Colonic manifestations of PTEN hamartoma tumor syndrome: Case series and systematic review

AIM:To investigate our clinical experience with the colonic manifestations of phosphatase and tensin homolog on chromosome ten(PTEN)hamartoma tumor syndrome(PHTS)and to perform a systematic literature review regarding the same.METHODS:This study was approved by the appropriate institutional review board prior to initiation.A clinical genetics database was searched for patients with PHTS or a component syndrome that received gastrointestinal endoscopy or pathology interpretation at our center.These patient’s records were retrospectively reviewed for clinical characteristics(including family history and genetic testing),endoscopy results and pathology findings.We also performed a systematic review of the literature for case series of PHTS or component syndromes that reported gastrointestinal manifestations and investigations published after consensus diagnostic criteria were established in 1996.These results were compiled and reported.RESULTS:Eight patients from our institution met initial inclusion criteria.Of these,5 patients underwent4.2 colonoscopies at mean age 45.8±10.8 years.All were found to have colon polyps during their clinical course and polyp histology included adenoma,hyperplastic,ganglioneuroma and juvenile.No malignant lesions were identified.Two had multiple histologic types.One patient underwent colectomy due to innumerable polyps and concern for future malignant potential.Systematic literature review of PHTS patients undergoing endoscopy revealed 107 patients receiving colonoscopy at mean age 37.4 years.Colon polyps were noted in92.5%and multiple colon polyp histologies were reported in 53.6%.Common polyp histologies included hyperplastic(43.6%),adenoma(40.4%),hamartoma(38.3%),ganglioneuroma(33%)and inflammatory(24.5%)polyps.Twelve(11.2%)patients had colorectal cancer at mean age 46.7 years(range 35-62).Clinical outcomes secondary to colon polyposis and malignancy were not commonly reported.CONCLUSION:PHTS has a high prevalence of colon polyposis with multiple histologic types.It should be considered a mixed polyposis syndrome.Systematic review found an increased prevalence of colorectal cancer and we recommend initiating colonoscopy for colorectal cancer surveillance at age 35 years.     

Celastrol increases glucocerebrosidase activity in Gaucher disease by modulating molecular chaperones

Gaucher disease is caused by mutations in the glucosidase, beta, acid gene that encodes glucocerebrosidase (GCase). Glucosidase, beta, acid mutations often cause protein misfolding and quantitative loss of GCase. In the present study, we found that celastrol, an herb derivative with known anticancer, anti-inflammatory, and antioxidant activity, significantly increased the quantity and catalytic activity of GCase. Celastrol interfered with the establishment of the heat-shock protein 90/Hsp90 cochaperone Cdc37/Hsp90-Hsp70-organizing protein chaperone complex with mutant GCase and reduced heat-shock protein 90-associated protein degradation. In addition, celastrol modulated the expression of molecular chaperones. Bcl2-associated athanogene 3 and heat shock 70kDa proteins 1A and 1B were significantly increased by celastrol. Furthermore, BAG family molecular chaperone regulator 3 assisted protein folding and maturation of mutant GCase. These findings provide insight into a therapeutic strategy for Gaucher disease and other human disorders that are associated with protein misfolding.Gaucher disease (GD), one of the most prevalent human metabolic storage disorders, is caused by inadequate glucocerebrosidase (GCase) (1, 2). Loss of GCase activity leads to accumulation of toxic amounts of glucocerebroside and glucosylsphingosine, causing metabolic dysfunction that eventually results in hepatosplenomegaly, cytopenias, bone disease, and, in some patients, central nervous system manifestations. Mutations in the glucosidase, beta, acid (GBA) gene that encodes GCase are the most common causes of GD (3–5). These mutations commonly result in amino acid substitutions in GCase that significantly reduce protein stability without disrupting intrinsic catalytic activity (6). Changes in the GCase peptide sequence alter the conformation of the protein making it vulnerable to degradation mechanisms involving Parkin, casitas b-lineage lymphoma (Cbl), heat-shock protein 90 (Hsp90), and the endoplasmic reticulum-associated degradation (ERAD) pathway (7). Moreover, modulating the pathways involved in the folding and degradation of mutant GCase has been shown to be effective in increasing its activity (8).Celastrol is derived from the root of Tripterygium Wilfordii (Thunder of God Vine) and Celastrus Regelii. It has been demonstrated to have antioxidant (9), anti-inflammatory (10), and anticancer (10–13) effects. Recent studies have shown that celastrol blocks protein degradation by inhibiting proteasomal function (13, 14) and prevents the degradation of mutant enzymes in certain lysosomal storage diseases (15). The molecular mechanisms by which celastrol exerts these effects, however, remain unknown. Zhang et al. (16, 17) showed that celastrol interferes with Hsp90 binding to Hsp90 cochaperone Cdc37 (Cdc37), suggesting that celastrol affects biologic processes by modulating molecular chaperones. Our recent discoveries in GD demonstrated that Hsp90 is not only a critical chaperone that assists protein folding but is also important in targeting the misfolded GCase for degradation (18, 19). Therefore, the potential therapeutic value of celastrol is of great interest in protein folding-related disorders.We investigated the effect of celastrol on GCase folding and degradation. Using two common GBA mutations in type I (N370S/N370S) and type II/III (L444P/L444P) GD, we found that celastrol increased the catalytic activity of mutant GCase. Celastrol interfered with the recruitment of Cdc37 to Hsp90 halting the assembly of the requisite chaperone complex. Inhibition of Hsp90 reduced its recognition of mutant GCase and therefore limited the proteasomal degradation of the mutant protein. Additionally, celastrol triggered a reorganization of the gene expression pattern of molecular chaperones such as DnaJ homolog subfamily B members 1 and 9 (DNAJB1/9), heat shock 70kDa proteins 1A and 1B (HSPA1A/B), and Bcl2-associated athanogene 3 (BAG3). The presence of BAG family molecular chaperone regulator 3 (BAG3) further stabilized the nascent GCase protein and assisted its folding and catalytic activity.     

Redox modification of cell signaling in the cardiovascular system

Oxidative stress is presumed to be involved in the pathogenesis of many diseases, including cardiovascular disease. However, oxidants are also generated in healthy cells, and increasing evidence suggests that they can act as signaling molecules. The intracellular reduction-oxidation (redox) status is tightly regulated by oxidant and antioxidant systems. Imbalance between them causes oxidative or reductive stress which triggers cellular damage or aberrant signaling, leading to dysregulation. In this review, we will briefly summarize the aspects of ROS generation and neutralization mechanisms in the cardiovascular system. ROS can regulate cell signaling through oxidation and reduction of specific amino acids within proteins. Structural changes during post-translational modification allow modification of protein activity which can result in altered cellular function. We will focus on the molecular basis of redox protein modification and how this regulatory mechanism affects signal transduction in the cardiovascular system. Finally, we will discuss some techniques applied to monitoring redox status and identifying redox-sensitive proteins in the heart. This article is part of a Special Section entitled "Post-translational Modification."     

Comparison of the Diamond-Forrester method and Duke Clinical Score to predict obstructive coronary artery disease by computed tomographic angiography

We sought to evaluate the ability of the Diamond and Forrester method (DFM) and the Duke Clinical Score (DCS) to predict obstructive coronary artery disease (CAD) on coronary computed tomographic angiography (CCTA) and the effect of these different risk scores on the appropriateness level using the 2010 Appropriate Use Criteria. Consecutive symptomatic patients who underwent CCTA for evaluation of CAD (n = 114) were classified as having a low, intermediate, or high pretest probability using the DFM and DCS. Using the Appropriate Use Criteria, the indications for CCTA were classified according to the pretest probability and previous testing. The CCTA results were classified as revealing obstructive (≥70% stenosis), nonobstructive (<70%), or no CAD. When the patients' risk was classified using the DFM, 18% were low, 65% intermediate, and 17% high risk. When using the DCS, 53% of patients had a reclassification of their risk, most of whom changed from intermediate to either low or high risk (50% low, 19% intermediate, 35% high risk). The net reclassification improvement for the prediction of obstructive CAD was 51% (p = 0.01). Of the 37 patients who were reclassified as low risk, 36 (97%) lacked obstructive CAD. Appropriateness for CCTA was reclassified for 13% of patients when using the DCS instead of the DFM, and the number of appropriate examinations was significantly fewer (68% vs 55%, p <0.001). In conclusion, reclassification of risk using the DCS instead of the DFM resulted in improved prediction of obstructive CAD on CCTA, especially in low-risk patients. More patients were categorized as having a high pretest probability of CAD, resulting in reclassification of their examination indications as uncertain or inappropriate. These results identify the need for improved pretest risk scores for noninvasive tests such as CCTA and suggest that the method of risk assessment could have important implications for patient selection and quality assurance programs.