Relationship of erythrocyte membrane polyunsaturated fatty acids and prostate-specific antigen levels in Jamaican men.

OBJECTIVE: To investigate the relationship between erythrocyte membrane polyunsaturated fatty acid (PUFA) and serum prostate- specific antigen (PSA) levels in Jamaican men, as there may be an association between prostate cancer incidence and dietary fatty acids, and prostate cancer incidence in Jamaica is among the highest in the world. PATIENTS AND METHODS: Blood from 107 Jamaican men was analysed for 32 individual fatty acids and PSA levels. Special attention was given to correlations between Omega3 and Omega6 PUFAs and PSA. Data were analysed using standard linear regression methods. RESULTS: The mean PSA was 18.6 ng/mL (normal 0-4.0); for age groups of 51-60, 61-70 and 71-80 years the levels were 14, 26 and 23 ng/mL, respectively. Eicosapentaenoic acid (Omega3) levels decreased as PSA exceeded 10 ng/mL (P = 0.02). Arachidonic acid (Omega6) levels decreased as PSA was < 2 ng/mL (P = 0.02). Linoleic acid (Omega6) levels decreased in men with PSA levels of 2-10 ng/mL (P = 0.04). In men with a PSA of > 10 ng/mL there was a positive correlation between the ratio of Omega6 to Omega3 PUFAs and PSA (P = 0.036); there was also a negative correlation between the ratio of Omega3 to Omega6 PUFAs and PSA (P = 0.08). When the ratio of Omega3 PUFAs over the products of Omega6 PUFAs were used, this trend was significant (P= 0.03). CONCLUSIONS: Increased levels of Omega6 PUFAs and the ratio of Omega6/Omega3 PUFAs in Jamaican men are associated with an increased mean PSA level and risk of prostate cancer. Additional studies are needed to establish a causal link between dietary fatty acid intake and the development of prostate cancer in Jamaican men.

Characterizing prostatic adenocarcinomas in men with a serum prostate specific antigen level of < 4.0 ng/mL.

OBJECTIVE: To characterize prostate cancer in men undergoing radical prostatectomy who have a prostate-specific antigen (PSA) level of < 4.0 ng/mL, hypothesizing that a low PSA is not caused by diminished tumour production of PSA, nor does it signify clinically insignificant disease. PATIENTS AND METHODS: Seventy-nine men (mean age 59.3 years, range 43-77) with a PSA level of < 4.0 ng/mL were identified from 702 who had a radical prostatectomy between 1994 and 2000. Demographic and clinical data were analysed; pathological specimens were evaluated by routine haematoxylin and eosin staining and immunohistochemistry with anti-PSA antibody, for both pathological staging and grading, and for the presence of PSA production. Tumours were classified as 'clinically insignificant' if the tumour volume was < 0.5 mL and the Gleason score < 7. RESULTS: The mean (SD, range) preoperative PSA level was 3.04 (0.85, 0.8-3.8) ng/mL Indications for biopsy included an abnormal digital rectal examination (61%), a PSA velocity of > 0.75 ng/mL/year (12%), a strong family history of prostate cancer (3%), obstructive urinary symptoms (2%), or no obvious indication (23%). Thirty-eight (48%) tumours were clinically insignificant. Of 41 clinically significant cancers, 13 had a final Gleason score of > or = 7, 20 had extraprostatic extension and 11 had a tumour volume of > or = 10 mL Of the 79 prostate cancer specimens 78 stained strongly for PSA; the exception was a Gleason 9 tumour. With a mean (range) follow-up of 3.5 (0.18-6) years only one patient had a biochemical recurrence (PSA > or = 0.1 ng/mL). CONCLUSIONS: Most prostate cancers in men with a PSA level of < 4.0 ng/mL are clinically significant and PSA-producing. Many of these tumours are high-grade, high-volume and extraprostatic. We are currently exploring factors to explain why serum PSA is not elevated in these men, including tumour location, pattern of invasion and microvessel density.

Indications and contraindications for nerve-sparing radical prostatectomy.

Nerve-sparing radical prostatectomy can be performed safely in most men undergoing radical prostatectomy. As is true in many aspects of prostate cancer diagnosis and therapy, the key element is patient selection. With many prostate tumors diagnosed at an earlier stage, the authors have seen a shift toward more favorable pathologic findings at the time of surgery. Concomitant with the success of early detection of prostate cancer is the realization that men are younger at the time of diagnosis and more interested in preserving sexual function. This article has described factors associated with an increased risk for extraprostatic tumor and, subsequently, an increased possibility of postprostatectomy cancer recurrence. Except for the previously mentioned absolute contraindications, none of these factors, by themselves, should be used to exclude a patient from nerve-sparing prostatectomy. Instead, meticulous attention must be given to the surgical dissection. If any doubt remains regarding residual tumor, the surgeon should err on the side of caution and remove the neurovascular bundle. The use of standardized intraoperative frozen-section analysis can help guide these decisions. The patient must be informed before surgery regarding the risks of nerve-sparing surgery, the potency rates of the surgeon, and the possibility that, to ensure adequate cancer control, the nerves may be sacrificed despite any preoperative optimism favoring the potential for their salvage.

Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers.

We have shown recently (B. A. Yoshida et al., Cancer Res., 59: 5483-5487) that mitogen-activated protein kinase kinase 4 (MKK4) can suppress AT6.1 rat prostate cancer metastases in vivo. Evaluation of the expression of components of the MKK4 signaling cascade showed a loss or down-regulation of expression of MKK4 or c-Jun, a downstream mediator of MKK4, in six of eight human prostate cancer cell lines. Given these findings, we next assessed whether MKK4 dysregulation occurs during the development of clinical prostate cancer. Immunohistochemical studies showed high levels of MKK4 expression in the epithelial but not the stromal compartment of normal prostatic tissues. In neoplastic tissues, a statistically significant, direct, inverse relationship between Gleason pattern and MKK4 was established. These results demonstrate that MKK4 protein is consistently down-regulated during prostate cancer progression and support a role for dysregulation of its signaling cascade in clinical disease. To test the possibility that down-regulation of MKK4 protein is the result of allelic loss, metastatic prostate cancer lesions were examined for loss of heterozygosity (LOH) within the MKK4 locus (D17S969). These studies showed a 31% (5 of 16) LOH of MKK4 that is not associated with coding region mutations, which suggests that the nucleotide sequence of the gene in the remaining allele is infrequently mutated.

Targeting of cancer cells with monoclonal antibodies specific for C3b(i).

PURPOSE: The goal of this research is to determine the feasibility of an immunotherapeutic approach based on the use of monoclonal antibodies (mAb) to target complement activation fragments on opsonized cancer cells. METHODS: We investigated whether treatment of LNCaP and C4-2 human prostate cancer cell lines with normal human serum would allow for deposition of sufficient amounts of the complement-activation protein C3b and its fragments [collectively referred to as C3b(i)] such that these proteins could serve as cancer-cell-associated antigens for targeting by mAb. Radioimmunoassays, flow cytometry, and magnetic purging with specific immunomagnetic beads were used for the analyses. RESULTS: In vitro opsonization of human prostate cancer cells with normal human serum resulted in deposition of C3b(i) in sufficient quantity (approx. 100,000 molecules/cell) for the cells to be targeted in a variety of protocols. We found that 51Cr-labeled and C3b(i)-opsonized cancer cells could be specifically purged at high efficiency (95%-99%) using anti-C3b(i) mAb covalently coupled to magnetic beads. Flow-cytometry experiments indicated that most normal white cells were not removed under similar conditions. Opsonization of cancer cells with sera from men with prostate cancer led to lower levels of cell-associated IgM and, subsequently, lower amounts of C3b(i) deposited than in normal subjects. Prototype experiments suggested that this deficiency could be corrected by addition of IgM from normal donor plasma. CONCLUSION: mAb directed against complement-activation products may provide new opportunities to deliver diagnostic and therapeutic agents selectively to cancer cells and tumor deposits. These opportunities may include ex vivo purging of C3b(i)-opsonized cancer cells prior to autologous bone marrow or stem cell transplantation.

Surgical and postoperative factors affecting length of hospital stay after radical prostatectomy.

BACKGROUND: Radical prostatectomy continues to comprise the mainstay of therapy for localized prostate carcinoma. However, caring for radical prostatectomy patients accounts for approximately half of the $1.7 billion annual cost of prostate carcinoma treatment. Length of stay (LOS) after surgery appears to be one of the main components of this cost. The first step in reducing cost is to identify those variables associated with LOS. Radical prostatectomy can be performed using two very different surgical techniques and with each technique different costs are incurred. The objective of the current study was to identify factors associated with LOS as a function of surgical approach. To reduce potential biases due to patient requests for longer hospitalization or physician preferences in that regard, secondary objectives were to identify factors associated with time to fluid intake (TTF) and time to consume solid foods (TTS). METHODS: An institutional-based, retrospective chart review of 313 men with clinically localized prostate carcinoma who underwent either a perineal (RPP) or retropubic (RRP) prostatectomy at a single university center from March 1988 to October 1996 was undertaken. Information regarding LOS was available for 311 patients. Linear regression models were used to assess the association between covariables and LOS. Poisson regression models for count data were used to assess associations between covariables and the secondary endpoints of TTF and TTS. Covariables included: preoperative (age, race, prostate specific antigen, Gleason score, clinical stage, lymph node resection, comorbidity, and admission time), intraoperative (surgical approach, surgeon, operative time, estimated blood loss, transfusion requirement, anesthetic approach, and American Society of Anesthesiologists score), and postoperative (pain management complications and transfusions) parameters. RESULTS: The median LOS was 4 days (range, 1-19 days) for RPP and 5 days (range, 3-16 days) for RRP approaches. The final model included six main effects and three interaction terms. Overall, LOS decreased over time with LOS decreasing at a faster rate in patients who underwent RPP. In general, patients who underwent RRP had an increased LOS compared with patients who underwent RPP. Complications from surgery and age increased the LOS for all patients; however, the increase was greater in patients who underwent RPP. In addition, the use of intraoperative epidural anesthesia and the increased use of postoperative narcotics were associated with increased LOS for patients undergoing both surgical approaches. TTF and TTS were significantly longer for patients who underwent the retropubic approach compared with those patients who underwent the perineal approach. After adjustment for surgical approach no other covariables were found to be associated with TTF. After adjustment for surgical approach, the occurrence of complications was found to be associated with TTS, indicating that patients who experienced complications took longer before they could tolerate solid foods. CONCLUSIONS: In view of the importance of clinical care pathways in reducing medical expenditures from radical prostatectomy, the results of the current study may contribute to the further refining of these pathways by highlighting the differences and similarities among the variables affecting LOS as a function of surgical approach.

Targeting angiogenic pathways involving tumor-stromal interaction to treat advanced human prostate cancer.

Interfering with and preventing tumor angiogenesis is an attractive therapeutic approach for treating cancer metastases. This commentary presents treatment strategies that may enhance the effectiveness of anti-angiogenic therapy by selectively targeting newly sprouting and immature vessels, inhibiting the production of angiogenic factors, and disrupting extracellular matrices. We propose several clinical paradigms, including hormonal ablation, intermittent androgen suppression, chemotherapy, and radiation therapy, that 'injure' nascent vasculature and interrupt the cancer cell-stromal relationship, thereby potentiating the efficacy of experimental anti-angiogenic agents. These stromal-epithelial interactions play an important role in the development, proliferation and dissemination of prostate cancer, as well as guiding the processes of tumor neovascularization. Successful utilization and targeting of tumor angiogenesis requires an increased understanding of tumor cell-stromal cell-endothelial cell relationships, most notably the intricate intracellular signalling cascades mediated by growth factors and the extracellular matrix.

Quantitative polymerase chain reaction does not improve preoperative prostate cancer staging: a clinicopathological molecular analysis of 121 patients.

PURPOSE: To improve on current staging and monitoring methods for prostate cancer, we applied the technique of quantitative polymerase chain reaction to measure the degree of tumor burden in the circulation and correlate this with pathological tumor stage. A reproducible, highly sensitive and specific, reverse transcriptase-polymerase chain reaction amplification technique to quantify prostate specific antigen (PSA) and prostate specific membrane antigen gene expression in the peripheral circulation was developed. Using a 32phosphorus-gamma-adenosine triphosphate-5'PSA and prostate specific membrane antigen primer incorporation assay, the ribonucleic acid signal extracted from a single neoplastic cell (LNCaP) premixed in 10 cc normal whole blood could be amplified. PSA and prostate specific membrane antigen polymerase chain reaction indexes have been created for clinical application. MATERIALS AND METHODS: From September 1994 through July 1995 specimens from 121 patients were prospectively analyzed for PSA and prostate specific membrane antigen signals. RESULTS: Circulating PSA producing cells were present in 29 of 33 patients (88%) with metastatic prostate cancer. Two of 19 patients (11%) with no known prostate cancer exhibited positive signals (1 later had prostate cancer), establishing a sensitivity of 88% and specificity of 94% for our assay. Positive PSA polymerase chain reaction signals were detected in 30 of 51 patients (59%) with stages pT1 and pT2 disease and in 13 of 18 (72%) with stage pT3 cancer. No statistically significant relationship of a positive PSA polymerase chain reaction signal to pathological stage, tumor grade, apical involvement or positive surgical margins was found, and no benefit was derived by measuring the quantity of circulating PSA polymerase chain reaction signals. Circulating prostate specific membrane antigen polymerase chain reaction signals were identified mostly in patients with advanced prostate cancer and offered no benefit to preoperative staging. CONCLUSIONS: Given the high incidence of false positive signals in patients with pathologically determined localized disease, in our experience polymerase chain reaction based assays offer no immediate benefit for preoperative prostate cancer staging. The prognostic significance of detecting circulating prostate specific signals awaits longer followup in this cohort of patients, which is currently under study.

Current management of renal cell carcinoma.

Renal cell carcinoma is the most common malignancy of the kidney and accounts for about three percent of all adult neoplasms. This article reviews the clinical presentation, diagnosis, staging, and treatment of this disease.

In vitro modulation of tumor progression-associated properties of hormone refractory prostate carcinoma cell lines by cytokines.

BACKGROUND: Cytokines exert cytostatic and immunomodulatory effects on carcinoma cells. Growth inhibition of human prostate carcinoma by cytokines has been demonstrated both in vitro and in vivo, whereas the cellular and molecular changes in prostate carcinoma properties after cytokine treatment have never been characterized. We have thus investigated whether the intrinsic properties of prostate carcinoma cells that are associated with tumor development and progression can be altered by direct cytokine treatment. METHODS: LNCaP, DU-145, and PC-3 cell lines were treated with tumor necrosis factor-alpha (TNF-alpha) (200 U/mL), interferon-gamma (IFN-gamma) (500 U/mL), human leukocyte interferon (IFN-alpha) (500 U/mL), and interleukin-2 (IL-2) (400 U/mL). The expression of (prostate-specific antigen [PSA] and prostate-specific membrane [PSM]), androgen receptor (AR), growth factors, oncogenes, collagenase, cell adhesion molecules, HLA antigens, cell adhesion to human bone marrow stroma, and cell growth were determined by quantitative polymerase chain reaction (PCR) analysis, fluorescence-activated cell sorter (FACS) analysis, and cell attachment and proliferation assays, and were compared with non-treated cells. RESULTS: PCR analysis indicated that only LNCaP cells expressed PSA, PSM, and AR mRNA. Cytokine treatment did not alter PSM mRNA expression, whereas a 15-fold decrease in PSA and a 5-fold reduction in AR mRNA expression was detected in TNF-alpha-treated cells. The down regulation of PSA production was also demonstrated at the protein level in a dose-dependent fashion. A fivefold decrease in PSA mRNA was also detected in IL-2-treated LNCaP cells but without a reduction in AR. Down regulated epidermal growth factor receptor (EGF-R) and basic fibroblast growth factor (b-FGF) mRNA expressions were detected in TNF-alpha- and IFN-alpha-treated DU-145 and PC-3 cells, whereas, only reduced EGF-R expression was observed in LNCaP cells. IFN-gamma and IL-2 treatment down regulated the expression of collagenase Type IV mRNA in DU-145 and PC-3 cells, whereas tumor transforming growth factor-beta (TGF-beta) and IL-6 mRNA expressions did not exhibit any essential changes after cytokine treatment. A reduction in c-myc mRNA expression was observed in TNF-alpha- and IFN-alpha-treated cells, whereas no change in HER-2 expression was noted in any cytokine treated cells. Up regulated P-cadherin, but not E-cadherin, mRNA expression was detected in TNF-alpha- and IFN-gamma-treated PC-3 cells. FACS analysis revealed that all but IL-2-treated cells had enhanced HLA Class I expression, with the maximum effect seen in TNF-alpha-treated LNCaP cells (threefold increase). Up regulated HLA Class II expression was seen only in IFN-gamma-treated cells. All cytokine-treated DU-145 and PC-3 cells expressed reduced levels of alpha3, but not beta1, integrin. Up regulated of ICAM-1 expression was seen in all cytokine treated DU-145 and PC-3 cells, whereas no change in CD44 occurred. Cytokine treatment reduced the binding affinity of LNCaP and DU-145, but not of PC-3 cells, to human bone marrow stromal cells, and all cytokines but IL-2 showed a mild to moderate growth inhibition to prostate cancer cells, with a marked inhibition only observed in TNF-alpha-treated LNCaP cells. CONCLUSIONS: Cytokine treatment can effectively alter several prostate carcinoma properties that are closely associated with tumor invasion and a metastatic phenotype, suggesting that immunotherapy via the local delivery of cytokines may have a potentially therapeutic role in the treatment of hormone-refractory prostate cancer through both direct and indirect antitumor mechanisms.

Dose response of fish oil versus safflower oil on graft arteriosclerosis in rabbit heterotopic cardiac allografts.

With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7.9 +/- 1.9 microns versus 34.0 +/- 13.0 microns, analysis of variance: p = 0.054). Low-dose safflower oil also had a slight, but nonsignificant, beneficial effect on graft vessel disease when compared to control rabbits. The same trends were observed in the degree of histologic rejection (0 = none to 3 = severe) in fish oil- and safflower oil-treated animals. Rejection score correlated weakly but significantly (p = 0.0001) with mean luminal occlusion (r = 0.52) and intimal thickness (r = 0.46). Therefore allograft coronary disease in this model appeared to exhibit an unfavorable, direct-dose response to fish oil and safflower oil, independent of effects on plasma lipids.(ABSTRACT TRUNCATED AT 400 WORDS)

The reversibility of canine vein-graft arterialization.

We assessed the reversibility of functional and morphological changes of arterialized vein segments by returning them to the venous circulation. Thirteen dogs underwent right carotid and femoral veno-arterial grafting. After 12 weeks, veno-arterial grafts were removed for contractility (norepinephrine [NE] and 5-hydroxytryptamine [5-HT]), luminal prostacyclin (PGI2), and morphometric analyses; the remaining segments were used as left jugular and femoral veno-venous grafts. After another 12 weeks, the veno-venous grafts were harvested. To NE, veno-arterial grafts (ED50, 5.4 +/- 0.1 [-log M]) were less sensitive than control veins (ED50, 6.0 +/- 0.2) or veno-venous grafts (ED50, 6.4 +/- 0.2) but were more sensitive than control arteries (ED50, 4.0 +/- 0.1); the maximum tension of veno-arterial grafts (6.2 +/- 0.6 g) was greater than that of veins, less than that of arteries (9.8 +/- 1.0 g), and comparable with that of veno-venous grafts (5.1 +/- 1.1 g). To 5-HT, veno-arterial (ED50, 7.5 +/- 0.1) and veno-venous (ED50, 7.3 +/- 0.2) grafts were more sensitive than arteries (ED50, 6.0 +/- 0.3), while the vein was unresponsive; the maximum tension of veno-arterial grafts (5.0 +/- 0.7 g) was less than that of arteries (6.9 +/- 0.9 g) and greater than that of veno-venous grafts (1.4 +/- 0.3 g). PGI2 production in veins (3.6 +/- 0.8 ng/ml), veno-arterial grafts (3.9 +/- 0.8 ng/ml), and veno-venous grafts (3.3 +/- 0.9 ng/ml) was comparable and less than that of arteries (6.4 +/- 0.9 ng/ml). Veno-arterial graft intimal thickness (127 +/- 8 microns) and intimal area (15.6 +/- 1.8 x 10(3) microns 2) tended to be greater than that in the veno-venous graft (113 +/- 9 microns and 12.4 +/- 1.8 x 10(3) microns 2); also, the veno-arterial graft medial area (103.0 +/- 7.3 x 10(3) microns 2) was greater than that of the veno-venous graft (80.3 +/- 6.9 x 10(3) microns 2), thereby resulting in a similar relative intimal area (13 +/- 1%). Therefore, some changes associated with arterialization, for example, adrenergic sensitivity, maximum tension to 5-HT, medial thickening, and perhaps intimal hyperplasia, reverted toward venous values when replaced in the venous environment, possibly due to variations in pressure, flow, shear stress, and/or graft preparation techniques. Luminal PGI2 was unchanged in the grafts, implying that graft contractility was not modulated by luminal PGI2.

Mechanisms responsible for inhibition of vein-graft arteriosclerosis by fish oil.

Favorable changes in lipoproteins, inhibition of platelet aggregation, reduction of serum thromboxane (TX), altered plasma-membrane fluidity, and reduced production of growth factors (mitogens) have all been implicated as possibly being involved in the inhibition of arteriosclerosis by fish oil (FO), which is rich in omega 3 fatty acids; however, causal relations are mostly lacking. Several putative mechanisms responsible for the salutary effects of FO were investigated in a canine model of accelerated vein-graft arteriosclerosis. Venoarterial autografts (N = 192) were implanted in 48 hypercholesterolemic dogs divided into six groups: group A, control; B, FO (as MaxEPA, 200 mg/kg/day eicosapentaenoic acid); C, aspirin (ASA, 50 mg/kg/day); D, TX synthetase inhibitor (TXSI [CGS-12970], 10 mg/kg/day); E, FO + ASA; and F, FO + TXSI. At sacrifice 3 months later, there was no significant difference in plasma lipoproteins, hepatic low density lipoprotein-receptor concentration, red blood cell fragility, bleeding time, or platelet count compared with controls; the decrease in platelet aggregation (30 +/- 5% [mean +/- SEM]) was similar in all treatment groups. Arterialized vein-graft intimal thickening was significantly inhibited by FO (with or without ASA), while ASA alone was ineffective. Conversely, serum TX was significantly lower only in the ASA and FO + ASA groups. Serum mitogenic activity was higher at 3 months in the control group versus all treatment groups. Compared with baseline values, serum mitogenic activity rose significantly over time in the control and the TXSI groups, and an increase or rising trend was present in all other treatment groups except for the FO-treated animals. Thus, the salutary biologic effect of FO in this hypercholesterolemic model of arterialized vein grafts may have been more related to in vivo inhibition of platelet-mitogen growth factor release than to changes in lipoproteins, low density lipoprotein receptors, platelet function, or eicosanoid metabolism. These observations underscore the need for further studies to clarify the interactions between FO (omega 3 fatty acids) and paracrine cellular mitogenic factors in the context of atherosclerosis prevention.