The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599

Intravascular ultrasound study of angiographically mildly diseased coronary arteries

AbstractObjectives. We hypothesized that intravascular ultrasound may identify significant coronary artery narrowing in the mildly diseases artery of patients with or one- or two-vessel coronary artery disease.Bacground. Necropsy studies have revealed that coronary angiography may underestimate stenosis severity in vessels that appear mildly diseased. Intravascular ultratound has been shown to detect atherosclerotic changs in a angiographically normal coronary arteries and to correlate better with histologic findings.Methods. In 20 patients, we performed intravascular ultrasound imaging (3.5F catheter, 30-MHz transducer) in 37 coronary arteries that were considered mildly diseased (<50% diameter narrowing) by qualitative angiography. The angiographic diagnosis was no significant coronary artery in eight patients, one-vessel disease to seven and two-vessel disease in five. Each vessel, except for the left main coronary artery, was divided into proximal, mid and distal segments. Percent area narrowing and minimal lumen diameter were subsequently quantified by both ultrasound and quantitative angiography.Results. Mean maximal arterial area narrowing by ultrasound in the 67 segments studied was 36 ± 20% (range 0% to 80.2%) and 19 ± 23% (range 0% to 82%) by quantitative angiography of these same (p < 0.001, paired ttest). Mean minimal lumen diameter of the segments was 3.3 ± 0.9 mm by ultrasound and 2.7 ± 0.8 mm by quantitative angiography. In 10 patients there were 19 angiographically mildly diseased segments where the percent arterial area narrowing by ultrasound was ≥50%. Intravascular ultrasound revealed that the more proximal (reference) segmnt had >25% intimal thickening in 12 of the 19 underestimated segments. In six stenosed segments (32%), total vessel area increased compared with that of the adjacent proximal vessel segment because of compensatory dilation.Conclusions. Intravascular ultrasound identified potentially significant coronary artery disease in vessels that appear to be only mildly diseased by angiography

Association Between Tumor Mutation Profile and Clinical Outcomes Among Hispanic-Latino Patients With Metastatic Colorectal Cancer

In the United States, CRC is the third most common type of cancer and the second leading cause of cancer-related death. Although the incidence of CRC among the Hispanic population has been declining, recently, a dramatic increase in CRC incidents among HL younger than 50 years of age has been reported. The incidence of early-onset CRC is more significant in HL population (45%) than in non-Hispanic Whites (27%) and African-Americans (15%). The reason for these racial disparities and the biology of CRC in the HL are not well understood. We performed this study to understand the biology of the disease in HL patients. We analyzed formalin-fixed paraffin-embedded tumor tissue samples from 52 HL patients with mCRC. We compared the results with individual patient clinical histories and outcomes. We identified commonly altered genes in HL patients (APC, TP53, KRAS, GNAS, and NOTCH). Importantly, mutation frequencies in the APC gene were significantly higher among HL patients. The combination of mutations in the APC, NOTCH, and KRAS genes in the same tumors was associated with a higher risk of progression after first-line of chemotherapy and overall survival. Our data support the notion that the molecular drivers of CRC might be different in HL patients. Copyright © 2022 Philipovskiy, Ghafouri, Dwivedi, Alvarado, McCallum, Maegawa, Konstantinidis, Hakim, Shurmur, Awasthi, Gaur and Corral.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Unique antibody responses to malondialdehyde-acetaldehyde (MAA)-protein adducts predict coronary artery disease.

Malondialdehyde-acetaldehyde adducts (MAA) have been implicated in atherosclerosis. The purpose of this study was to investigate the role of MAA in atherosclerotic disease. Serum samples from controls (n = 82) and patients with; non-obstructive coronary artery disease (CAD), (n = 40), acute myocardial infarction (AMI) (n = 42), or coronary artery bypass graft (CABG) surgery due to obstructive multi-vessel CAD (n = 72), were collected and tested for antibody isotypes to MAA-modifed human serum albumin (MAA-HSA). CAD patients had elevated relative levels of IgG and IgA anti-MAA, compared to control patients (p<0.001). AMI patients had a significantly increased relative levels of circulating IgG anti-MAA-HSA antibodies as compared to stable angina (p<0.03) or CABG patients (p<0.003). CABG patients had significantly increased relative levels of circulating IgA anti-MAA-HSA antibodies as compared to non-obstructive CAD (p<0.001) and AMI patients (p<0.001). Additionally, MAA-modified proteins were detected in the tissue of human AMI lesions. In conclusion, the IgM, IgG and IgA anti-MAA-HSA antibody isotypes are differentially and significantly associated with non-obstructive CAD, AMI, or obstructive multi-vessel CAD and may serve as biomarkers of atherosclerotic disease

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p&lt;0.05) and chemokines CCL2, CXCL10 and CXCL13 (p&lt;0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p&lt;0.002). Tofacitinib significantly decreased plasma CXCL10 (p&lt;0.005) at Day 28 compared with placebo.ConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599

MAA-Adduction and its Implications.

<p>MAA-Adduction and its Implications.</p

Serum Concentrations of IgM, IgG and IgA Antibodies 24 Hours post-AMI.

<p>A subgroup of patients (n = 10) were evaluated 24 hours post-AMI for the presence of circulating IgM, IgG and IgA anti-MAA antibody levels (Figure 3A) and the total serum IgM, IgG, and IgA concentrations (Figure 3B). Results are expressed as relative mg/L or g/L of Human IgM, IgG, and IgA using a standard curve. *P<0.01 significantly different comparing AMI and 24 hours post-AMI.</p

Light and Confocal Microscopy of MAA in the Culprit AMI Aspirated Tissue.

<p>Panel A and B illustrates a Masson’s Trichrome staining at low (20X) and high magnification (80X) with panel B as the inset box of panel A. Panel C is the rabbit IgG isotype control stain. Panel D illustrates the rabbit anti-MAA staining with Cy3 reporter (80X). Note the absence of collagen or fibrosis and the presence of cholesterol clefts in Panel A which are typical of an atheroma. Also note the localization of MAA in Panel D (white arrows) to cellular vacuolization and necrosis as noted by the arrows on the Masson’s Trichrome in Panel B (black arrows).</p

Relative Serum Concentrations of anti-MDA LDL and anti-MAA LDL IgG Antibody are not Different in Individuals with Coronary Artery Disease (CAD) and in Individuals who Present with an Acute Myocardial Infarction (AMI).

<p>CAD patients were grouped in the following categories; control patients (n = 82), patients with chest pain and CAD (Non-Obstructive CAD, n = 40), patients presenting with AMI (n = 42), and patients with significant Multi-Vessel Obstructive CAD requiring coronary bypass grafting (n = 72). Serum anti-MDA LDL (Figure 2A) and anti-MAA LDL (Figure 2B). There is no significant difference in serum antibody levels when comparing all study groups (p>0.5).</p

Relative Serum Concentrations of anti-MAA IgM, IgG and IgA Antibodies are Increased in Individuals with Coronary Artery Disease (CAD) and in Individuals who Present with an Acute Myocardial Infarction (AMI).

<p>CAD patients were grouped in the following categories; control patients (n = 82), patients with chest pain and CAD (Non-Obstructive CAD, n = 40), patients presenting with AMI (n = 42), and patients with significant Multi-Vessel Obstructive CAD requiring coronary bypass grafting (n = 72). Serum anti-MAA antibodies were evaluated for the isotypes IgM (Figure 1A), IgG (Figure 1B), and IgA (Figure 1C). *P<0.001 significantly increased compared to controls. #P<0.03 significantly increased compared to Non-Obstructive CAD. $P<0.003 significantly increased compared to Multi-Vessel Obstructive CAD.</p