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Fulltext Microvessel density and vascular endothelial growth factor receptors in breast carcinoma under the influence of rapamycin and platelet factor 4

Muhammad Sakri MS, Abdul Rahman WFW, Tengku Din TADA, Idris FM, Jaafar H

Indian J Pathol Microbiol, 2020 4 23;63(2):205-209.
PMID: 32317516 DOI: 10.4103/IJPM.IJPM_496_19

Background: Vascular endothelial growth factor receptors (VEGFRs) are major endothelial growth factor receptors that influence the growth of a tumor. Microvessel density.
(: MVD) is the quantification method of various aspects of tumor vasculature that indicates angiogenic activity. This study aims to analyze the correlation between MVD to the expression of VEGFRs on breast cancer tissue.
Materials and Method: A total of 60 N-methyl-N-nitrosourea (MNU)-induced breast carcinomas in rats were suppressed by using antiangiogenic drugs. The rats were then sacrificed, and the tumor was fixed in 10% formalin, paraffin embedded, and immunohistochemistry stained using VEGFRs and CD34.
Result: One-way ANOVA test showed a significant difference in all markers that have been used (P < 0.05) on MNU-breast tumor treated with rapamycin (M= 90.1664, SD= 7.4487), PF4 (M= 93.7946, SD= 7.1303) and rapamycin + PF4 (M= 93.6990, SD= 1.8432). We obtained a significant reduction of MVD count on breast carcinoma for rapamycin group (M= 25.6786, SD= 9.7075) and rapamycin + PF4 group (M= 30.5250, SD= 13.6928) while PF4 group (M=47.7985, SD=4.8892) showed slightly increase compared to control (M= 45.1875, SD= 4.4786). There was a moderately strong, positive correlation between angiogenic markers; Flt-1 (r= 0.544, n=60, P < 0.005) and Flt-4 (r= 0.555, n= 60, P < 0.005) while Flk-1 (r= 0.797, n= 60, P < 0.005) showed a strong, positive correlation with MVD.
Conclusion: MVD was strongly correlated to the VEGFRs expression on breast carcinoma.

Matched MeSH terms: Sirolimus/therapeutic use*
Safety and effectiveness of the self-aPposing, bAlloon-delivered, siRolimus-eluting stent for the Treatment of the coronary Artery disease: SPARTA, a multicenter experience

Montefusco A, De Filippo O, Gili S, Mancone M, Calcagno S, Cirillo P, et al.

Coron Artery Dis, 2020 01;31(1):27-34.
PMID: 31658146 DOI: 10.1097/MCA.0000000000000790

AIMS: To assess the long-term outcomes of patients treated with sirolimus-eluting Stentys stent in a real-life setting.
BACKGROUND: Few data regarding the safety and effectiveness of self-apposing sirolimus-eluting Stentys stent are available.
METHODS: 278 patients (30% stable coronary artery disease, 70% acute coronary syndromes, and 54% on unprotected left main) treated with sirolimus eluting Stentys stent were retrospectively included in the self-aPposing, bAlloon-delivered, siRolimus-eluting stent for the Treatment of the coronary Artery disease multicenter registry. Major adverse cardiovascular events (MACE, a composite of cardiac death, myocardial infarction, target lesion revascularization, stent thrombosis) were the primary end-point, single components of MACE were the secondary ones.
RESULTS: After 13 months (interquartile range 5-32), MACE was 14%. Stent thrombosis occurred in 3.9% of the patients (2.5% definite stent thrombosis and 1.4% probable stent thrombosis), 66% of them presenting with ST-segment elevation myocardial infarction (STEMI) at admission. Cardiovascular death, target lesion revascularization and myocardial infarction was 4.7%, 8.3%, and 7.2%, respectively. At multivariate analysis, risk of MACE was increased by diabetes (hazard ratios 4.76; P = 0.002) but was not affected by the indication leading to sirolimus-eluting Stentys stent implantation (marked vessel tapering vs. coronary ecstasies, hazard ratios 0.74, P = 0.71).
CONCLUSION: Sirolimus-eluting Stentys stent may represent a potential solution for specific coronary anatomies such as bifurcation, ectasic, or tapered vessels. Risk of stent thrombosis appears related to clinical presentation with STEMI and to anatomic features, stressing the importance of the use of intracoronary imaging for self-expandable stents implantation.

Matched MeSH terms: Sirolimus/administration & dosage
Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells

Chew GS, Myers S, Shu-Chien AC, Muhammad TS

Mol Cell Biochem, 2014 Mar;388(1-2):25-37.
PMID: 24242046 DOI: 10.1007/s11010-013-1896-z

Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPARα). Currently, there is a growing interest in determining the role of PPARα in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPARα are limited. We previously revealed that IL-6 inhibits PPARα gene expression through CAAT/enhancer-binding protein transcription factors in hepatocytes. In this study, we determined that STAT1/3 was the direct downstream molecules that mediated the Janus kinase 2 (JAK2) and phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in IL-6-induced repression of PPARα. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPARα protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPARα mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPARα promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPARα promoter activity. In the presence of inhibitors of JAK2 and mTOR (AG490 and rapamycin, respectively), IL-6-regulated protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited simultaneously, and the IL-6-induced repression of PPARα protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPARα gene transcription, involving the modulation of JAK2/STAT1-3 and PI3K/AKT/mTOR by inducing the binding of STAT1 and STAT3 to STAT-binding sites on the PPARα promoter. Together, these findings represent a new model of IL-6-induced suppression of PPARα expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPARα mRNA expression.

Matched MeSH terms: Sirolimus/pharmacology
Fulltext Unrestricted use of polymer-free sirolimus eluting stents in routine clinical practice

Krackhardt F, Kočka V, Waliszewski M, Toušek P, Janek B, Trenčan M, et al.

Medicine (Baltimore), 2020 Feb;99(8):e19119.
PMID: 32080086 DOI: 10.1097/MD.0000000000019119

Stent designs with ultrathin struts may further increase the procedural success of challenging lesion subsets. The objective of this study was to assess the safety and efficacy of ultrathin strut, polymer-free sirolimus eluting stent (PF-SES) implantations in a large scale, unselected patient population.Adult patients underwent percutaneous coronary interventions (PCI) with a thin-strut PF-SES. Data from two all-comers observational studies having the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled. The accumulated target lesion revascularization (TLR) rate at 9-12 months was the primary endpoint. All dual antiplatelet therapy strategies according to the applicable guidelines were permissible.In total, 7243 patients were prospectively enrolled for PCI with PF-SES in stable coronary artery disease or acute coronary syndrome (ACS). Major risk factors in the overall cohort were diabetes (37.3%), ST elevation myocardial infarction (18.1%) and non-ST myocardial infarction (24.6%). The follow-up rate was 88.6% in the overall population. The TLR rate in the overall cohort was 2.2% whereas definite/probable stent thrombosis (ST) occurred in 0.7%. In patients with in-stent restenosis lesions, the major adverse cardiac events rate was 6.4% whereas the corresponding rate for isolated left main coronary artery (LMCA) disease was highest with 6.7% followed by patients with culprit lesions in vein bypasses (VB, 7.1%). The mortality rate in patients treated in VB lesions was highest with 5.4%, followed by the isolated LMCA subgroup (3.4%) and ACS (2.6%).PCI with PF-SES in an unselected patient population, is associated with low clinical event and ST rates. Furthermore, PF-SES angioplasty in niche indications demonstrated favorable safety and efficacy outcomes with high procedural success rates.

Matched MeSH terms: Sirolimus/therapeutic use*
Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73

Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, et al.

Breast Cancer Res Treat, 2011 Jul;128(2):301-13.
PMID: 20686837 DOI: 10.1007/s10549-010-1055-0

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.

Matched MeSH terms: Sirolimus/administration & dosage