AMG 900 can be an common pot aurora kinase inhibitor with extreme capability for many 3 aurora kinases, but little off-target inhibition. Preclinical investigation of individual agent AMG 900 demonstrated inhibition of growth in 26 tumefaction cell lines of both strong and hematologic malignancies, including cell lines resistant to paclitaxel and other AKIs. The initial in phase I study in advanced solid tumors happens to be ongoing. buy Enzalutamide 28 VE 465 A skillet aurora kinase chemical linked to MK0457, VE 465 inhibits a bunch of off target kinases beyond aurora kinases at clinically relevant doses. . 140 Pre-clinical tissue culture cells and murine xenograft designs verify action in CML as single agent and with imatinib140, multiple myeloma 141, hepatocellular carcinoma142, ovarian cancer 143, and myeloid leukemia144. Presently, no studies in humans are continuing. 28 5. 7 AS703569/R 763 Discovered through cell based approach for drug design, AS703569 is an orally available aurora kinase that exhibits potent off-target inhibition of FLT3, BCR Abl, VEGFR 2, IGFR, Akt. 145 Pre-clinical research in cell cultures and murine xenografts displays antiproliferative Organism activity in solid wood and hematologic cancers including non small cell lung, breast, pancreas adenocarcinoma, colorectal adenocarcinoma, prostate, cervix, ovary, osteogenic sarcoma, biphenotypic leukemia, acute promyelocytic leukemia, ALL, AML, CML, and MM. The first phase I study of AS703569 in humans was conducted utilizing a two arm, doseescalation program in patients with high level solid malignancies. The very first arm administered AS703569 on days 1 and 8 every 21 days and the second arm administered AS 703569 on days 1, 2 and 3 every 21 days as a single oral dose. Fifteen people were enrolled with the most common malignancies being uterine and breast carcinomas. At study guide, no supplier Tipifarnib DLT or MTD had been established and 1 patient experienced tumorprogression while on study. A second study also considered 2 different dosing schedules in patients with hematological malignancies. 149 Forty-three whole patients were assigned to receive AS703569 once daily on days 1 3 and 8 10 every 21 days or once daily on days 1 6 actually 21 days. The majority of patients had de novo AML or secondary AML. The MTD for both administration agendas was determined to become 37mg/m2/day, with mucositis and neutropenia offering as DLT. PK information established a Tmax of 2 4 hours and t1/2 of 10 20 hours. 10 showing greater quantity of objective responses within this small cohort and task was simple with plan of administration on days 1 3. A few clinical studies in both strong and hematologic malignancies, including mixture reports with chemotherapy are either ongoing or recently completed.

There is a correlation between your 6E10 reactive area and the numbers of GFAP cells in individual animals. AD is usually a slowly developing condition that is difficult to diagnose, especially in the early stages. At the start of the CI 1011 treatment, the aged mice had plentiful amyloid pathology but CI 1011 treatment paid off the total amyloid load in their brains. Thick key plaques were only moderately affected, whereas calm plaques were more considerably paid down in CI 1011 treated rats. This effect natural product library resembles those in tet off APP rats suggesting that thick core plaques, containing W pleated sheet amyloid structures, are specially stable structures. For that reason, effective treatments for AD might require a combination of reduced AB creation and improved clearance of active plaques. In CI 1011 treated aged mice, the diffuse, 6E10 peripheral regions of the dense core plaques were very nearly entirely dissolved leaving just the dense cores whole while not exactly total suppression of new AB generation in tet off APP mice after growth of plaque pathology was not adequate to advertise settlement of diffuse or dense core plaques, Urogenital pelvic malignancy even after 6 months. Ergo, it’s possible that as well as inhibiting AB generation, CI 1011 might increase endogenous AB clearance. Moreover, the level and lipidation status of mind ApoE highly affects AB deposition. Our finding of reduced brain ApoE in CI 1011 treated hAPP rats shows that in addition to reduced AB generation, deposit of existing AB into plaques might be reduced upon ACAT inhibition. The participation of microglia within the clearance of brain amyloid plaques remains controversial and seems to depend on their activation phenotype. We show immunohistochemical proof of microglial activation that coincided with decreased amyloid load in CI 1011 handled old hAPP mice. The nature of CI 1011 caused clearance result towards diffuse amyloid is somewhat reminiscent of clearance of diffuse amyloid deposits by external application of anti AB antibodies in Tg2576 mice. Apparently, in reports where intra order Ibrutinib hippocampal lipopolysaccharide shots were used to boost microglial activation in plaque keeping 11 and 16 month old APP PS1 rats, efficient area specific clearance of diffuse amyloid deposits was discovered while dense primary plaques remained unchanged. . These results are very similar to our present results and support the conclusion that clearance of diffuse amyloid deposits is probably mediated by activated microglia. We evaluated activated microglia solely on the basis of Iba 1 immunoreactivity, which has no bearing on the practical phenotype of microglia, even though our data suggest recruitment of activated microglia in plaque surroundings.

Additivity was identified by the big difference in the region under the curve between the control and gemcitabine AZD7762 being not significantly different from the amount of the differences between the control and gemcitabine or AZD7762 alone using a two way ANOVA design with natural product library an interaction term. For H2AX, data were analyzed using ANOVA. Estimates of differences between means, means, and statistical significance were all produced from the ANOVA model. For in vivo tumor development, tumor volume doubling was established for each xenograft by determining the earliest day on which it was at the very least twice as large as on the first day of treatment. A cubic smoothing spline was used to obtain the actual time of doubling, and the Kaplan Meier method was used to analyze the doubling times derived from the smoothed growth curves. Log rank test was employed for comparisons between any two treatment groups. Benefits AZD7762 radiosensitizes pancreatic cancer cells through inhibition of Chk1 To start to find out if the inhibitor, AZD7762 is a radiation sensitizer we handled MiaPaCa 2 pancreatic cancer cells with low cytotoxic levels of gemcitabine and AZD7762 based on the schedule illustrated Gene expression in Fig. 1A and then examined light success with a clonogenic assay. We discovered that AZD7762 alone significantly sensitized MiaPaCa 2 cells to radiation, making a RER of 1. 5 0. 08. The mixture of AZD7762 with gemcitabine more improved radiosensitization beyond that observed with gemcitabine alone. AZD7762 and gemcitabine produced additive effects on radiosensitization over a variety of gemcitabine concentrations and under conditions which produced small to significant cytotoxicity. The cytotoxicity produced by AZD7762 in combination with 50 nM gemcitabine was significantly greater than that caused by exactly the same concentration of gemcitabine or AZD7762 alone, which can be consistent with our previous Lenalidomide clinical trial information demonstrating chemosensitization by Chk1 inhibition. We obtained similar information in MPanc96 cells where AZD7762 produced sensitization to radiation and gemcitabine radiation. To verify that AZD7762 inhibits Chk1/2 inside our models, we examined Chk1 and Chk2 signaling. As expected, we discovered that Chk1 autophosphorylation was restricted and that Cdc25A was stabilized by AZD7762 in reaction to gemcitabine, radiation, or gemcitabine radiation. Taken together these results show that AZD7762 inhibits Chk1. ATR and ATM mediated phosphorylation of Chk1 and Chk2 were increased by the addition of AZD7762 to gemcitabine and/or radiation, probably a result of the increased level of DNA damage current under these treatment conditions. We used siRNA to selectively deplete Chk1 or Chk2 from MiaPaCa 2 cells, to handle the relative contributions of inhibition of Chk1 or Chk2 by AZD7762 to radiosensitization. In accordance with non specific siRNA addressed cells, the Chk1 depleted cells were sensitized to light equally as the Chk2 depleted cells weren’t.

To evaluate the responsiveness of the CYP2C causes to induction by xenobiotics and the performance of putative sensitive factors, transient transfection has generally been conducted in hepatic carcinoma cell lines such as HepG2 or human primary hepatocytes. Both CAR/PXR REs seem to contribute to service of the promoter by PXR and CAR, however the site at 1839 is more important. While mutation of the PXR binding site at fi1839 bp alone very nearly eliminated rifampicin/PXR mediated promoter activation, Evacetrapib LY2484595 For example, mutation of the CAR/PXR RE at fi2897 alone lowered rifampicin/PXR activation by 30%. This information shows that the site at 1839 bp is important for induction, as the site at 2897 co-operates with the site at 1839 bp. The CAR/PXR RE at 1839 is further proved to be necessary for transactivation in the context of the 12kb CYP2C9 advocate by PXR and rifampicin in HepG2 cells. While activation of the promoter by PXR/rifampicin and CAR in HepG2 cells was more moderate than the activation of the CYP2C9 promoter, this activation was completely abolished by mutation of the CAR/PXR RE at 1892/ 1877. Mutation Metastasis of the CAR/PXR RE of CYP2C8 at 8805/ 8790 totally abolished induction of CYP2C8 promoter activity by CITCO and rifampicin in primary human hepatocytes, but mutation of the putative site at 2796/ 2780 had no impact on promoter activation, suggesting that only the distal site is involved in activation of the CYP2C8 gene by CAR and PXR ligands. Each CYP2C promoter has also been proven to be activated by GR and its ligand dexamethasone via one GRE which is located within the first 2kb of the three causes. The induction by dexamethasone was greater for CYP2C9 than for 2C8 and 2C19 in transfection assays in HepG2 cells. Mutation of the GR aspects of CYP2C9, CYP2C19, and CYP2C8 canceled Chk2 inhibitor dexamethasone induction. Because 2C9 and 2C19 share the same GRE, the varying degree of dexamethasone induction on the list of three CYP2C genes is independent of the element it self. Maybe supporter framework or nucleotides flanking the GRE can play a role. Just the CYP2C9 gene has been examined for upregulation by the VDR ligand 1,25 2D3 in human primary hepatocytes. The proximal CAR/PXR RE at 1839/ 1824 binds VDR in vitro. When this element was transfected into HepG2 cells and linked to the TK promoter, a modest but reproducible induction by 1,25 2D3 was noticed in VDR transfected HepG2 but not in VDR nontransfected cells. However, the TK promoter is a strong promoter, and the part of this VDR RE in the induction of CYP2C9 by 1, 25 dihydroxyvitamin D3 has not been established in the context of the original CYP2C9 promoter. It is of note that the CAR/PXR REs in the promoters of most three human CYP2C genes are activated by both CAR or PXR, and gel shift assays confirm that both receptors bind strongly to the determined sensitive elements within the human CYP2C gene promoters.

RV afterload reduction would depend on pulmonary vasodilation. Hesperadin, an inhibitor of human Aurora W, prevented the phosphorylation of substrate with IC50 of 40 nM. Growth of cultured system forms was also sensitive and painful to Hesperadin. Hesperadin blocked nuclear division and cytokinesis, although not other aspects of the cell order Dasatinib cycle. Consequently, growth arrested cells accumulated multiple kinetoplasts, flagella and nucleoli, like the effects of RNAi dependent knockdown of TbAUK1 in classy BF cells. Molecular designs believed high affinity binding of Hesperadin to both preserved and fresh sites in TbAUK1. Collectively, these data demonstrate that cell cycle progression is important for infections with T. brucei, and that parasite Aurora kinases may be targeted with small molecule inhibitors. Keywords Trypanosoma brucei, Aurora kinase, mitosis, histone H3, histone H2B, Hesperadin, treatment Introduction Human African trypanosomiasis Plastid can be a vector borne infection brought on by two sub species of Trypanosoma brucei. HAT is invariably lethal when untreated, and spreads rapidly through populations when treatment and surveillance plans are disrupted. Current treatments could be costly, difficult to administer and have substantial risks of toxicity. The problem is aggravated by the increasing incidence of drug-resistant trypanosomes, making the need for new therapies acute. The current research tests the hypothesis that regulatory proteins of the cell cycle are logical and druggable goals for therapy. Here we focus on the T. brucei Aurora kinase 1 because it is essential for mitotic progression in cultured trypanosomes, and as we report in this study, is essential for disease in a mouse model. Moreover, inhibitors of Aurora kinase family Lonafarnib solubility members are earnestly being pursued as treatments against cancer. Aurora kinases manage key events related to chromatin condensation, spindle function and cytokinesis. Yeast contain a single Aurora kinase homologue, while animals contain three. Aurora An is localized to the area from prophase to telophase and is vital for centrosome readiness, segregation, and the construction of the mitotic spindle. The activity of Aurora An is mediated indirectly by the little G protein Ran, and right by TPX2, a substrate and binding partner. Aurora An activity is also attenuated by PP1. The fungus Ipl1 and Aurora T are each considered chromosomal passenger proteins. Early in mitosis Aurora T phosphorylates Ser 10 on histone H3. This function is detectable with antibodies, and is widely-used as a biomarker for mitotic progression. The event of Ser 10 phosphorylation is unclear. In Drosophila, although not in humans, it contributes towards chromosome condensation. The phosphorylated H3 has been identified one of the chromosome individual proteins, and along with methylation of Lys 9, displaces heterochromatin protein 1 during mitosis.

A recently available Phase III clinical trial in metastatic pancreatic cancer demonstrated a statistically significant but clinically modest improvement in over all survival for patients treated with gemcitabine plus erlotinib versus gemcitabine alone. Specific therapies including marimastat, and tipifarnib with gemcitabine have not produced significant survival developments over gemcitabine alone. Thus, the finding that the inclusion of erlotinib to Decitabine 1069-66-5 gemcitabine produced a substantial improvement in survival in comparison to gemcitabine alone is of interest. How can laboratory studies help us improve on these resultsfi One obvious approach is much better patient selection. As an example, it’s conceivable that the effectiveness of the mix of gemcitabine with EGFR inhibitors may be superior by pinpointing populations of people most vulnerable to EGFR inhibition, such as those who lack Ras activation or who produce a rash in reaction to EGFR inhibitor therapy. Another way of enhance the medical efficacy of molecularly targeted agents in conjunction with gemcitabine or gemcitabine radiation is through pre-clinical determination of the suitable sequence of EGFR inhibitor, and gemcitabine, radiation. For example, in the aforementioned clinical trial, EGFR chemical was handed concurrently with gemcitabine and developed a modest survival advantage. It appears possible that survival might have been improved if the most effective preclinical routine had been used. Other goals, for example Chk1, need to be investigated in conjunction with gemcitabine Infectious causes of cancer radiation therapy. The using greater pre-clinical types such as tumefaction xenografts produced from primary human tumors can be crucial in order to change results directly to the clinic. Furthermore, the effects of treatment combinations on tumor stem cells versus major tumor may possibly provide insight in to potential therapeutic effectiveness. This decade will concentrate on preclinical studies in the best available model systems, incorporating molecularly targeted therapies with gemcitabine light with the goal of producing better patient responses. Aurora kinase An is amplified with different incidence in numerous human order Fingolimod cancers including head and neck squamous cell carcinoma. We investigated whether AURKA is a potential therapeutic target in HNSCC. Practices We performed an immunohistochemical analysis of AURKA expression in cyst samples and paired normal. HNSCC cells treated with siRNA particular for AURKA were assessed for protein expression ranges and AURKA mRNA by Western blot analysis and RT PCR. Cyst cells treated with paclitaxel and siRNA were examined for cell growth by MTT assay and for cell cycle distribution by flow cytometry. HNSCC cells and primary tumors unveiled high expression levels of AURKA. Most primary tumors also showed large kinase activity of the molecule. Qualified AURKA inhibition improved the sub G1 cell fraction, with a concomitant decrease in the G1 cell populace, indicating induction of apoptosis and hence substantially suppressed proliferation of HNSCC cells.

Inhibition of ACAT function in cells either by genetic or pharmacological means is demonstrated to effortlessly reduce A technology. Metaanalysis of genetic information suggests that SOAT1 is linked to the risk of AD and that a standard polymorphism that results in lowered Erlotinib ic50 ACAT action might confer protection against AD. Several ACAT inhibitors have been developed by the pharmaceutical industry for treatment of atherosclerosis and hyperlipidemia which are safe for human use and can be utilized to review the role of ACAT in AD. We have previously shown that the 2 month treatment with CP 113818 remarkably reduced amyloid pathology and correlated with improved spatial learning in transgenic mice expressing human APP 751 containing the London and Swedish mutations. Avasimibe is a widely studied ACAT inhibitor that’s structurally unrelated to CP 113818. The pharmacological profile of avasimibe is somewhat distinctive from CP 113818. For example, IC 50 values for avasimibe and CP 113818 are 391 and 6 n M for HepG2 cells, and 664 and 63 n M for THP 1 cells, respectively. Though IC 50 values are lower for CP 113818, the ACAT1/ACAT2 selectivity is slightly greater for avasimibe. As a proof of principle experiment, we have addressed two Cellular differentiation age brackets of nontransgenic mice and female hAPP FAD with two different doses of avasimibe. Avasimibe was applied in the form of implantable biopolymer pellets for just two months. Serum cholesterol levels suggested that avasimibe therapy was significantly less effective in inhibiting ACAT when compared with CP 113818, while neuropathological and bio-chemical studies of brain amyloid plaque weight are still continuing. This effect was expected, taking into consideration the approximately 10-fold higher IC 50 value of avasimibe in comparison with CP 113818. As yet another evidence of concept design for ACAT task regulating A technology, we’ve applied ACAT1 RNAi in individual H4 neuroglioma cells. Lowering ACAT1 protein levels by about 50-cycle resulted in significant decreases in APP mapk inhibitor CTF levels in cell lysates in addition to secreted An in the conditioned media. Altogether, we’ve successfully used a few independent pharmacological and genetic methods to reduce ACAT activity in cell based and animal models, that have proved to effectively attenuate A generation and amyloid pathology. An important distinction between ACAT inhibitors and statins could be the process whereby they attenuate An era. Inhibition of HMG-COA reductase by statins shuts down the L mevalonate pathway affecting many cholesterol and isoprenoid dependent processes inside the cell. Cholesterol-rich membrane domains such as lipid rafts that are enriched in secretase and both activities are strongly affected by statin treatment. We’ve used 2 dimensional LC MS to recognize proteins that bind to APP differentially in ACAT inhibitor treated cells. A few ER proteins, including chaperones of the GRP family, were defined as ACAT chemical open APP interacting proteins.

It is a high priority in cancer research to produce approaches to managing this form of breast cancer. About 3 months later, human breast tumor cells Imatinib ic50 were implanted into the humanized mammary fat pads. Recognized xenografts were then passaged in the mammary fat pads of receiver humanized NOD/SCID rats for the studies. Preparing human breast cancers for engraftment. Individual breast tumors from needle biopsies or tumors passaged in mice were suspended in complete medium on ice. Cancers were minced into approximately 1 mm items under sterile conditions and then utilized in 15 ml conical tubes containing medicines, 250 U/ml hyaluronidase, and 3 mg/ml collagenase. Samples were incubated at 37 C until minced cells dissociated into individual cells. Cells were pelleted and supernatants discarded. Cells were washed in PBS. Cells were re-suspended in 5 10 ml rbc lysis buffer and incubated for 15 minutes at 37 C. Cells were pelleted and cleaned in 10 ml PBS. Cells were re-suspended in an Cellular differentiation equal level of 0. 05% trypsin EDTA and incubated for 5 minutes at 37 C. Trypsin was inactivated with complete medium, and cells were pelleted and then washed twice with PBS. All centrifugation steps were performed at 230 g for five minutes at 4 C. Cells were resuspended in complete medium and filtered via a sterile 40 fim filter. 1 fifi106 tumefaction cells and 5 fifi105 fibroblasts were combined and added to the same amount of a 1:1 combination of Matrigel and Collagen I. The suspension was maintained ice until injection. The cell suspension mixture was injected in to the region of humanization with a 27 gauge needle. The last volume was 35 fil per mammary gland. Until their maximum length reached approximately 0 established tumors implanted in the right and left humanized mammary fat pads of NOD/SCID mice were allowed to grow. 7 to 1. 0 cm. Mice were sacrificed and single cell suspensions order Lenalidomide were prepared from each tumefaction for further passaging in mice. Microarray analysis. Total RNA from xenograft tumors and human counterpart was amplified, purified, and labeled, and microarray hybridizations were performed utilizing Agilent 4fifi44K Whole Human Genome Microarrays. For Cy3 controls, we employed Stratagene Human Universal Reference enriched with equal levels of RNA in the MCF7 and ME16C cell lines. Microarrays were hybridized overnight, cleaned, dried, and scanned applying an Agilent Scanner. The image files were examined and packed to the UNC CH Microarray Database. Final normalized log2 ratios for every probe were obtained after removing probes using a Lowess normalized intensity value of less than 10 within the Cy5 sample and/or the control. Program normalization methods were then employed as previously described, and innate sub-type varieties were determined from your PAM50 microarray based analysis described in Parker et al..

data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place mostly at sites of DNA damage, and are in keeping with previous work showing that, following their DNA damage localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates. Various functional studies were carried out by us to ascribe a specific function to KAP1 Ser473. As an example, we found that mutating Ser473 did not affect KAP1 phosphorylation on Ser824 or KAP1 SUMOylation, which has been implicated in transcriptional silencing. natural product libraries More over, in line with prior findings, we discovered that DNA damage did not perceptibly modify KAP1 interactions with its binding partners SETDB1, HDAC1 and MDM2. Essentially, we discovered that the recently reported serum induction of KAP1 Ser473 phosphorylation was not affected by AZD7762, indicating that another kinase targets this site upon serum stimulation. In accordance with this and the truth that we observed levels of IRinduced KAP1 Ser473 phosphorylation in most cells of an asynchronously increasing population, we found no correlation between DNA damage induced cell cycle stage and KAP1 Ser473 phosphorylation Metastasis. Furthermore, though a recent report concluded that cell cycle controlled KAP1 phosphorylation on Ser473 handles the connection between KAP1 and HP1b, we observed no influence of mutating Ser473 on the binding of KAP1 to HP1. We for that reason conclude that the results of Ser473 phosphorylation are too delicate to be detected by existing assays, or that this phosphorylation site regulates confirmed undefined KAP1 capabilities. Discussion We have applied a chemical genetics approach, as Chk1 derivative that can utilize the ATP analogue N6B ATPgS having a mutated, to recognize proteins that can serve as immediate substrates for Chk1. Through determining a large specific HDAC inhibitors quantity of Chk1 phosphorylation sites by using this technique, we’ve further refined the Chk1 consensus sequence. Amazingly, our studies show that, in addition to the representation of certain amino-acid residues at specific positions inside the Chk1 target motif, there are also other residues that are markedly under-represented in certain positions. Thus, we are light emitting diode to the overall goal consensus motif for Chk1 being R/K R/K d/e t S /T X r/k page1=46, where capital and lower case letters reveal selection and table selection, respectively. Significantly, through further investigations in to different subsets of Chk1 goals, we have found that the rules for Chk1 target recognition can’t be explained only on the basis of selecting or counter selecting for certain residues at specific positions. Rather, more complex, context dependent selections also seem to function, and it seems that more than one class of target motif might occur, maybe going towards Chk1 using adaptor proteins to acknowledge its substrates.

The first double-blind placebo controlled study failed to show a reduction in neointimal hyperplasia detected by IVUS after 6 months of treatment with probucol versus placebo nor in restenosis rate detected by QCA. The rate of development of CIMT was slowed by therapy with pioglitazone versus glimipride at all time points during the 72 week follow-up time. 3. Conclusion and discussion The main interest of cardiovascular experts in surrogate stop details as a proxy for clinical outcomes stems from the fact the evaluation of the result of therapy on surrogate outcomes is often faster and takes a smaller Anastrozole ic50 variety of patients to show. Therefore, the reward of fast approval that turn out to be safe and effective needs to be balanced against harms that may happen later when drugs approved on the basis of surrogate end points turn out to have major safety issues or to lack efficacy. Besides, the clearly recognized natural limitations of non-invasive imaging modalities in addition to quantitative coronary angiography in providing an exact Papillary thyroid cancer estimate of plaque burden can clearly distort the connection of clinical outcomes and surrogate endpoints. One of the current imaging methods, determining plaque progression/regression since it produces good quality pictures of the early atherosclerotic plaques, vessel wall, and coronary lumen with quantitative identification of most atheroma factors and is effective at correlating increments in atheroma volume to future MACE. Nevertheless, IVUS remains an invasive imaging modality with limited access in certain catheterization price AG-1478 labs and regardless of the high quality images it provides, it doesn’t overcome the inherent limitation of surrogate endpoints and medication related adverse events highlighted above. Furthermore, the disparity between the results of the traditional IVUS and IVUS radiofrequency dimensions inferred in the afore-mentioned darapladib research, warrants further research into which outcome measure to use and which one translates into adverse clinical outcomes. Consequently, given all of the current limitations in different imaging techniques available to assess the intrinsic limitations with surrogate endpoints, and plaque volume and composition, one should be careful in using the outcomes of surrogate end-point tests in patient care. Astute cardiovascular scientists are currently using the available imaging modalities in learning the pleiotropic effects of FDA approved medications that possess good safety profile through the use of surrogate endpoints that will hopefully translate to useful clinical outcomes and enhance the on label usage of medications. Saying all that, using surrogate endpoints in assessing the effectiveness of novel pharmacologic therapies in reducing negative clinical cardio-vascular outcomes remains controversial.