Biomedical subjects

David Mauger

Publications and source records attributed to David Mauger.

At least 19 recordsLinked to original sources

PubMed2026

Aberrant mucin expression and keratinization distinguishing severe from mild asthma revealed by interpretable machine learning.

Type 2 (T2) immune cells dominate the airways of patients with mild-moderate asthma (MMA) with a more complex type 1 (T1)-T2 mixed immune response evident in treatment-refractory severe asthma (SA). We hypothesized that comparing the transcriptomes of the airway epithelium of patients with SA and MMA would reveal molecular signatures associated with more severe disease in the context of a complex immune response. Using our interpretable machine learning tool, SLIDE, meaningful latent factors (context-specific gene co-expression networks) were revealed that distinguished SA from MMA. Unexpectedly, an aberrant high expression of normally host-protective, membrane-tethered, and IFN-inducible mucins, MUC1 and MUC4, was identified in SA. Gene networks in the significant latent factors discriminating SA from MMA corresponded to enrichment of a keratinization program in SA airways. Keratinization was marked by increased expression of the stress keratin KRT16, signifying squamous metaplasia suggesting adaptive reprogramming of the airway epithelium in response to chronic stress. These mucins and KRT16 were inversely associated with lung function in 2 separate asthma cohorts. Imaging of endobronchial biopsies revealed significantly higher KRT16 protein expression in SA compared with MMA that strongly correlated with MUC1 protein expression. Our study identifies dysregulated host-protective and maladaptive repair responses in SA distinguishing from MMA.

Humans↗

PubMed2025

α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization.

BACKGROUND: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. RESULTS: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by-ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). CONCLUSIONS: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Adult↗

PubMed2007

Low-dose naltrexone therapy improves active Crohn's disease.

OBJECTIVES: Endogenous opioids and opioid antagonists have been shown to play a role in healing and repair of tissues. In an open-labeled pilot prospective trial, the safety and efficacy of low-dose naltrexone (LDN), an opioid antagonist, were tested in patients with active Crohn's disease. METHODS: Eligible subjects with histologically and endoscopically confirmed active Crohn's disease activity index (CDAI) score of 220-450 were enrolled in a study using 4.5 mg naltrexone/day. Infliximab was not allowed for a minimum of 8 wk prior to study initiation. Other therapy for Crohn's disease that was at a stable dose for 4 wk prior to enrollment was continued at the same doses. Patients completed the inflammatory bowel disease questionnaire (IBDQ) and the short-form (SF-36) quality of life surveys and CDAI scores were assessed pretreatment, every 4 wk on therapy and 4 wk after completion of the study drug. Drug was administered by mouth each evening for a 12-wk period. RESULTS: Seventeen patients with a mean CDAI score of 356 +/- 27 were enrolled. CDAI scores decreased significantly (P= 0.01) with LDN, and remained lower than baseline 4 wk after completing therapy. Eighty-nine percent of patients exhibited a response to therapy and 67% achieved a remission (P < 0.001). Improvement was recorded in both quality of life surveys with LDN compared with baseline. No laboratory abnormalities were noted. The most common side effect was sleep disturbances, occurring in seven patients. CONCLUSIONS: LDN therapy appears effective and safe in subjects with active Crohn's disease. Further studies are needed to explore the use of this compound.

Adult↗

PubMed2005

Characterization of the intronic splicing silencers flanking FGFR2 exon IIIb.

The cell type-specific alternative splicing of FGFR2 pre-mRNA results in the mutually exclusive use of exons IIIb and IIIc, which leads to critically important differences in receptor function. The choice of exon IIIc in mesenchymal cells involves activation of this exon and repression of exon IIIb. This repression is mediated by the function of upstream and downstream intronic splicing silencers (UISS and DISS). Here we present a detailed characterization of the determinants of silencing function within UISS and DISS. We used a systematic mutational analysis, introducing deletions and substitutions to define discrete elements within these two silencers of exon IIIb. We show that UISS requires polypyrimidine tract-binding protein (PTB)-binding sites, which define the UISS1 sub-element, and an eight nucleotide sequence 5'-GCAGCACC-3' (UISS2) that is also required. Even though UISS2 does not bind PTB, the full UISS can be replaced with a synthetic silencer designed to provide optimal PTB binding. DISS is composed of a 5'-conserved sub-element (5'-CE) and two regions that contain multiple PTB sites and are functionally redundant (DISS1 and DISS2). DISS1 and DISS2 are separated by the activator sequence IAS2, and together these opposing elements form the intronic control element. Deletion of DISS in the FGFR2 exon IIIb context resulted in the near full inclusion of exon IIIb, and insertion of this silencer downstream of a heterologous exon with a weak 5' splice site was capable of repressing exon inclusion. Extensive deletion analysis demonstrated that the majority of silencing activity could be mapped to the conserved octamer CUCGGUGC within the 5'CE. Replacement of 5'CE and DISS1 with PTB-binding elements failed to restore repression of exon IIIb. We tested the importance of the relative position of the silencers and of the subelements within each silencer. Whereas UISS1, UISS2, DISS1, and DISS2 appear somewhat malleable, the 5'CE is rigid in terms of relative position and redundancy. Our data defined elements of function within the ISSs flanking exon IIIb and suggested that silencing of this exon is mediated by multiple trans-acting factors.

Alternative Splicing↗

PubMed2005

Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women.

OBJECTIVES: To determine if insulin-like growth factor 1 (IGF-1) and androgen levels (1) correlate with the presence and severity of acne in adult men and women, and (2) correlate directly with each other and interact in affecting acne. DESIGN: Case-control study and single-center examination of hormone levels in a cohort of volunteers. SETTING: Academic referral center. PATIENTS: Thirty-four subjects (8 women and 8 men with clinical acne, 10 women and 8 men without clinical acne). Clinical acne is defined by a history of persistent acne (acne present on most days for several years), recent acne treatment, and the presence of 10 or more inflammatory acne lesions and 15 or more comedones. INTERVENTIONS: Single visit for serum sampling. MAIN OUTCOME MEASURES: Serum levels of IGF-1 and androgens were determined, adjusted for age, and compared based on the presence or absence of clinical acne using an analysis of covariance. Correlations between hormone levels and acne lesion counts were calculated within each subgroup. Correlations were also calculated between serum levels of IGF-1 and androgens. Further statistical testing was conducted to determine whether IGF-1 or androgens had a greater effect on acne lesion counts. RESULTS: Dehydroepiandrosterone (DHEAS), dihydrotestosterone (DHT), and IGF-1 correlated positively with acne lesion counts in women. Androstenedione and DHEAS correlated with acne lesion counts in men. Although the age-adjusted mean serum levels of IGF-1 were higher in women with clinical acne than in women without clinical acne, this difference did not achieve statistical significance. No difference in IGF-1 level was noted in men based on the presence of clinical acne. In women with clinical acne, IGF-1 correlated with DHT. In men with clinical acne, IGF-1 correlated with DHEAS and androstenedione. In men and women with clinical acne, the effects of androgens on increased acne lesion counts were dependent on the influence of IGF-1. CONCLUSIONS: Increased IGF-1 levels in addition to androgens may influence acne in adult men and women. While IGF-1 appears to have a stronger effect on acne in women, androgens may play a greater role in acne for men. However, in both men and women these hormones are interrelated, possibly owing to reciprocal effects on hormone production.

Acne Vulgaris↗

PubMed2005

Effects of polyamine synthesis inhibitors on primary tumor features and metastatic capacity of human breast cancer cells.

We have previously reported that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces pulmonary metastasis from MDA-MB-435 human breast cancer xenografts without affecting the volume of the primary tumors (Manni et al. Clin Exp Mets 20:321, 2003). In these experiments, we show that DFMO treatment (2% in drinking H(2)O) reduced the growth fraction of the primary tumors by 60%. However, this effect was counter-balanced by a similar reduction in non-apoptotic necrosis, thus accounting for the preservation of tumor volume in DFMO-treated mice. DFMO treatment caused a 4-fold increase in cytoplasmic staining for cleaved caspase-3 (as opposed to the nuclear staining observed in control tonsil tissue) in the absence of histologic evidence of apoptosis. DFMO treatment reduced the number of mice with pulmonary metastasis by approximately 80% and the number of metastasis per mouse by >90% in association with a reduction in invasiveness of the primary tumor in the surrounding dermis and muscle by approximately 30%. DFMO treatment increased ERK phosphorylation in the tumors, an effect that has been found by us in vitro to be causally linked to the anti-invasive effect of the drug (Manni et al. Clin Exp Metast 2004; 21: 461]. DFMO also increased tyrosine phosphorylation of STAT-3 and expression of STAT-1 and JNK proteins. Administration of SAM486A (1 mg/kg/i.p. daily), an inhibitor of S-adenosylmethionine decarboxylase, either individually or in combination with DFMO, was not found to exert any biological or biochemical effects, most likely as a result of its failure to suppress tissue polyamine levels under these experimental conditions.

Amidines↗

PubMed2005

Death receptor apoptosis signaling mediated by FADD in CD30-positive lymphoproliferative disorders involving the skin.

BACKGROUND: The CD30-positive lymphoproliferative disorders lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and systemic anaplastic large cell lymphoma (S-ALCL) are lesions that overlap clinically, histopathologically, and immunophenotypically. Their biologic behaviors, however, vary considerably. In particular, lesions of LyP regress spontaneously while those of S-ALCL persist and often progress. Apoptosis has been suggested as the mechanism by which the lesions of LyP regress, but the underlying signaling pathways remain unclear. In this study, we used newly developed activation state-specific antibodies to demonstrate apoptosis signaling through the death receptor-mediated pathway regulated by FADD and caspase 3. METHODS: Dual immunohistochemistry for CD30 and activated forms of FADD and caspase 3 was performed on cutaneous biopsy specimens from 27 patients with CD30-positive lymphoproliferative disorders involving the skin. The patients included 18 with primary cutaneous CD30-positive LPDs (15 with LyP and 3 with C-ALCL) and 9 with S-ALCL. RESULTS: The proportion of CD30-positive cells expressing activated FADD was significantly different between primary cutaneous CD30-positive lymphoproliferative disorders and S-ALCL (36.4% vs. 14.5%, P = 0.0083). Expression of cleaved caspase 3 was also significantly different between primary cutaneous lesions and S-ALCL (9.2% vs. 1.9%, P = 0.048). CONCLUSIONS: Although a larger number of cases should be studied to validate these results, these data provide evidence that differences in signaling through the death-receptor apoptosis pathway mediated by FADD may be responsible for the varying biologic behaviors of CD30-positive lymphoproliferative disorders involving the skin.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function.

Current guidelines for asthma care categorize asthma severity based on the frequency of asthma symptoms, medication use, and lung function measures. The objective of this study was to determine whether lung function measures are consistent with levels of asthma severity as defined by the National Asthma Education and Prevention Program/Expert Panel Report 2 Guidelines. Parents of children aged 5-18 years with asthma seen in two outpatient subspecialty clinics completed questionnaires regarding asthma medication use and symptom frequency over the preceding 1 and 4 weeks, respectively. All children performed spirometry. When asthma severity was based on the higher severity of asthma symptom frequency or medication use, asthma was mild intermittent in 6.9% of participants, mild persistent in 27.9%, moderate persistent in 22.4%, and severe persistent in 42.9%. FEV(1) % predicted did not differ by level of asthma severity. FEV(1)/FVC decreased as asthma severity increased (p < 0.0001) and was abnormal in 33% of the participants, and a greater percentage of participants had an abnormal FEV(1)/FVC as asthma severity increased (p = 0.0001). In children, asthma severity classified by symptom frequency and medication usage does not correlate with FEV(1) categories defined by National Asthma Education and Prevention Program Guidelines. FEV(1) is generally normal, even in severe persistent childhood asthma, whereas FEV(1)/FVC declines as asthma severity increases.

Adolescent↗

PubMed2004

Treatment of Wilms tumor-related hypertension with losartan and captopril.

Hypertension is commonly associated with Wilms tumor, but hypertension secondary to renin-secreting Wilms tumor is uncommon. We present an infant with severe hypertension and renin hypersecretion, which was resistant to multiple antihypertensive agents. Blood pressure was eventually controlled with a combination of captopril and losartan.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2004

Cellular mechanisms mediating the anti-invasive properties of the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) in human breast cancer cells.

We have shown that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces in vitro invasiveness and metastatic capacity of MDA-MB-435 breast cancer cells. These experiments investigated the mechanisms mediating the anti-invasive properties of DFMO. DFMO did not affect phosphorylation of FAK or Akt, but increased ERK phosphorylation by approximately threefold. To test the biologic significance of this finding, we tested the effect of the MEK inhibitor PD98059 on in vitro invasiveness of MDA-MB-435 breast cancer cells, both in the absence and in the presence of the proinvasive peptide hepatocyte growth factor (HGF) as a chemoattractant. We observed that PD98059 treatment reversed the anti-invasive effect of DFMO under both experimental conditions. Next, we tested the influence of DFMO on the production of the prometastatic peptide osteopontin (OPN) and the anti-metastatic protein thrombospondin-1 (TSP-1). DFMO treatment, while not affecting OPN production, markedly increased the TSP-1 level in the conditioned media. This effect was abolished by putrescine administration, thus indicating the specificity of the DFMO action through the polyamine pathway. PD98059 completely blocked the stimulatory effect of DFMO on TSP-1 production, which supports a mediatory role for activation of the MAPK pathway in the upregulation of this anti-metastatic peptide by DFMO. In summary, our results show that the increase in ERK phosphorylation induced by DFMO plays a critical role in the anti-invasive action of the drug and in its ability to upregulate TSP-1 production.

Breast Neoplasms↗

PubMed2004

Specific sequence configurations of HIV-1 LTR G/C box array result in altered recruitment of Sp isoforms and correlate with disease progression.

Basal and activated human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) activity, and in return, viral replication is partly dependent on interactions of the G/C box array with the Sp family of transcription factors. Analysis of LTR Sp binding site sequence variants revealed a C-to-T change at position 5 within Sp site III that increased in frequency and a 5T mutation within Sp site II, which decreased in frequency during the course of HIV disease. These results suggest LTR Sp binding site sequence variants may prove useful as viral molecular markers indicative of progressive HIV-1-induced disease.

Base Sequence↗

PubMed2004

The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Pulmonary hypertension is an integral part of the pathophysiology of the respiratory failure associated with congenital diaphragmatic hernia. Hypothesizing that the evolution of the pulmonary hypertension would determine clinical outcome, the authors examined pulmonary artery pressures in relation to survival in their CDH patients. METHODS: The authors performed a retrospective chart review of all neonates with the CDH from 1991 to 2002 at their institution eliminating infants with complex congenital heart disease, prematurity, or limited treatment. Cardiac ECHO data were used to estimate pulmonary artery pressures as a ratio to systemic pressure. Statistical analyses of estimated pulmonary pressure ratios stratified by survival status and time were performed using chi2 and Fisher's Exact Test methods. RESULTS: Forty-seven full-term CDH infants with 428 cardiac ECHO evaluations were studied. Long-term survival rate was 74%. Forty-nine percent of patients had normal pulmonary artery pressure estimates within the first 3 weeks of life. All patients survived. Seventeen percent had persistent systemic or suprasystemic pressure estimates unrelieved by treatment interventions resulting in 100% mortality rate. Thirty-four percent had intermediate reductions in pressure estimates over time with 75% survival rate. Systemic pulmonary artery pressures were associated with decreased survival at all time-points when compared with normal-pressure survivors: week 1, 60% (P <.003); week 3, 38% (P <.007); week 6, 0% (P <.02). CONCLUSIONS: The evolution of pulmonary hypertension is a critical determinant of survival in CDH patients with current treatment strategies. Three groups can be modeled with markedly different clinical performance patterns. Using serial cardiac ECHO examinations, pulmonary artery pressure estimations can be used to predict clinical outcome.

Blood Pressure↗

PubMed2004

Region-specific distribution of human immunodeficiency virus type 1 long terminal repeats containing specific configurations of CCAAT/enhancer-binding protein site II in brains derived from demented and nondemented patients.

Previous studies have shown that two CCAAT/enhancer binding protein (C/EBP) binding sites (sites I and II) within the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) are critically important for efficient virus replication within cells of the monocyte lineage, a primary cell type infected by HIV-1. Sequence variation at C/EBP sites I and II has been shown to alter the affinity of C/EBP factors to these sites. Specifically, sequence variation within C/EBP binding site II has been shown to alter binding of purified C/EBP beta protein and basal activity of the HIV-1 LTR. We have previously demonstrated that the C/EBP site II consensus cladeB (ConB) variant was highly conserved in brain- and peripheral blood-derived LTRs of individuals with advanced HIV-1 disease. Given these important observations, the regional distribution of LTRs containing the C/EBP site II ConB variant derived from brain tissues of patients with and without HIV-1-associated dementia (HIVD) was examined. A statistically significant difference was found in the distribution of LTRs containing the C/EBP site II ConB variant in brain regions derived from patients with and without HIVD. In addition, we have previously shown that LTRs containing C/EBP site II 4C and 6G variants (designated according to the position at which nucleotide change occurred relative to ConB, followed by the actual nucleotide found at the variant position) were only found in brain tissue of patients with HIVD. As an extension of these observations, the regional distribution of LTRs containing C/EBP site II 4C or 6G variants derived from the brains of patients with HIVD was examined and a statistically significant difference was observed. We have shown that LTRs containing a low-affinity C/EBP site II 4C variant accumulated in the cerebellum. LTRs containing the 4C site variant in conjunction with the consensus cladeB (ConB) site I exhibited the lowest basal LTR activity of any of the LTRs examined. These results suggest that LTRs containing the C/EBP site II 4C configuration may promote the establishment of a latent provirus in the cerebellum, a region of the HIVD brain that exhibits little viral gene expression. Furthermore, LTRs containing a high affinity C/EBP site II 6G variant accumulated in the mid-frontal gyrus, a site of highly productive replication. In addition, LTRs containing the C/EBP site II 6G variant with the ConB at site I exhibited the highest basal LTR activity. In conclusion, distinct LTR populations with specific C/EBP site II configurations were found in different neuroanatomical regions of the brain, potentially due to differences in the molecular architecture of the LTR, viral entry pathways, and/or brain microenvironments.

AIDS Dementia Complex↗

PubMed2004

Method of mutation analysis may contribute to discrepancies in reports of (V599E)BRAF mutation frequencies in melanocytic neoplasms.

Explore the source record for details and available documents.

DNA Mutational Analysis↗

PubMed2004

Biological activity of the S-adenosylmethionine decarboxylase inhibitor SAM486A in human breast cancer cells in vitro and in vivo.

The antitumor activity of the S-adenosylmethionine decarboxylase (SAMDC) inhibitor SAM486A in human breast cancer cells was investigated. Our in vitro study focused on testing the effects of SAM486A on the proliferation, clonogenicity, invasiveness, cell signaling and PA levels of hormone-independent MDA-MB-435 human breast cancer cells. We also investigated the antitumor action, effects on polyamine pools and tolerability of SAM486A administered to nude mice carrying MDA-MB-435 xenografts. SAM486A suppressed anchorage-independent and -dependent growth and invasiveness of breast cancer cells and the inhibition of cell growth was associated with suppression of spermine synthesis. Combined administration of SAM486A and alpha-difluoromethylornithine (DFMO), a selective inhibitor of ornithine decarboxylase (ODC), exerted greater antiproliferative and anti-invasive effects and induced an overall greater suppression of cellular PA levels than the individual treatments. Both SAM486A and DFMO increased phosphorylation of STAT-1, -3, ERK1/2 and p38, thus indicating activation of both STAT signaling and the MAPK pathway. SAM486A (1 mg/kg) significantly suppressed the growth and spermine levels of established MDA-MB435 breast tumors in nude mice. SAM486A exerts a potent antitumor action in MDA-MB-435 breast cancer cells both in vitro and in vivo. Inhibition of cellular spermine is consistently observed with SAM486A treatment and may mediate its antitumor action. Combination treatment with DFMO may allow the use of lower and, hence, less toxic doses of each compound with preservation of optimal therapeutic effect. The role of activation of STAT signaling and the MAPK pathway in the antitumor action of SAM486A remains to be determined.

Adenosylmethionine Decarboxylase↗

PubMed2003

Relative validity of food frequency questionnaire nutrient estimates in the Black Women's Health Study.

PURPOSE: The Black Women's Health Study (BWHS) was designed to investigate determinants of health and disease in US black women. More than 64,000 women are enrolled in the BWHS cohort. This study assessed the relative validity of the 68-item food frequency questionnaire (FFQ) used in the BWHS baseline questionnaire. METHODS: Four hundred and eight BWHS enrollees were asked to provide three telephone, 24-hour recalls and one written 3-day food diary over a one-year period. Means and Pearson correlations were computed to compare estimates for energy, total fat, saturated fat, protein, carbohydrate, dietary fiber, calcium, iron, vitamin C, folate, beta-carotene, and vitamin E from the FFQ, recalls, and diaries. RESULTS: Mean energy intake (kcal) was higher for the diary (1716) than the FFQ (1601) or recalls (1510). Other nutrient estimates (% kcal or per 1000 kcal) were similar across methods, except beta-carotene (FFQ higher). Correlations (energy-adjusted, except for energy, and corrected for intraperson variation) between the FFQ and the recalls were higher than for the diary data and were between 0.5 and 0.8, except for energy and vitamin E (both <0.3). CONCLUSION: The BWHS FFQ will support meaningful analyses of diet-health associations for 10 of the 11 energy-adjusted nutrient intake variables analyzed.

Adult↗

PubMed2003

Effects of alpha-difluoromethylornithine on local recurrence and pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice.

We have recently shown that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis reduces pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice. The present experiments were designed to further explore PA involvement in breast cancer metastasis, using GFP-tagged MDA-MB-435 cells that can be tracked at the single cell level. Administration of DFMO significantly reduced the number of mice with pulmonary metastasis as well as the number of metastases per mouse. Both single-cell and multicellular metastatic deposits were similarly suppressed, thus suggesting that DFMO was inhibiting lung colonization by tumor cells rather than preventing progression of single-cell deposits to overt metastasis. DFMO administration also significantly reduced local recurrences following removal of the primary tumor. Prolongation of DFMO treatment to 14 weeks did not yield a superior antimetastatic effect beyond that provided by a 10-week course of therapy. Discontinuation of DFMO, on the other hand, was associated with local regrowth of the tumors and, possibly, recurrence of pulmonary metastasis. These data provide a rationale for testing the efficacy of anti-PA treatment within the context of adjuvant therapy of breast cancer.

Animals↗

PubMed2002

Correlation between presumed sinusitis-induced pain and paranasal sinus computed tomographic findings.

BACKGROUND: The correlation between facial and/or head pain in patients clinically suspected of having sinusitis and actual localized findings on sinus computed tomographic (CT) imaging are poorly understood. OBJECTIVE: To prospectively evaluate the relationship of paranasal sinus pain symptoms with CT imaging. METHODS: Two hundred consecutive patients referred by otolaryngologists and internists for CT of the paranasal sinuses participated by completing a questionnaire immediately before undergoing CT. Three radiologists blinded to the patients' responses scored the degree of air/fluid level, mucosal thickening, bony reaction, and mucus retention cysts using a graded scale of severity (0 to 3 points). The osteomeatal complexes and nasolacrimal ducts were also evaluated for patency. Bivariate analysis was performed to evaluate the relationship between patients' localized symptoms and CT findings in the respective sinus. RESULTS: One hundred sixty-three patients (82%) reported having some form of facial pain or headache. The right temple/forehead was the most frequently reported region of maximal pain. On CT imaging the maxillary sinus was the most frequently involved sinus. Bivariate analysis failed to show any relationship between patient symptoms and findings on CT. Patients with a normal CT reported a mean 5.88 sites of facial or head pain versus 5.45 sites for patients with an abnormal CT. CONCLUSIONS: Patient-based responses of sinonasal pain symptoms fail to correlate with findings in the respective sinuses. CT should therefore be reserved for delineating the anatomy and degree of sinus disease before surgical intervention.

Facial Pain↗