Scenarios for modeling solar radiation modification.

Making informed future decisions about solar radiation modification (SRM; also known as solar geoengineering)-approaches such as stratospheric aerosol injection (SAI) that would cool the climate by reflecting sunlight-requires projections of the climate response and associated human and ecosystem impacts. These projections, in turn, will rely on simulations with global climate models. As with climate-change projections, these simulations need to adequately span a range of possible futures, describing different choices, such as start date and temperature target, as well as risks, such as termination or interruptions. SRM modeling simulations to date typically consider only a single scenario, often with some unrealistic or arbitrarily chosen elements (such as starting deployment in 2020), and have often been chosen based on scientific rather than policy-relevant considerations (e.g., choosing quite substantial cooling specifically to achieve a bigger response). This limits the ability to compare risks both between SRM and non-SRM scenarios and between different SRM scenarios. To address this gap, we begin by outlining some general considerations on scenario design for SRM. We then describe a specific set of scenarios to capture a range of possible policy choices and uncertainties and present corresponding SAI simulations intended for broad community use.

The efficacy of adjuvant radiotherapy in dermatofibrosarcoma protuberans: a systemic review and meta-analysis.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare and locally aggressive tumour, with a high recurrence rate, even after complete surgical excision. Adjuvant radiotherapy (RT) has been suggested to reduce the risk of local recurrence after inadequate surgical resection in patients with narrow or positive surgical margins. However, the overall efficacy of adjuvant RT has not been well studied because of the rarity of DFSP and lack of an appropriate comparison group. OBJECTIVE: We sought to evaluate the efficacy of adjuvant RT for DFSP by conducting a systemic review and meta-analysis to provide a more evidence-based measure of its effectiveness. METHODS: We conducted a systemic review of articles published before 31 June 2015. Due to the rarity of the disease, we included all studies that reported DFSP patients who received adjuvant RT (postoperatively). The pooled recurrence rates were analysed from these extracted data. RESULTS: Twelve studies met the inclusion criteria. The pooled estimate of the recurrence rate for all adjuvant radiotherapy was 11.74% (95% CI 7.4-17.38; n = 167). Patients with positive/close had a pooled recurrence rate of 14.23% (95% CI 8.13-22.49; n = 92), whereas there was no recurrence in patients with negative margins. The pooled estimate of the recurrence rate between surgery alone and surgery combined with adjuvant radiotherapy showed no significant difference (odds ratio 0.31, P = 0.07), although there was a trend that adjuvant RT had a lower recurrence rate than surgery alone. CONCLUSION: Adjuvant RT might be considered for all patients undergoing surgical excision, even if a negative surgical margin has been achieved. Furthermore, for patients with large or recurrent tumours, especially when wide excision with negative margin would result in a significant functional or cosmetic deficit, postoperative radiotherapy is highly recommended in order to achieve a lower recurrence rate.

Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis.

Epithelial ovarian cancer (EOC) invasion and metastasis are complex phenomena that result from the coordinated action of many metastatic regulators and must be overcome to improve clinical outcomes for patients with these cancers. The identification of novel therapeutic targets is critical because of the limited success of current treatment regimens, particularly in advanced-stage ovarian cancers. In this study, we found that tetraspanin 8 (TSPAN8) is overexpressed in about 52% (14/27) of EOC tissues and correlates with poor survival. Using small interfering RNA-mediated TSPAN8 knockdown and a competition assay with purified TSPAN8 large extracellular loop (TSPAN8-LEL) protein, we identified TSPAN8-LEL as a key regulator of EOC cell invasion. Furthermore, monotherapy with TSPAN8-blocking antibody we developed shows that antibody-based modulation of TSPAN8-LEL can significantly reduce the incidence of EOC metastasis without severe toxicity in vivo. Finally, we demonstrated that the TSPAN8-blocking antibody promotes the internalization and concomitant downregulation of cell surface TSPAN8. Collectively, our data suggest TSPAN8 as a potential novel therapeutic target in EOCs and antibody targeting of TSPAN8 as an effective strategy for inhibiting invasion and metastasis of TSPAN8-expressing EOCs.

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

BACKGROUND: In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT). METHODS: This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time. RESULTS: Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. CONCLUSIONS: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

Effect of etanercept therapy on psoriasis symptoms in patients from Latin America, Central Europe, and Asia: a subset analysis of the PRISTINE trial.

BACKGROUND: Psoriasis prevalence and characteristics in Asia, Central Europe, and Latin America have not been thoroughly investigated and there are no large trials for biologic treatments for patients from these regions. The goal of this analysis was to report clinical response to anti-tumor necrosis factor-alpha treatment in these patients. METHODS: Patients from Argentina, Czech Republic, Hungary, Mexico, Taiwan, and Thailand (N=171) were included in this subset analysis of the PRISTINE trial. Patients with stable moderate-to-severe plaque psoriasis were blinded and randomized to receive etanercept 50 mg once weekly (QW) or biweekly (BIW) for 12 weeks, followed by 12 weeks of open-label QW treatment with etanercept 50 mg through week 24 (QW/QW vs. BIW/QW). Concomitant methotrexate (≤20 mg/week) and mild topical corticosteroids or other agents were permitted at the physician's discretion, in accordance with therapeutic practice. RESULTS: As early as week 8, 26.7 % in the etanercept QW group and 44.0 % in the BIW group achieved Psoriasis Area and Severity Index (PASI) 75. At weeks 12 and 24, respectively, PASI 75 increased to 39.5 % and 62.8 % in the QW/QW group and 66.7 % and 83.3 % in the BIW/QW group. PASI 75 was significantly different between treatment groups from week 8 through the end of study (p<0.05). The Kaplan-Meier estimate of the proportions achieving PASI 75 in QW/QW and BIW/QW groups, respectively, was 27.4 % and 45.8 % through week 8; 41.9 % and 68.7 % through week 12; and 72.5 % and 95.2 % through week 24. CONCLUSIONS: Treatment with etanercept 50 mg provided rapid relief of psoriasis symptoms in patients from Asia, Central Europe, and Latin America. A more rapid response was observed in patients who received BIW treatment for the first 12 weeks which was sustained after reducing to QW dosing for the subsequent 12 weeks. Response rates were similar to those observed in the overall PRISTINE population. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00663052 .

Phase 1 trial of neoadjuvant radiation therapy before prostatectomy for high-risk prostate cancer.

PURPOSE: To evaluate, in a phase 1 study, the safety of neoadjuvant whole-pelvis radiation therapy (RT) administered immediately before radical prostatectomy in men with high-risk prostate cancer. METHODS AND MATERIALS: Twelve men enrolled and completed a phase 1 single-institution trial between 2006 and 2010. Eligibility required a previously untreated diagnosis of localized but high-risk prostate cancer. Median follow-up was 46 months (range, 14-74 months). Radiation therapy was dose-escalated in a 3 × 3 design with dose levels of 39.6, 45, 50.4, and 54 Gy. The pelvic lymph nodes were treated up to 45 Gy with any additional dose given to the prostate and seminal vesicles. Radical prostatectomy was performed 4-8 weeks after RT completion. Primary outcome measure was intraoperative and postoperative day-30 morbidity. Secondary measures included late morbidity and oncologic outcomes. RESULTS: No intraoperative morbidity was seen. Chronic urinary grade 2+ toxicity occurred in 42%; 2 patients (17%) developed a symptomatic urethral stricture requiring dilation. Two-year actuarial biochemical recurrence-free survival was 67% (95% confidence interval 34%-86%). Patients with pT3 or positive surgical margin treated with neoadjuvant RT had a trend for improved biochemical recurrence-free survival compared with a historical cohort with similar adverse factors. CONCLUSIONS: Neoadjuvant RT is feasible with moderate urinary morbidity. However, oncologic outcomes do not seem to be substantially different from those with selective postoperative RT. If this multimodal approach is further evaluated in a phase 2 setting, 54 Gy should be used in combination with neoadjuvant androgen deprivation therapy to improve biochemical outcomes.

Kimura's disease mimicking an earlobe keloid.

Kimura's disease (KD) is a rare chronic inflammatory disorder of unknown aetiology. It usually presents as soft-tissue masses predominantly in the head or neck region. We report a case of an asymptomatic tumour on the left earlobe mimicking a keloid. The tumour was histopathologically diagnosed as KD. This case suggests the importance of conducting skin biopsies of keloidal lesions on head and neck regions, particularly in patients who have peripheral eosinophilia and increased IgE levels.

Plasma-cell cheilitis: successful treatment with intralesional injections of corticosteroids.

Plasma-cell cheilitis is a rare inflammatory disorder of the lip characterized histologically by a band-like infiltrate of plasma cells in the upper dermis. It is considered an oral counterpart of plasma-cell balanitis. Clinically, it presents as a circumscribed, flat to slightly raised, eroded area of the lip. The cause of plasma-cell cheilitis is unknown, and the treatment is often disappointing. We describe a 55-year-old woman who had a long-lasting painful, swollen, and eroded area on her lips, which responded poorly to various topical treatments. Biopsy showed a band-like infiltrate composed mainly of mature plasma cells in the dermis. A diagnosis of plasma-cell cheilitis was made after excluding contact dermatitis, lichen planus, bacterial, fungal and spirochaete infections, and an extramedullary plasmacytoma. Dramatic improvements were observed after intralesional injections of corticosteroids. The lesion cleared up after two treatments, and there has been no recurrence in 1 year of follow-up.

No association of cytokine gene polymorphisms in Chinese patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common chronically relapsing skin disease associated with the activation of T-helper 2 cells. Recent studies have shown that polymorphisms in the genes for interleukin (IL)-4, the IL-4 receptor, IL-13, and signal transducer and activator 6 (STAT6) may contribute to susceptibility of AD. To date, no cytokine gene polymorphism study has been conducted on Chinese patients with AD. AIMS: To determine whether genetic polymorphisms of the cytokine genes might influence the development of AD. METHODS: DNA samples were obtained from 94 patients and 186 control subjects. Using direct sequencing and microsatellite genotyping, we examined 22 polymorphisms in eight cytokine genes including the genes for IL-4, -10, -12B and -13, the IL-4 receptor, tumour necrosis factor (TNF)-alpha, STAT6, and interferon (IFN)-gamma. RESULTS: No significantly different allelic and genotypic distributions of the cytokine gene polymorphisms could be found between patients and controls. Moreover, no association was observed with disease onset, gender, the presence of elevated serum total IgE level or blood eosinophilia. CONCLUSION: Our study suggests that the analysed genetic polymorphisms of cytokine genes do not appear to be associated with AD susceptibility in our Chinese population.

Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients.

BACKGROUND: An uncommon histiocytosis primarily involving the lymph nodes, Rosai-Dorfman disease (RDD, originally called sinus histiocytosis with massive lymphadenopathy) involves extranodal sites in 43% of cases; cutaneous RDD (C-RDD) is a rare form of RDD limited to the skin. The clinicopathological diagnosis of C-RDD may sometimes be difficult, with different clinical profiles from those of its nodal counterpart, and occasionally misleading histological pictures. There have been few multipatient studies of C-RDD and documentation of its histological spectrum is rare. OBJECTIVES: To identify the clinical and histopathological profiles, associated features, and the chronological changes of this rare histiocytosis. METHODS: From 1991 to 2002, patients diagnosed as having C-RDD were collected in four academic hospitals. Clinical presentations, treatments, and courses of each case were documented. In total, 21 biopsy specimens obtained from these patients were re-evaluated and scored microscopically with attention to the uncommon patterns and chronological evolution both clinically and histologically. RESULTS: We examined six patients with C-RDD, three men and three women. The mean age at the first visit was 43.7 years. The clinical presentations were mostly papules, nodules and plaques, varying with the duration and depth of lesions. Although the anatomical distribution was wide, the face was most commonly involved. Evolutional changes were identified clinically, as the lesions typically began with papules or plaques and grew to form nodules with satellite lesions and resolved with fibrotic plaques before complete remission. No patient had lymphadenopathy or extracutaneous lesions during follow-up (mean 50.5 months). At the end of follow-up, the lesions in four patients had completely resolved irrespective of treatment; two patients had persistent lesions. The histopathological pattern of the main infiltrate, the components of cells and the stromal responses showed dynamic changes according to the duration of lesions. The characteristic Rosai-Dorfman cells (RD cells) were found in association with a nodular or diffuse infiltrate in 15 lesions (71%). Four lesions (19%) demonstrated a patchy/interstitial pattern. One lesion (5%) assumed the pattern of a suppurative granuloma. RD cells were less readily found in these atypical patterns. Conspicuous proliferation of histiocytes associated with RD cells was found in three lesions, including xanthoma, localized Langerhans cell histiocytosis and xanthogranuloma. Along with lymphocytes, plasma cells were present in all lesions, often in large numbers with occasional binucleated or trinucleated cells. Variably found in the lesions were neutrophils (nine lesions, 43%) and eosinophils (13 lesions, 62%). The former occasionally formed microabscesses, while the latter were often few in number. Vascular proliferation was a relatively constant feature (90%). Fibrosis was found in 10 lesions (48%). CONCLUSIONS: Our study further confirms that C-RDD is a distinct entity with different age and possibly race distributions from RDD. Compared with its nodal counterpart, C-RDD demonstrates a wider histopathological spectrum with different clinicopathological phases depending on duration of the lesions. Awareness of these features is helpful in making a correct diagnosis. The associations of C-RDD with other histiocytoses may have important implications for the pathogenesis of this rare histiocytosis.

Plasmacellular differentiation in extranodal marginal zone B cell lymphomas of the ocular adnexa: an analysis of the neoplastic plasma cell phenotype and its prognostic significance in 136 cases.

AIM: To determine (a) the expression of plasma cell related antigens in extranodal marginal zone B cell lymphomas (EMZL) of the ocular adnexa; and (b) the prognostic value of plasmacellular differentiation in these tumours. METHODS: A consecutive case series of 136 ocular adnexal EMZL obtained from three ocular pathology centres over 20 years was analysed retrospectively. An extensive immunohistochemical panel, including the plasma cell related antigens VS38c, CD38, CD138, multiple myeloma oncogene-1-protein (MUM1/IRF4), and CREB binding protein (CBP) was performed. EMZL were defined as "plasmacellular differentiated" on the basis of morphological features, evidence of cytoplasmic immunoglobulin, negativity for BSAP/PAX5, and expression of at least one of the investigated plasma cell related antigens. Controls included normal or hyperplastic lymphatic tissues. Detailed clinical data were collected for most patients, and compared with the results of immunohistochemistry. The end points considered for statistical analysis were development of local tumour recurrence, development of systemic disease, and lymphoma related death. RESULTS: 57 (42%) of the 136 ocular adnexal EMZL showed a plasmacellular differentiation; 45 of these plasmacytoid cases were primary tumours. In contrast with most admixed normal plasma cells, which displayed co-expression of MUM1/IRF4, Vs38c, CD38, CD138, and CBP, the plasmacellular differentiated EMZL tumour cells demonstrated co-expression of all five plasma cell related antigens in only six of 57 (11%) plasmacellular differentiated ocular adnexal EMZL. The most commonly expressed plasma cell related antigen was MUM1/IRF4, immunoreactivity being seen in 56/57 (98%) plasmacellular differentiated EMZL examined. Although the association of plasmacellular differentiation in primary ocular adnexal EMZL and disseminated disease was statistically significant on univariate analysis (p = 0.042), this was weaker on multivariate analysis. CONCLUSION: Plasmacellular differentiated tumour cells in EMZL demonstrate an aberrant immune profile for plasma cell related antigens when compared with normal plasma cells. On multivariate analysis, plasmacellular differentiation in ocular adnexal EMZL was not significantly associated with local recurrence, the development of systemic disease, or with lymphoma related death.

Enhancement of topical 5-aminolaevulinic acid delivery by erbium:YAG laser and microdermabrasion: a comparison with iontophoresis and electroporation.

BACKGROUND: 5-aminolaevulinic acid (ALA) is used as a protoporphyrin IX-precursor for the photodynamic therapy of superficial skin cancer and cutaneous metastases of internal malignancies. However, the permeability of hydrophilic ALA across the skin is very low. OBJECTIVES AND METHODS: The objective of this study was to optimize and enhance the in vitro skin permeation of ALA by two resurfacing techniques: erbium:yttrium-aluminium-garnet (Erb:YAG) laser and microdermabrasion. Light microscopic changes in pig skin caused by these techniques were also compared. The electrically assisted methods, iontophoresis and electroporation, were also used to facilitate ALA permeation across laser- or microdermabrasion-treated skin. RESULTS: Among the modalities tested in this study the Erb:YAG laser showed the greatest enhancement of ALA permeation. The laser fluence was found to play an important role in controlling the drug flux, producing enhancement ratios from 4-fold to 246-fold relative to the control. The skin permeation of ALA across microdermabrasion-treated skin was approximately 5-15-fold higher than that across intact skin. Both the ablated effect of the stratum corneum (SC) and ALA flux were proportional to the treatment duration of microdermabrasion. The application of iontophoresis or electroporation alone also increased the ALA permeation by approximately 15-fold and 2-fold, respectively. The incorporation of iontophoresis or electroporation with the resurfacing techniques caused a profound synergistic effect on ALA permeation. CONCLUSIONS: This basic study has encouraged the further investigation of ALA permeation by laser or microdermabrasion.

Improved survival rates in sebaceous carcinoma of the eyelid.

PURPOSE: To review the clinicopathological features, management, and survival rates for patients with sebaceous gland carcinoma of the eyelid, and to analyse the reasons for improved survival. METHODS: In the west of Scotland between 1975 and 2001, 32 cases were identified through the pathology index for sebaceous carcinoma. Pathology specimens were reviewed in all cases. The clinical data were obtained from hospital records and the database provided by the Regional Cancer Registry. RESULTS: A total of 22 female and 10 male patients were identified. Follow-up ranged from 6 months to 15 years, median of 4.8 years. Primary treatment involved excisional techniques in 27 cases, exenteration in two cases, enucleation in two cases, and two cases required adjuvant radiotherapy. Intraepithelial spread and masquerade presentations delayed the diagnosis. Poorly differentiated tumours were associated with an unfavourable outcome. Three patients developed local tumour recurrence and one metastatic disease. In all, 10 patients died from nontumour-related causes and one died from metastatic sebaceous carcinoma. The overall tumour mortality rate in the west of Scotland was 3%. CONCLUSIONS: From this study, patients in the west of Scotland have a better prognosis than is indicated in the literature. Astute clinical suspicion and accurate histopathological diagnosis, together with radical and aggressive surgical approaches were key factors.

Coexistence of localized Langerhans cell histiocytosis and cutaneous Rosai-Dorfman disease.

Rosai-Dorfman disease (RDD; sinus histiocytosis with massive lymphadenopathy) and Langerhans cell histiocytosis (LCH) are two different yet pathogenetically related histiocytic disorders. While systemic and localized forms have been identified in both diseases, each has its own characteristic histological, immunohistochemical and ultrastructural profile. Rarely, either RDD or LCH can also occur in the context of certain malignant neoplasms. However, the coexistence of RDD and LCH has never been described. We report a case of cutaneous RDD in which a focus of LCH was found. Clinical and laboratory examinations revealed no evidence of extracutaneous involvement of RDD or LCH. We believe that this is the first report of such a coexistence, and the possible pathogenesis is discussed.

A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy.

PURPOSE: To prospectively assess the health-related quality of life (HRQOL) and changes in HRQOL during the first year after 3 different treatments for clinically localized prostate cancer. METHODS AND MATERIALS: Ninety men with T1-T2 adenocarcinoma of the prostate were treated with curative intent between May 1998 and June 1999 and completed a quality-of-life Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire before treatment (T0) and 1 month (T1), 3 months (T3), and 12 months (T12) after treatment. Forty-four men were treated with permanent source interstitial brachytherapy (IB), 23 received external beam radiotherapy (EBRT), and 23 men were treated with radical prostatectomy (RP). The mean age of the entire study population was 65.9 years (median 67, range 42-79). The mean pretreatment prostate-specific antigen level of the entire study population was 6.81 ng/mL (median 6.25, range 1.33-19.6). The Gleason score was

Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expressions by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages.

Several natural flavonoids have been demonstrated to perform some beneficial biological activities, however, higher-effective concentrations and poor-absorptive efficacy in body of flavonoids blocked their practical applications. In the present study, we provided evidences to demonstrate that flavonoids rutin, quercetin, and its acetylated product quercetin pentaacetate were able to be used with nitric oxide synthase (NOS) inhibitors (N-nitro-L-arginine (NLA) or N-nitro-L-arginine methyl ester (L-NAME)) in treatment of lipopolysaccharide (LPS) induced nitric oxide (NO) and prostaglandin E2 (PGE2) productions, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) gene expressions in a mouse macrophage cell line (RAW 264.7). The results showed that rutin, quercetin, and quercetin pentaacetate-inhibited LPS-induced NO production in a concentration-dependent manner without obvious cytotoxic effect on cells by MTT assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide as an indicator. Decrease of NO production by flavonoids was consistent with the inhibition on LPS-induced iNOS gene expression by western blotting. However, these compounds were unable to block iNOS enzyme activity by direct and indirect measurement on iNOS enzyme activity. Quercetin pentaacetate showed the obvious inhibition on LPS-induced PGE2 production and COX-2 gene expression and the inhibition was not result of suppression on COX-2 enzyme activity. Previous study demonstrated that decrease of NO production by L-arginine analogs effectively stimulated LPS-induced iNOS gene expression, and proposed that stimulatory effects on iNOS protein by NOS inhibitors might be harmful in treating sepsis. In this study, NLA or L-NAME treatment stimulated significantly on LPS-induced iNOS (but not COX-2) protein in RAW 264.7 cells which was inhibited by these three compounds. Quercetin pentaacetate, but not quercetin and rutin, showed the strong inhibitory activity on PGE2 production and COX-2 protein expression in NLA/LPS or L-NAME/LPS co-treated RAW 264.7 cells. These results indicated that combinatorial treatment of L-arginine analogs and flavonoid derivates, such as quercetin pentaacetate, effectively inhibited LPS-induced NO and PGE2 productions, at the same time, inhibited enhanced expressions of iNOS and COX-2 genes.