Aims Clinicians use multi-gene/biomarker prognostic tests and free online tools to optimize treatment in early ER+/HER2− breast cancer. Here we report the comparison of recurrence risk predictions by CanAssist Breast (CAB), Nottingham Prognostic Index (NPI), and PREDICT along with the differences in the performance of these tests across Indian and European cohorts. Methods Current study used a retrospective cohort of 1474 patients from Europe, India, and USA. NPI risk groups were categorized into three prognostic groups, good (GPG-NPI index ≤ 3.4) moderate (MPG 3.41–5.4), and poor (PPG > 5.4). Patients with chemotherapy benefit of < 2% were low-risk and ≥ 2% high-risk by PREDICT. We assessed the agreement between the CAB and NPI/PREDICT risk groups by kappa coefficient. Results Risk proportions generated by all tools were: CAB low:high 74:26; NPI good:moderate:poor prognostic group- 38:55:7; PREDICT low:high 63:37. Overall, there was a fair agreement between CAB and NPI[κ = 0.31(0.278–0.346)]/PREDICT [κ = 0.398 (0.35–0.446)], with a concordance of 97%/88% between CAB and NPI/PREDICT low-risk categories. 65% of NPI-MPG patients were called low-risk by CAB. From PREDICT high-risk patients CAB segregated 51% as low-risk, thus preventing over-treatment in these patients. In cohorts (European) with a higher number of T1N0 patients, NPI/PREDICT segregated more as LR compared to CAB, suggesting that T1N0 patients with aggressive biology are missed out by online tools but not by the CAB. Conclusion Data shows the use of CAB in early breast cancer overall and specifically in NPI-MPG and PREDICT high-risk patients for making accurate decisions on chemotherapy use. CAB provided unbiased risk stratification across cohorts of various geographies with minimal impact by clinical parameters.
Molecular effects of sterol-enriched wheat bran oil (eWBA) on lipid metabolism, inflammatory markers, and liver proteome associated with nonalcoholic/metabolic-related fatty liver disease (MAFLD) are not completely known. In this study, dietary eWBA intervention was used to investigate its effect in ameliorating liver injury in high fat diet (HFC)-fed C57BL/6 mice. Specifically, we examined eWBA's effects on (i) differentially expressed hepatic factors which regulate carbohydrate and lipid homeostasis markers, such as sterol regulatory element-binding protein-2 (SREBP-2), peroxisome proliferator-activated receptors-γ (PPARγ), pro-protein convertase subtilisin/kexin type-9 (PCSK9), low-density lipoprotein receptor (LDL-R), and apolipoprotein-E (APO-E) factors, and (ii) levels of two cytokines, tumor necrosis factor (TNF-α) and transforming growth factor beta (TGF-β). Liver of HFC-fed mice exhibited characteristic features of MAFLD, such as increased liver injury serum markers (SGOT, SGPT), liver lipids, and PCSK9 protein. Mice fed eWBA-supplemented HFC exhibited amelioration of serum cholesterol, triglycerides, SGOT, and SGPT levels as well as a reduction in liver lipids and PCSK9 and SREBP-2 proteins. Pro-inflammatory and profibrogenic cytokines in the liver of the groups fed with eWBA -supplemented HFC were normalized with respect to the group without eWBA. To conclude, eWBA reduces the expression of SREBP-2, APO-E, and PCSK9 in the liver which down regulates various signal molecules thereby ameliorates liver injury in a mouse model of MAFLD. Down-regulated FAS and ZNF-236 of liver proteins with eWBA intervention could be the initial markers for steatosis.
Glycosaminoglycans (GAGs) play an important role in lipoprotein metabolism. In liver, it facilitates the uptake of remnants through receptor-independent endocytosis. However, changes in liver GAGs during diet-induced hypercholesterolemia with normal levels of fat feeding are unknown. Present paper highlights the effect of diet-induced hypercholesterolemia with normal levels (5%) of fat on liver GAGs and other associated lipoprotein receptors. Hypercholesterolemia was induced in rats by feeding diet supplemented with 0.5% cholesterol and 0.125% bile salts. Hypercholesterolemia showed significantly decreased GAGs of both heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS) classes of molecules. Quantitative real-time polymerase chain reaction analysis of GAG biosynthetic enzymes and other genes revealed significant changes in expression profile. The decrease in GAGs was prevented by simvastatin treatment; a drug that inhibits endogenous cholesterol synthesis that was used as a positive control in our study. Furthermore, there was a comparatively decreased binding of GAGs from hypercholesterolemic rats to lipoprotein lipase. LRP1 which plays a major role in lipoprotein uptake was also significantly decreased, and it was attenuated in simvastatin-treated hypercholesterolemic rats. Furthermore, LDLR and ApoE were also decreased significantly in liver of hypercholesterolemic rats. Thus, diet-induced hypercholesterolemia results in dysregulation of cholesterol homeostasis apparently through changes in GAGs in conjunction with other associated players.
Hypercholesterolemia is one of the factors contributing to cardiovascular problems. Erythrocytes are known to contribute its cholesterol to atherosclerotic plaque. Our earlier study showed that erythrocytes overexpress chondroitin sulphate/dermatan sulphate (CS/DS), a linear co-polymer, during diabetes which resulted in increased cytoadherence to extracellular matrix (ECM) components. This study was carried out to determine whether diet-induced hypercholesterolemia had any effect on erythrocyte CS/DS and impacted cytoadherence to ECM components. Unlike in diabetes, diet-induced hypercholesterolemia did not show quantitative changes in erythrocyte CS/DS but showed difference in proportion of un-sulphated and 4-O-sulphated disaccharides. Erythrocytes from hypercholesterolemic rats showed increased adhesion to ECM components which was abrogated to various extents when subjected to chondroitinase ABC digestion. However, isolated CS/DS chains showed a different pattern of binding to ECM components indicating that orientation of CS/DS chains could be playing a role in binding.
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