Oncogene activation increases susceptibility to apoptosis. Thus, tumorigenesis must depend, in part, on compensating mutations that protect from programmed cell death. A functional screen for cDNAs that could counteract the proapoptotic effects of the myc oncogene identified two related bHLH family members, Twist and Dermo1. Both of these proteins inhibited oncogene-and p53-dependent cell death. Twist expression bypassed p53-induced growth arrest. These effects correlated with an ability of Twist to interfere with activation of a p53-dependent reporter and to impair induction of p53 target genes in response to DNA damage. An underlying explanation for this observation may be provided by the ability of Twist to reduce expression of the ARF tumor suppressor. Thus, Twist may affect p53 indirectly through modulation of the ARF/MDM2/p53 pathway. Consistent with a role as a potential oncoprotein, Twist expression promoted colony formation of E1A/ras-transformed mouse embryo fibroblasts (MEFs) in soft agar. Furthermore, Twist was inappropriately expressed in 50% of rhabdomyosarcomas, a tumor that arises from skeletal muscle precursors that fail to differentiate. Twist is known to block myogenic differentiation. Thus, Twist may play multiple roles in the formation of rhabdomyosarcomas, halting terminal differentiation, inhibiting apoptosis, and interfering with the p53 tumor-suppressor pathway.

No abstract

Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF. However, colchicine has a wide range of anti-inflammatory activities, and studies indicate that it may be beneficial in a variety of other conditions. This paper reviews the evidence for the well-established use of colchicine in gout, as well as several other rheumatic diseases. In addition, we highlight the potential benefit of colchicine in cardiac disease, including coronary artery disease in patients both with and without gout.

Although colchicine has been a focus of research, debate and controversy for thousands of years, it was only approved by the United States Food and Drug Administration in 2009. Over the past decade, advances in the knowledge of colchicine pharmacology, drug safety and mechanisms of action have led to changes in colchicine dosing and to potential new uses for this very old drug. In this review, we discuss the pharmacologic properties of colchicine and summarize what is currently known about its mechanisms of action. We then discuss and update the use of colchicine in a variety of illnesses, including rheumatic and, most recently cardiovascular diseases.

Objective We examined gene expression profiles in peripheral blood leukocytes (PBL) of patients with osteoarthritis (OA) in comparison with non-OA controls to evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee OA. We also determined whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict increased risk of disease progression in subjects with symptomatic radiographic knee OA Methods Three independent cohorts of patients with knee OA and non-OA controls were studied: two cohorts (“learning cohort” and “validation cohort”) recruited at New York University Hospital for Joint Diseases (NYUHJD) and one (“validation cohort”) at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and confirmed by QPCR. Radiographic progression at 2 years was assessed in 86 patients Results We identified 173 genes significantly up- or down-regulated (≥1.5-fold change) in OA PBL, at a False Discovery Rate (FDR) of 5%. Cluster analysis revealed two distinct subclasses among these OA patients: those with increased expression (≥2-fold) of IL-1β compared to controls, and those with expression comparable to controls. Overexpression of IL-1β in OA subclasses was validated using QPCR (p<0.0001) in all three cohorts. Patients with the inflammatory “IL-1β signature” had higher pain scores, decreased function and were at higher risk for radiographic progression. Conclusion PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1β identifies a subset of OA patients with increased pain who are at higher risk for radiographic progression.

No abstract

Gout is characterized by the deposition of monosodium urate crystals and by acute and chronic inflammation in response to crystals so deposited. Multiple case reports and series describe the deposition of monosodium urate in the spine as a rare manifestation of gout, but the actual prevalence of spinal involvement is unknown and likely to be higher than generally anticipated. Here we review the characteristics of 131 previously reported cases of spinal involvement in gout. We focus in particular on the use of imaging modalities and the extent to which they correlate with presenting symptoms and tissue diagnoses. The recent innovation of using dual-energy computerized tomography to identify urate crystal deposition holds promise for reducing the need for surgical intervention and for establishing a true prevalence rate for spinal gout.

Objective To evaluate the relationships of quantitative and semi-quantitative (SQ) assessments of synovium with knee OA severity by radiographic and 3T MRI findings. Methods 58 knee OA patients underwent non-fluoroscopic fixed-flexion knee radiographs. Dynamic contrast-enhanced (CE) 3T MRI was performed pre-/post-gadolinium administration to quantify synovial volume (qSV). SQ synovial outcomes were assessed on CE and unenhanced images. Two radiologists scored X-rays using the OARSI atlas; inter-reader agreement was assessed using Kappas and concordance correlation coefficients. Multiple linear and logistic regression analysis was used to assess associations among variables while controlling the effects of age, BMI, gender and meniscal extrusion. Results KL grade, diseased compartment joint space width (dcJSW) and diseased compartment joint space narrowing (dcJSN) were significantly associated with synovial proliferation, measured as CE qSV (β = 0.78, p = 0.0001; β = -0.22, p = 0.0003; β = 0.53, p = 0.0001, respectively). Furthermore, qSV strongly correlated with total subchondral BML volume (β = 0.22, p = 0.0003). KL grade, dcJSW, and dcJSN were significantly associated with BLOKS SQ infrapatellar synovitis (OR [95%CI]: 9.05, [1.94,42.3]; 0.75 [0.54,1.03]; 2.22 [1.15,4.31], respectively) and effusion (OR [95%CI]: 5.75, [1.23,26.8]; 0.70, [0.50,0.98]; 1.96, [1.02,3.74], respectively). CE SQ synovitis also significantly associated with KL and dcJSN (β = 0.036, p = 0.0040; β = 0.015, p=0.0266, respectively), and BLOKS synovitis. Conclusion Synovitis is a characteristic feature of advancing knee OA stages, and is significantly associated with KL, JSW, JSN, and BMLs. BLOKS synovitis scoring on unenhanced MRI is associated with CE synovitis measures.