Academic literature on the topic 'Atherosclerosis – Chemotherapy'

e12525 Background: Anthracyclines and monoclonal antibodies targeting HER2/neu receptors are widely used antineoplastic agents in breast cancer treatment. Both therapies have been known to cause cardiovascular adverse effects, notably chemotherapy-induced congestive heart failure, especially if used in combination. Multiple factors have been postulated to increase the risk of doxorubicin and trastuzumab-associated cardiotoxicity, including a pre-existing coronary artery disease, but the role of latent atherosclerosis has not been widely studied. Methods: We retrospectively reviewed health records of female breast cancer patients at our institution treated with doxorubicin or trastuzumab between 2012 and 2017. Using echocardiography, we identified patients with underlying atherosclerotic lesions at the start of the treatment and those who subsequently developed cardiotoxicity. Chemotherapy-induced cardiomyopathy was defined as a drop in the ejection fraction (EF) to < 50% from the normal EF of > 53% pre-therapy. We used a χ2 test to search for the relationship between atherosclerosis and subsequent cardiotoxicity. Results: A total of 518 patient records were reviewed. Of 518 patients with breast cancer, 93 (18%) received doxorubicin or trastuzumab-based chemotherapy. The median age for breast cancer diagnosis was 58. Sixty-one patients (66%) were identified to have atherosclerosis on echocardiography at the time of the first chemotherapy cycle. The most common location for atherosclerotic lesions was in the aortic arch and proximal upper abdominal aorta. Of 61 patients with atherosclerosis, ten (16.4%) subsequently developed chemotherapy-induced cardiomyopathy (p = 0.77). A post hoc analysis was performed to compare the two cohorts aged 40 to 50 (p = 0.49) and 51 to 75 (p = 1.00) as they represented the majority of breast cancer cases. Conclusions: The role of atherosclerosis in doxorubicin and trastuzumab-induced toxicity remains unclear. We did not observe any statistical correlation between atherosclerosis at the start of chemotherapy and increased rates of cardiac injury. A younger population may be more susceptible to cardiotoxicity, but further research is needed as the study has limitations. Although we identified patients with latent atherosclerosis, additional evaluation via carotid artery intima-media thickness measurements would yield more precision. Other methods such as the use of computed tomography and coronary artery calcium scores would also allow for assessing atherosclerotic plaque burden. Still, not all patients were subjected to these techniques. Furthermore, the study was challenged by the small sample size and its retrospective nature. Larger prospective studies are essential to explore this area further. Identifying the means of reducing cardiovascular complications remains a priority as heart disease is currently the leading cause of death among breast cancer survivors.

Abstract Cardiovascular disease is a well-described late effect of treatment for Hodgkin’s Disease (HD), generally attributed to high dose radiation therapy (RT) to the mediastinum and neck. Increased carotid artery intima-media thickness (CIMT), measured by ultrasound, is a valid marker of subclinical atherosclerosis and is associated with an increased risk of future vascular disease. We evaluated CIMT in 31 patients with HD, (22 males, 9 females), mean age 21 (range 9–39) years, between 2 and 241 months from diagnosis. Thirty patients received chemotherapy, including anthracyclines. Sixteen patients were treated with RT to the bilateral neck and mediastinum; 4 received high dose (36Gy) RT and 12 received lower dose (21–25Gy) RT. One patient received lower dose RT only to the bilateral neck. Fourteen patients were treated with chemotherapy alone. CIMT was assessed using a standardized scanning and reading protocol. The CIMT was calculated as the mean of the maximum measurement at 12 sites; near and far walls of the common carotid, bifurcation and internal carotid arteries bilaterally. The mean CIMT for the total cohort was 0.757mm. Among 5 patients (mean age 13, range 9–16 years), evaluated while actively receiving therapy or within one year from completion of therapy, mean CIMT was 0.715, equivalent to the mean CIMT found in healthy 30 year old adults (Stein, Stroke 2004). In a multivariate linear regression analysis CIMT was significantly associated with increasing time since diagnosis (p=0.035), age (p=0.016), and male gender (p=0.014). There was no difference in CIMT between those patients treated with chemotherapy alone vs. chemotherapy and radiation therapy. Subclinical atherosclerosis in patients with HD may evolve early in the course of treatment and survivorship and then increase with age and time from diagnosis. Type of treatment was not a significant predictor of CIMT in our cohort suggesting that factors other than RT play a role in the development of subclinical atherosclerosis. Further studies are needed to better elucidate the etiology of atherosclerotic disease in HD survivors. Screening with CIMT may detect subclinical atherosclerosis and allow for earlier intervention to prevent cardiovascular disease in this population.

Atherosclerosis is a chronic inflammatory disease caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a critical factor at all stages of atherosclerosis progression. Proinflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. Accordingly, strategies to inhibit immune activation and impede immune responses towards anti-inflammatory activity are an alternative therapeutic strategy to conventional chemotherapy on cardiocerebrovascular outcomes. Since a number of Chinese medicinal plants have been used traditionally to prevent and treat atherosclerosis, it is reasonable to assume that the plants used for such disease may suppress the immune responses and the resultant inflammation. This review focuses on plants that have immunomodulatory effects on the production of inflammatory cytokine burst and are used in Chinese traditional medicine for the prevention and therapy of atherosclerosis.

In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: −49% in LDE-PTX and −59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in −57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor α gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.

Testicular germ cell tumours are the most common malignancy in men aged 20 to 40 years. They are subdivided into seminoma and non-seminomatous germ cell tumours (NSGCTs). Both seminoma and NSGCT occur at about the same rate, however some tumours contain a combination of both. Cisplatin-based chemotherapy is used adjuvantly in high-risk stage 1 mixed and NSGCT patients and contributes towards oncological cure in almost all metastatic cases, regardless of histology. However, cardiovascular toxicity is a major concern. In addition to acute endothelial toxicity and associated risk of arterial thrombosis, accelerated atherosclerosis may be the result of chemotherapy-associated latent cardio-metabolic dysfunction. A 45-year-old man began treatment with cisplatin-based chemotherapy for testicular cancer. On day 9, he suffered an anterior ST segment elevation myocardial infarction (STEMI). There was proximal occlusion of the left anterior descending (LAD) artery but otherwise normal coronary arteries. Ten months following chemotherapy, he had another STEMI. There was a fresh obstructive lesion in the previously angiographically normal mid LAD, new diffuse coronary atheroma elsewhere and a deterioration in lipid profile despite statin therapy. Acute and longer-term cardiovascular risks of cisplatin-based chemotherapy may have different underlying pathophysiological mechanisms. These issues are of growing relevance in a population of patients expected to have excellent cancer-related outcomes.

[Formulae and special characters can only be approximated here. Please see the pdf version of the abstract for an accurate reproduction.] Atherosclerosis is a common degenerative disease in which the clinical manifestations are often through stroke or myocardial infarction. Some of the established risk factors for atherosclerosis include elevated plasma low-density lipoprotein (LDL)-cholesterol levels, obesity, diabetes mellitus (DM) and cigarette smoking. Of the risk factors, an elevation in plasma LDL is one of the most established and the most researched. This is partly a consequence of the deposition of cholesterol within arterial intima being a crucial step in the progression of atherosclerosis, combined with the finding that LDL particles are a major transporter of cholesterol in circulation. Recently there is increasing evidence showing a role of the other major transporter of cholesterol in circulation, chylomicron remnants, in the progression of atherosclerosis. The notion of atherosclerosis as a postprandial phenomenon has been further substantiated by the emergence of evidence showing a direct role of chylomicron remnants in arterial cholesterol deposition. Based on evidence that chylomicron remnants are proatherogenic, the suggestion arises that accumulation of postprandial lipoproteins in plasma may add another dimension of risk to the development of coronary artery disease (CAD). This thesis tests the general hypothesis that individuals with or at high risk of CAD have postprandial dyslipidaemia and that this metabolic abnormality is correctable with a class of lipid-lowering drugs called statins. To test the hypothesis, clinical studies were conducted in normolipidaemic CAD patients, heterozygous familial hypercholesterolaemia (FH) and postmenopausal women with type 2 DM. Determination of postprandial dyslipidaemia by comparison with control populations were conducted initially in each patient group (Studies 1, 3 and 5), followed by intervention studies investigating possible modulation of the dyslipidaemia with a statin (Studies 2, 4 and 6). Six observation statements based on case-control comparisons of postprandial lipaemia in patients with or at risk of CAD and the effects of statins on postprandial dyslipidaemia in the patient groups were derived from the general hypothesis. The observation statements were examined in the individual studies described below. Postprandial lipoprotein metabolism was assessed using a number of methods. For comparison of postprandial lipaemia in Studies 1 and 2, a classic oral fat challenge was utilised. As markers of chylomicrons and chylomicron remnants, retinyl palmitate and triglyceride were measured postprandially as well as apolipoprotein (apo) B48 concentrations, a specific marker of intestinal lipoproteins. ApoB48 was also measured in the fasting state and found to predict the postprandial responses of retinyl palmitate, triglyceride and apoB48. This suggested that fasting measurement of apoB48 could be used as a simple indicator of postprandial dyslipidaemia. Consequently for Studies 3 - 6, fasting apoB48 measurements were used as primary markers of postprandial dyslipidaemia. Other markers for chylomicrons and their remnants utilised were fasting plasma concentrations of remnant-like particle-cholesterol (RLP-C) and apoC-III. As well as these static markers, chylomicron remnant catabolism was measured using a stable isotope breath test. The breath test involves the intravenous injection of a chylomicron remnant-like emulsion labelled with ¹³C-oleate and measurement of enriched ¹³CO2 in expired breath by isotope ratio mass spectrometry. The fractional catabolic rate (FCR) of the injected emulsion was subsequently calculated using multi-compartmental modeling (SAAM II). The studies are presented in this thesis as published and unpublished works. In Study 1, postprandial lipoprotein metabolism was compared between 18 normolipidaemic CAD patients (cholesterol 4.54 ± 0.12 mmol/L, triglyceride 1.09 ± 0.16) with 13 asymptomatic healthy controls using an oral fat challenge. Normolipidaemic CAD patients had higher postprandial area-under-curve (AUC) for triglyceride (+34%, p=0.019), retinyl palmitate (+74%, p=0.032) and apoB48 (+36%, p<0.001). Fasting apoB48 was also higher (+41%, p=0.001) and found to correlate significantly with AUC of triglyceride (p=0.017), retinyl palmitate (p=0.001) and apoB48 (p<0.001). The data suggest that normolipidaemic CAD patients have increased concentrations of intestinal lipoproteins in the fasting and postprandial state. In addition to these findings, significant correlations of fasting apoB48 with postprandial markers (p<0.02) suggests the fasting marker to be a simpler surrogate marker for the degree of total postprandial lipaemia. Study 2 investigated the effect of atorvastatin treatment on postprandial dyslipidaemia found in the 18 near-normolipidaemic CAD patients from Study 1. The trial was conducted in a randomised, placebo-controlled design, using oral fat challenges before and after 12-weeks atorvastatin/placebo treatment. Compared with the placebo group, atorvastatin decreased the total postprandial AUC for iii triglyceride (-22%, p=0.05) and apoB48 (-34%, p=0.013). Fasting markers of apoB48 (-35%, p=0.019) and RLP-C (-36%, p=0.032) also decreased significantly. Atorvastatin was also found to increase LDL-receptor activity by +218% (p<0.001) as reflected in binding studies. The data suggest atorvastatin reduces the fasting levels of intestinal lipoproteins as well as total postprandial lipaemia, but without acute dynamic changes in postprandial lipaemia. The reduction in fasting and total postprandial lipoprotein levels could be partly attributed to an increase in LDL-receptor mediated removal from circulation. In Study 3, postprandial lipaemia was compared in 15 heterozygous FH patients with 15 healthy controls. FH patients had higher fasting concentrations of apoB48 (+56%, p<0.001) and RLP-C (+48%, p=0.003). The elevation in these fasting markers of chylomicrons and their remnants suggests FH patients have postprandial dyslipidaemia due to an accumulation of these particles in plasma. Study 4 examined the effects of long- (> 6 months) and short-term (4 weeks) simvastatin treatment on modulating postprandial dyslipidaemia found in the 15 FH patients from Study 3. Short- and long-term simvastatin treatment decreased the fasting concentrations of apoB48 (-29% and 15% respectively, p<0.05) and RLP-C (both -38%, p<0.001), but did not significantly alter the FCR of the injected chylomicron remnant-like emulsion. The data suggest that in heterozygous FH both long- and short-term simvastatin treatments decrease the fasting markers of postprandial lipoproteins by mechanisms that may not be mediated via processes differentiated by the 13CO2 breath test. This implies that the effect on postprandial lipaemia may be from a decrease in production and/or a possible increase in catabolism of triglyceride-rich lipoproteins (TRLs). In Study 5, postprandial lipaemia was compared in 24 postmenopausal women age and body mass index matched with 14 postmenopausal women with type 2 DM. Postmenopausal diabetic women were found to have higher fasting concentrations of apoB48 (+21%, p=0.021) and apoC-III (+16%, p=0.042) as well as lower FCR of the chylomicron remnant-like emulsion (-50%, p<0.001). The data suggest that postmenopausal diabetic women have postprandial dyslipidaemia, and that this is due to delayed catabolism of chylomicron remnants. Study 6 was an hypothesis-generating exercise examining the effects of 4-weeks pravastatin treatment on postprandial dyslipidaemia found in 7 postmenopausal women with type 2 DM from Study 5. Although plasma LDL-cholesterol was reduced (-19%, p=0.028), there were no significant effects found on fasting apoB48 concentrations (-12%, p=0.116) or the FCR of the chylomicron remnant-like emulsion (+38%, p=0.345). A larger sample size of patients and/or treatment with a more potent statin at a dosage known to affect chylomicron remnant metabolism would be required to demonstrate a significant reduction in postprandial dyslipidaemia in postmenopausal women with type 2 DM. The results of the above mentioned studies combined support the general hypothesis that postprandial dyslipidaemia is a feature of patients with or at risk of CAD. This defect may be demonstrated using fasting apoB48 as an indicator of the degree of postprandial lipaemia. Postprandial dyslipidaemia may reflect a reduction in catabolism, as suggested with the breath test in type 2 DM, and/or an over overproduction of chylomicrons. Both these mechanisms would also increase competition for lipolysis and clearance pathways between hepatically and intestinally-derived lipoproteins. The exact mechanisms by which postprandial dyslipidaemia occurs are yet to be determined. Statins appear to improve defective postprandial lipaemia in patients with or at risk of CAD, which is in agreement with the general hypothesis. The effectiveness of a statin is dependant on their potency in inhibiting cholesterol biosynthesis and increasing receptor mediated clearance of LDL and chylomicron remnants. The studies conducted in this thesis show that postprandial dyslipidaemia can be reduced by statins but not to the extent demonstrated in controls. However, the demonstrated reduction in fasting and total postprandial lipaemia translates to a lowering in overall arterial exposure to circulating proatherogenic particles. The elevation in fasting and postprandial levels of proatherogenic chylomicron remnants found in the patient groups described in this thesis indicates another dimension to their risk of coronary disease. The reductions in the overall levels of proatherogenic particles in patients with or at high CAD risk, infers a possible reduction in the risk of coronary disease in these patients.

Chan Yin Ling.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (leaves 147-167).
Abstracts in English and Chinese.
ABSTRACT --- p.III
ACKNOWLEDGEMENT --- p.X
TABLE OF CONTENTS --- p.XI
ABBREVIATIONS --- p.XV
LIST OF FIGURES --- p.XVII
LIST OF TABLES --- p.XXI
Chapter CHAPTER 1 --- INTRODUCTION --- p.1
Chapter 1.1 --- Introduction to Cardiovascular Disease and Atherosclerosis --- p.1
Chapter 1.1.1 --- Cardiovascular Disease --- p.1
Chapter 1.1.2 --- A therosclerosis --- p.3
Chapter 1.1.2.1 --- Structure of Arteries --- p.4
Chapter 1.1.2.2 --- Pathophysiology of Atherosclerosis --- p.5
Chapter 1.1.2.3 --- Endothelial Dysfunction --- p.8
Chapter 1.1.3 --- Current Western Therapies --- p.11
Chapter 1.1.3.1 --- Surgery --- p.11
Chapter 1.1.3.2 --- Western Medications --- p.13
Chapter 1.1.4 --- Traditional Chinese Medicine --- p.17
Chapter 1.1.4.1 --- Long History --- p.17
Chapter 1.1.4.2 --- As Alternative Medicine --- p.18
Chapter 1.1.4.3 --- Modernization of Chinese Medicine --- p.19
Chapter 1.2 --- Introduction and Selection of Chinese Medicine --- p.20
Chapter 1.2.1 --- Selection ofTCM Formulation from Pharmacopoeia --- p.20
Chapter 1.2.1.1 --- Compound Formulation --- p.20
Chapter 1.2.2 --- Introduction to the Herbal Medicines --- p.21
Chapter 1.2.2.1 --- Danshen (Salvia miltiorrhiza) --- p.21
Chapter 1.2.2.2 --- Gegen (Puerariae thomsonii and Puerariae lobata) --- p.22
Chapter 1.2.2.3 --- Yanhu (Corydalis yanhusuo) and its Exclusion --- p.24
Chapter 1.2.3 --- Source and Authentication of the Herbal Medicines --- p.25
Chapter CHAPTER 2 --- OPTIMIZATION OF DANSHEN-GEGEN FORMULA --- p.26
Chapter 2.1 --- Project History --- p.26
Chapter 2.2 --- aims for the present study --- p.27
Chapter 2.3 --- Methods and Materials --- p.30
Chapter 2.3.1 --- Extracts --- p.30
Chapter 2.3.2 --- Extraction Process --- p.31
Chapter 2.3.3 --- In vitro Antioxidation Model --- p.33
Chapter 2.3.4 --- Ex vivo Vasodilation Model --- p.35
Chapter 2.3.5 --- Statistical Analysis --- p.38
Chapter 2.4 --- Results --- p.39
Chapter 2.4.1 --- Vasodilation Results --- p.39
Chapter 2.4.2 --- Antioxidation Results --- p.43
Chapter 2.5 --- Discussion --- p.46
Chapter 2.6 --- Further Modification of the Formula --- p.49
Chapter 2.6.1 --- Extracts --- p.49
Chapter 2.6.2 --- Results --- p.49
Chapter 2.7 --- discussion --- p.52
Chapter CHAPTER 3 --- MARKER CHEMICAL CONTENTS OF HERBAL EXTRACTS AND THEIR PHARMACOLOGICAL PROPERTIES --- p.56
Chapter 3.1 --- HPLC Analysis of Marker Contents --- p.56
Chapter 3.1.1 --- Methods --- p.57
Chapter 3.1.2 --- Results --- p.58
Chapter 3.1.2.1 --- HPLC Chromatograms --- p.59
Chapter 3.1.2.2 --- Content Percentage of Marker Compounds --- p.63
Chapter 3.1.3 --- Discussion --- p.64
Chapter 3.2 --- Studies on Marker Compounds --- p.65
Chapter 3.2.1 --- Introduction --- p.65
Chapter 3.2.2 --- Methods and Materials --- p.67
Chapter 3.2.2.1 --- Source of Pure Compounds --- p.67
Chapter 3.2.2.2 --- Purification and Identification of SAB --- p.68
Chapter 3.2.2.3 --- Vasodilation model --- p.70
Chapter 3.2.2.4 --- Antioxidation Model --- p.71
Chapter 3.2.2.5 --- Structures of Pure Compounds --- p.72
Chapter 3.2.3 --- Results --- p.73
Chapter 3.2.3.1 --- Vasodilation Results --- p.73
Chapter 3.2.3.2 --- Antioxidation Results --- p.76
Chapter 3.3 --- Discussion --- p.79
Chapter 3.4 --- Synergistic Effect Study --- p.85
Chapter 3.4.1 --- Introduction --- p.85
Chapter 3.4.2 --- Methods --- p.85
Chapter 3.4.3 --- Results --- p.86
Chapter 3.4.4 --- Discussion --- p.88
Chapter 3.5 --- STUDY ON 3'-HYDROXYPlIERARIN AND 3'-METHOXYPUERARIN PURIFIED FROM YFGE --- p.90
Chapter 3.5.1 --- 3 '-hydroxypuerarin and 3'-methoxypuerarin --- p.90
Chapter 3.5.2 --- Methods and Materials --- p.91
Chapter 3.5.2.1 --- Purification by HPLC semi-preparation --- p.91
Chapter 3.5.2.2 --- Bioassays --- p.93
Chapter 3.5.3 --- Results --- p.94
Chapter 3.5.3.1 --- Vasodilation Study --- p.94
Chapter 3.5.3.2 --- Antioxidative Effect of Yege --- p.95
Chapter 3.5.4 --- Discussion
Chapter CHAPTER 4 --- MECHANISTIC STUDY --- p.98
Chapter 4.1 --- Introduction --- p.98
Chapter 4.1.1 --- Nitric Oxide-mediated Vasodilation --- p.99
Chapter 4.1.2 --- Prostacyclin-mediated Vasodilation --- p.100
Chapter 4.1.3 --- EDHF-mediated Vasodilation --- p.101
Chapter 4.1.4 --- Endothelium-dependent and -independent Vasodilations --- p.103
Chapter 4.2 --- Methods and Materials --- p.104
Chapter 4.3 --- Results --- p.107
Chapter 4.3.1 --- Danshen-Gegen Formula (DY80) --- p.107
Chapter 4.3.2 --- Salvianolic acid B --- p.112
Chapter 4.3.3 --- Daidzein --- p.117
Chapter 4.4 --- Discussion --- p.121
Chapter CHAPTER 5 --- STUDY ON LIPID PEROXIDATION AND UPTAKE BY MACROPHAGES --- p.128
Chapter 5.1 --- Study of DY 80 and SAB on Copper-ion induced Low Density Lipoprotein Oxidation --- p.128
Chapter 5.1.1 --- Pathologic Role of oxidized Low Density Lipoprotein --- p.128
Chapter 5.1.2 --- Antioxidants in Low Density Lipoprotein and Role of Transition Metals --- p.129
Chapter 5.1.3 --- Methods and Materials --- p.130
Chapter 5.1.4 --- Results --- p.131
Chapter 5.1.5 --- Discussion --- p.133
Chapter 5.2 --- Study of Scavenger Receptor Regulation in Macrophages --- p.135
Chapter 5.2.1 --- Introduction --- p.135
Chapter 5.2.2 --- Methods and Materials --- p.136
Chapter 5.2.3 --- Results --- p.139
Chapter 5.2.4 --- Discussions --- p.140
Chapter CHAPTER 6 --- General Discussion --- p.143
REFERENCES --- p.147