

Use of the rabbit ear artery to serially assess foreign protein secretion after site-specific arterial gene transfer in vivo. Evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression.

BACKGROUND: The development of molecular strategies for the treatment of restenosis has been hindered by low efficiencies of in vivo arterial transfection. Expression of intracellular marker proteins is generally evident in < 1% of vascular smooth muscle cells after in vivo arterial transfection. Efforts to improve the efficiency of in vivo gene transfer have been further impeded by the use of transgenes encoding for intracellular marker proteins, necessitating tissue removal and limiting survey for expression to one point in time. METHODS AND RESULTS: To study gene expression on a serial basis in vivo and determine the relation between a secreted gene product and transfection efficiency after in vivo arterial gene transfer, a method for performing and serially monitoring gene expression in vivo was developed using the central artery of the rabbit ear. Liposome-mediated transfection of plasmid DNA containing the gene for human growth hormone (hGH) was successfully performed in 18 of 23 arteries. Serum hGH levels measured 5 days after transfection ranged from 0.1 to 3.8 ng/mL (mean, 0.97 ng/mL); in contrast, serum drawn from the control arteries demonstrated no evidence of hGH production. Serial measurement of hGH from transfected arteries demonstrated maximum hGH secretion 5 days after transfection and no detectable hormone after 20 days. Despite these levels of secreted gene product documented in vivo, immunohistochemical staining of sections taken from the rabbit ear artery at necropsy disclosed only rare cells in which there was evidence of successful transfection. CONCLUSIONS: These experiments demonstrate a useful method of performing serial in vivo analyses of gene expression after vascular transfection and that anatomic analyses of transfection efficiency may underestimate the potential magnitude of expression in the case of a secreted gene product. These findings have implications for the clinical application of somatic gene therapy because low-efficiency transfection with a gene encoding for a secreted protein may achieve therapeutic effects not realized by transfection with genes encoding for proteins that remain intracellular.

Animals↗
PubMed1994

Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women.

BACKGROUND: The relative absence of coronary atherosclerosis in premenopausal women has been established. Estrogen is presumed to play a role in the protection of coronary arteries from atherosclerosis, and part of this protective effect appears to be mediated by amelioration of serum lipid profiles. However, all of the atheroprotective effect of estrogen is not explained by alteration of serum lipids. In this study, we attempt to identify evidence of estrogen receptors in coronary artery specimens of female patients and in human vascular smooth muscle cells. METHODS AND RESULTS: Postmortem coronary artery specimens were obtained from premenopausal (n = 18) and postmenopausal (n = 22) women who died with significant coronary artery disease (n = 19) and from noncardiac causes with normal coronary arteries (n = 21). Sections were examined for evidence of estrogen receptor expression using a monoclonal antibody stain. Radioligand binding assays for estrogen receptors were performed on human vascular smooth muscle cells in culture, and gel retardation assays were performed to confirm the presence of functional estrogen receptors. Estrogen receptor expression was identified by immunostaining in a total of 21 coronary arteries, with the majority of normal arteries (15 positive of 21 total, P = .0117) demonstrating evidence of estrogen receptor expression. Conversely, a minority (6 of 19, P = NS) of atherosclerotic arteries were positive for estrogen receptor expression. Furthermore, the relation between estrogen receptor expression and absence of coronary atherosclerosis was most evident in premenopausal subjects, with 10 of 12 normal arteries in this group demonstrating evidence of estrogen receptors, whereas only 1 of 6 atherosclerotic coronary arteries was positive (P = .0062). Radioligand binding assays confirmed the presence of estrogen receptors at significant concentrations in intact human vascular smooth muscle cells. Gel retardation assays also documented the presence of functional estrogen receptors in extracts from human vascular smooth muscle cells. CONCLUSIONS: This investigation provides evidence of estrogen receptors in smooth muscle cells from human coronary arteries. The demonstrated relation between the presence of the receptors and the absence of atherosclerosis in premenopausal women suggests that these receptors may play a functional role in coronary atheroprotection.

Adult↗
PubMed1994

Focal compensatory enlargement of human arteries in response to progressive atherosclerosis. In vivo documentation using intravascular ultrasound.

BACKGROUND: Previous postmortem studies have demonstrated compensatory enlargement of atherosclerotic arteries in animal models and patients. Conclusions regarding these changes were drawn based on a comparison of the dimensions of diseased arteries in one group of subjects with the dimensions of normal arteries in another group. This method admits potential confounding variables, such as demographics and other disease states, which might also have an impact on arterial size. METHODS AND RESULTS: Using intravascular ultrasound, we studied a total of 62 paired, adjacent normal and diseased sites in the superficial femoral arteries of 20 patients undergoing peripheral vascular interventions. Morphological assessment was performed using a computer-based image analysis system. Measurements were made of the cross-sectional area of the arterial lumen, the atherosclerotic plaque, and the outer border of the artery. These dimensions were then compared to determine the effects of progressive atherosclerosis on arterial morphology. Luminal cross-sectional area decreased from 21.1 +/- 2.2 mm2 in normal segments to 16.7 +/- 0.8 mm2 (P = .0001) in adjacent atherosclerotic segments. Similarly, minimal luminal diameter decreased from 5.7 +/- 0.2 to 5.0 +/- 0.1 mm2, and maximal luminal diameter decreased from 6.2 +/- 0.2 to 5.7 +/- 0.2 mm2. At these same sites, total arterial area was 32.9 +/- 1.6 and 37.9 +/- 1.9 mm2 (P = .0001) in normal and diseased segments, respectively. Minimal and maximal arterial diameters demonstrated similar increases (7.3 +/- 0.2 to 7.7 +/- 0.2 mm2 [P = .0015] and 7.6 +/- 0.2 to 8.3 +/- 0.2 mm2 [P = .0001], respectively). Regression analysis disclosed correlation of the cross-sectional area of plaque to the total arterial area (R = .70, P = .0001). CONCLUSIONS: Human arteries enlarge in response to progressive atherosclerosis. This compensatory mechanism results in an increase in arterial size that is proportionate to the cross-sectional area of plaque that has accumulated in the vessel. Intravascular ultrasound demonstrates that this process is focal compensatory enlargement at discrete sites of atherosclerotic narrowing immediately adjacent to more normal areas in which arterial size is smaller.

Adult↗
PubMed1994

Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only.

BACKGROUND: Hypoxia and indirect angiogenic factors may stimulate angiogenesis via induction of endothelial cell mitogen(s). To evaluate this hypothesis, we investigated whether low oxygen tension or cytokines known to promote neovascularization in vivo could modulate the expression of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in human vascular smooth muscle cells (SMCs). METHODS AND RESULTS: SMCs were treated with platelet-derived growth factor BB (PDGF-BB) or transforming growth factor-beta 1 (TGF-beta 1) or exposed to low oxygen tension in serum-free medium. Northern analysis detected low basal levels of VEGF and bFGF mRNA in extracts of unstimulated SMCs. However, both VEGF and bFGF transcripts increased after administration of PDGF-BB (10 or 20 ng/mL) or TGF-beta 1 (0.1 to 10 ng/mL). Hypoxia was a potent stimulus for VEGF gene expression but had no apparent effect on bFGF steady-state mRNA levels. CONCLUSIONS: These results indicate that certain indirect angiogenic cytokines, such as PDGF-BB or TGF-beta 1, may act via induction of bFGF and VEGF gene expression in cells resident near endothelial cells in vivo. Hypoxia constitutes a potent stimulus for VEGF gene expresion but does not regulate bFGF under the same experimental conditions.

Becaplermin↗
PubMed1994

Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector.

BACKGROUND: Previous investigations in live animals convincingly established that arterial gene transfer, while feasible, was compromised by a low transfection efficiency. More recent studies have shown that transfection efficiency may be substantially augmented by the use of recombinant adenoviral vectors. Most in vivo transfections reported to date, however, have used direct (operative) administration of the adenoviral vector. Clinical applications of arterial gene transfer (such as prevention of restenosis), however, would require local percutaneous delivery of the transgene. The present study was designed to extend in vivo intraoperative findings to percutaneous delivery system and to assess whether gene transfer remains site specific. METHODS AND RESULTS: A recombinant, replication-defective adenovirus modified to include an expression cassette for nucleus-targeted beta-galactosidase was introduced into rabbit iliac arteries in vivo using either a double-balloon catheter (DBC, n = 27) or a hydrogel-coated balloon catheter (HBC, n = 27). Contralateral arteries-normal, endothelium-denuded, or sham-transfected with a control adenoviral vector-served as controls. beta-Galactosidase expression was assessed by X-Gal staining. Cell-transduction efficiency was measured by morphometric analysis. Polymerase chain reaction (PCR) and histochemistry were used to detect the presence and/or expression of viral DNA in remote organs. Transgene expression was detected in all cases (46 of 46) between 3 and 14 days after transfection but was in no case detectable 28 days after transfection. In the DBC group, transgene expression was limited to endothelial cells when the endothelium was left intact and to rare medial cells (< 2.2%) when it had been removed. In contrast, HBC delivery resulted in transduction of up to 9.6% of medial smooth muscle cells (P = .0001). Optimized PCR and histochemistry failed to detect evidence of extra-arterial transfection except in a small number of cells (between 1 in 3 x 10(2) and 1 in 3 x 10(5) cells) in the livers of 2 animals in the DBC group. CONCLUSIONS: (1) Efficient, adenovirus-mediated, arterial gene transfer to endothelial and/or smooth muscle cells is feasible by percutaneous, clinically applicable techniques. (2) Consistent transfection of medial smooth muscle cells may be achieved when the endothelial layer is abraded. (3) Medial transfection is more efficient when an HBC, rather than a DBC, is used. (4) Percutaneous delivery of the adenoviral vector via HBC results in site-specific arterial gene transfer. Very-low-level extra-arterial transfection may occur, however, when the DBC is used.

Adenoviridae↗
PubMed1994

Increased gene expression after liposome-mediated arterial gene transfer associated with intimal smooth muscle cell proliferation. In vitro and in vivo findings in a rabbit model of vascular injury.

Arterial gene transfer represents a novel strategy that is potentially applicable to a variety of cardiovascular disorders. Attempts to perform arterial gene transfer using nonviral vectors have been compromised by a low transfection efficiency. We investigated the hypothesis that cellular proliferation induced by arterial injury could augment gene expression after liposome-mediated gene transfer. Nondenuded and denuded rabbit arterial strips were maintained in culture for up to 21 d, after which transfection was performed with a mixture of the plasmid encoding firefly luciferase and cationic liposomes. In non-denuded arteries, the culture interval before transfection did not affect the gene expression. In contrast, denuded arteries cultured for 3-14 d before transfection yielded 7-13-fold higher expression (vs. day 0; P < 0.005). Transfection was then performed percutaneously to the iliac arteries of live rabbits with or without antecedent angioplasty. Gene expression increased when transfection was performed 3-7 d postangioplasty (P < 0.05). Proliferative activity of neointimal cells assessed in vitro by [3H]thymidine incorporation, and in vivo by immunostaining for proliferating cell nuclear antigen, increased and declined in parallel with gene expression. These findings thus indicate that the expression of liposome-mediated arterial gene transfer may be augmented in presence of ongoing cellular proliferation.

Animals↗