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Objective: To evaluate use of a British English version of the validated French FLARE-RA questionnaire among American English speaking patients. In addition, to create a culturally adapted American English (AmE) FLARE-RA questionnaire and to examine its attributes of patient-reported RA flare status. Methods: Using standardized cultural adaptation guidelines, we cognitively debriefed 25 American English speaking rheumatoid arthritis (RA) outpatients and created AmE-FLARE-RA with their input. One hundred three additional RA patients were recruited. Patients completed the Routine Assessment of Patient Index Data 3 (RAPID3), patient global visual analogue scale (VAS), AmE-FLARE-RA, and self-reports of flare. Physician global VAS, physician-assessed flare, swollen and tender joint count (TJC), and clinical disease activity index (CDAI) were documented. AmE-FLARE-RA and disease activity measures were compared between patient-reported and physician-reported flare categories. Results: Patients were female (89%), with mean (SD) age 51.1 (± 15.3) years and mean disease duration (SD) 11.9 (± 10.1) years, with 26% in remission/low disease activity. Total AmE-FLARE-RA scores, RAPID3, CDAI, and patient global VAS were significantly higher for both patient-reported flares and physician-reported flares compared with non-flaring patients by self- or physician report (p < 0.05). Total AmE-FLARE-RA scores correlated significantly with RAPID3 (corr = 0.50, p < 0.0001) and with CDAI (corr = 0.45, p < 0.0001). Across "no flares," "one flare," and "several flare" groups, there was a non-significant increase in AmE-FLARE-RA scores (p = 0.07). Conclusion: The British English FLARE-RA was successfully adapted for AmE-speaking RA patients. AmE-FLARE-RA significantly correlated with RAPID3 and CDAI and distinguished between patient-reported and physician-reported flares, making it useful to detect flares in American RA patients. Key Points • The American English FLARE-RA (AmE-FLARE-RA) questionnaire is the result of cognitive debriefing with American RA patients using the British English version of the validated French FLARE-RA and incorporates patient-recommended language modifications.. • Patients self-reporting flares had significantly higher AmE-FLARE-RA scores, compared with those without flares at the time of visit. AmE-FLARE-RA scores correlate with RAPID3 and CDAI. • There was a non-statistically significant trend using the AmE-FLARE-RA scores when examining patients with no flare, one flare, or several flares. • AmE-FLARE-RA total scores are uniformly elevated (~ 6.0 on a 0–10 scale), regardless of discordance between patient and MD assessment of flare at time of visit (~ 30%) [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the diagnostic reliability of sentinel lymph node biopsy in patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx by reviewing the published literature. A systematic literature review was performed using MEDLINE from 1970 to 2011. With Boolean search strings, search terms included sentinel node, supraglottic, supraglottis, tongue, head and neck, oral, pharynx, laryngeal, and larynx. Additional studies were identified through article references. Duplicate data and articles were excluded based on treating institution and study inclusion time period. Additional studies were excluded if the head and neck subsite or tumor stage was not specifically identified or if the sentinel lymph node biopsy occurred in previously treated necks. All patients had sentinel lymph node biopsy performed followed by a concurrent neck dissection. Twenty-six studies met our inclusion criteria ( n = 766 patients). The pooled sensitivity and negative predictive value of SLNB for all head and neck tumors was 95 % (95 % CI 91-99 %) and 96 % (95 %CI 94-99 %), respectively. The overall sensitivity and negative predictive value of SLNB in the subset of oral cavity tumors ( n = 631) was 94 % (95 % CI 89-98 %) and 96 % (95 % CI 93-99 %), respectively. One-hundred percent of oropharyngeal ( n = 72), hypopharyngeal ( n = 5), and laryngeal ( n = 58) tumor sentinel lymph biopsy results correlated with subsequent neck dissections giving a negative predictive value of 100 %, showing that, sentinel lymph node biopsy is a valid diagnostic technique to correctly stage regional metastases in patients with head and neck squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background:Molecular pathways determining the malignant potential of premalignant breast lesions remain unknown. In this study, alterations in DNA methylation levels were monitored during benign, premalignant and malignant stages of ductal breast cancer development.Methods:To study epigenetic events during breast cancer development, four genomic biomarkers (Methylated-IN-Tumour (MINT)17, MINT31, RARβ2 and RASSF1A) shown to represent DNA hypermethylation in tumours were selected. Laser capture microdissection was employed to isolate DNA from breast lesions, including normal breast epithelia (n=52), ductal hyperplasia (n=23), atypical ductal hyperplasia (n=31), ductal carcinoma in situ (DCIS, n=95) and AJCC stage I invasive ductal carcinoma (IDC, n=34). Methylation Index (MI) for each biomarker was calculated based on methylated and unmethylated copy numbers measured by Absolute Quantitative Assessment Of Methylated Alleles (AQAMA). Trends in MI by developmental stage were analysed.Results:Methylation levels increased significantly during the progressive stages of breast cancer development; P-values are 0.0012, 0.0003, 0.012, <0.0001 and <0.0001 for MINT17, MINT31, RARβ2, RASSF1A and combined biomarkers, respectively. In both DCIS and IDC, hypermethylation was associated with unfavourable characteristics.Conclusion:DNA hypermethylation of selected biomarkers occurs early in breast cancer development, and may present a predictor of malignant potential. [ABSTRACT FROM AUTHOR]

Background:Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors.Methods:Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration.Results:Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells.Conclusion:In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC. [ABSTRACT FROM AUTHOR]

Tolerizing mice polygenically predisposed to lupus-like disease (NZB/NZW F1 females) with a peptide mimicking anti-DNA IgG sequences containing MHC class I and class II T cell determinants (pConsensus, pCons) results in protection from full-blown disease attributable in part to the induction of CD4+CD25+Foxp3+ and CD8+Foxp3+ regulatory T cells. We compared 45 000 murine genes in total white blood cells (WBC), CD4+ T cells, and CD8+ T cells from splenocytes of (NZBxNZW) F1 lupus-prone mice tolerized with pCons vs untreated naïve mice and found two-fold or greater differential expression for 448 WBC, 174 CD4, and 60 CD8 genes. We identified differentially expressed genes that played roles in the immune response and apoptosis. Using real-time PCR, we validated differential expression of selected genes (IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1) in the CD8+T cell microarray and determined expression of selected highly upregulated genes in different immune cell subsets. We also determined Smads expression in different immune cell subsets, including CD4+ T cells and CD8+ T cells, to detect the effects of TGF-β, known to be the major cytokine that accounts for the suppressive capacity of CD8+ Treg in this system. Silencing of anti-apoptotic gene Bcl2 or interferon genes (IFI202b and IFNar1 in combination) in CD8+ T cells from tolerized mice did not affect the expression of the other selected genes. However, silencing of Foxp3 reduced expression of Foxp3, Ifi202b and PD1—all of which are involved in the suppressive capacity of CD8+ Treg in this model. [ABSTRACT FROM AUTHOR]

Both the prototypic tricyclic antidepressant imipramine (IMI) and the herbal product St John's wort (SJW) can be effective in the treatment of major depressive disorder. We studied hypothalamic gene expression in rats treated with SJW or IMI to test the hypothesis that chronic antidepressant treatment by various classes of drugs results in shared patterns of gene expression that may underlie their therapeutic effects. Individual hypothalami were hybridized to individual Affymetrix chips; we studied three arrays per group treatment. We constructed 95% confidence intervals for expression fold change for genes present in at least one treatment condition and we considered genes to be differentially expressed if they had a confidence interval excluding 1 (or -1) and had absolute difference in expression value of 10 or greater. SJW treatment differentially regulated 66 genes and expression sequence tags (ESTs) and IMI treatment differentially regulated 74 genes and ESTs. We found six common transcripts in response to both treatments. The likelihood of this occurring by chance is 1.14 × 10-23. These transcripts are relevant to two molecular machines, namely the ribosomes and microtubules, and one cellular organelle, the mitochondria. Both treatments also affected different genes that are part of the same cell function processes, such as glycolytic pathways and synaptic function. We identified single-nucleotide polymorphisms in the human orthologs of genes regulated both treatments, as those genes may be novel candidates for pharmacogenetic studies. Our data support the hypothesis that chronic antidepressant treatment by drugs of various classes may result in a common, final pathway of changes in gene expression in a discrete brain region.Molecular Psychiatry (2004) 9, 237-251. doi:10.1038/sj.mp.4001470 Published online 13 January 2004 [ABSTRACT FROM AUTHOR]

Purpose: Fewer patients newly diagnosed with prostate cancer today have biopsy Gleason sums <6 compared to several years ago. Several tables and nomograms for predicting disease recurrence after definitive therapy provide little or no discrimination between biopsy Gleason sums 4, 5, and 6. We sought to examine the significance of biopsy Gleason sum for predicting biochemical failure following radical prostatectomy (RP) for men with biopsy Gleason sums of 4, 5, and 6.Materials and methods: We examined data from 988 men treated with RP between 1988 and 2002 who had biopsy Gleason sums of 4-6. Clinical and pathological variables as well as outcome information were compared between men with biopsy Gleason sums of 4-6. The log-rank and Cox proportional hazards analysis were used to determine whether biopsy Gleason sum provided unique prognostic information for men with low biopsy Gleason sums undergoing RP.Results: There was statistically significant, but overall weak correlation between biopsy Gleason sum and Gleason sum of the RP specimen (Spearman's r=0.277, P<0.001). As biopsy Gleason sum increased from 4 to 5 to 6, there was a steady rise (HR=1.31 for each one point increase in Gleason sum, Cox's model) in the risk of PSA failure (P=0.025, log-rank). On multivariate analysis comparing biopsy Gleason sum, preoperative PSA, clinical stage, year of surgery, percent of biopsy cores positive, and age for their ability to predict time to biochemical recurrence, only PSA (HR 2.09, CI 1.56-2.80, P<0.001) and biopsy Gleason sum (HR 1.33, CI 1.05-1.70, P=0.019) were significant independent predictors of PSA failure.Conclusions: Despite weak correlation between biopsy and pathologic Gleason sum among men with biopsy Gleason sum 4-6 tumors, grade was a significant independent predictor of PSA failure following RP. In the range of 4-6, biopsy Gleason sum acted as a continuous variable for predicting PSA failure. The routine use of Gleason sums 4 and 5 to grade prostate needle biopsy specimens should not be abandoned.Prostate Cancer and Prostatic Diseases (2003) 6, 261-265. doi:10.1038/sj.pcan.4500673 [ABSTRACT FROM AUTHOR]

The article evaluates the dosage compensation (DC) of the Z chromosome of chicken. It investigates the effect of DC in terms of sexual bias elimination. It explores two studies that differ in assessing the degree of DC and the methods of analyzing DC. It also reexamines the data sets of the two studies including the comparable chick embryonic brain data.