Right transradial coronary angiography in the setting of tortuous brachiocephalic/thoracic aorta ("elephant head"): Impact on fluoroscopy time and contrast use.

OBJECTIVES: Assess the impact on fluoroscopy time and contrast use in patients with tortuous brachiocephalic/thoracic aortas undergoing right transradial coronary angiography (RTCA) and provide strategies to manage. BACKGROUND: Unfavorable anatomy with severe brachiocephalic/thoracic tortuosity, referred to as an "elephant head," remains a significant obstacle for RTCA. METHODS: We reviewed the coronary angiograms of patients who underwent RTCA and had tortuous aortas. Angiography was attempted first using a universal catheter (Tiger) and switched to a left coronary specific catheter (Judkins Left [JL]) if challenging. Fluoroscopy time, contrast volume, and greatest distance from the patient's midline to the catheter in the aorta were recorded. RESULTS: Forty-nine patients (62.6 ± 12.0 years, 69.4% male) were included. Fifteen (30.6%) patients underwent successful angiography with a Tiger catheter; 34 (69.4%) patients required switching to JL catheter. The average distance of Tiger catheters to the midline of the spine was 0.78 ± 0.41 cm versus 1.28 ± 0.44 cm (p = .001) in JL catheters. Tiger catheter use resulted in less fluoroscopy time (6.48 ± 4.73 min) and contrast use (58.87 ± 43.53 ml) than in cases switched to JL (13.26 ± 10.76 min [p = .026]; 86.5 ± 69.95 ml [(p = .017]). CONCLUSIONS: For patients undergoing RTCA with significant brachiocephalic/thoracic aorta tortuosity, "elephant head," a Tiger catheter can be used efficiently for curvatures <1 cm from the middle of the spine. We propose that for curvatures >1 cm, operators should consider immediately switching to a JL catheter.

Deoxyelephantopin alleviates lipopolysaccharide-induced septic lung injury through inhibiting NF-ĸB/STAT3 axis.

Sepsis induces multiple organ dysfunction syndromes, such as acute kidney, liver, or lung injury. Septic lung injury is associated with excessive apoptosis and inflammatory responses in hepatocytes. Deoxyelephantopin is a sesquiterpene lactone found in Elephantopus scaber L, and has immunomodulatory, antibacterial, anti-inflammatory, and antifungal properties. The role of deoxyelephantopin in sepsis-associated lung injury was investigated. First, human bronchial epithelial cells (BEAS-2B) and human pulmonary artery endothelial cells (HPAEC) were treated with lipopolysaccharide to induce cytotoxicity. Treatment with lipopolysaccharide reduced cell viability of BEAS-2B and HPAEC, and promoted cell apoptosis through down-regulation of poly (ADP-ribose) polymerase (PARP) and B-cell lymphoma 2 (Bcl-2), and up-regulation of cleaved PARP and B-cell lymphoma-associated X protein (Bax). Second, lipopolysaccharide-treated BEAS-2B and HPAEC were incubated with increasing concentrations of deoxyelephantopin, that is, 1, 5, or 10 µM. Deoxyelephantopin enhanced cell viability and reduced cell apoptosis of lipopolysaccharide-treated BEAS-2B and HPAEC. Third, deoxyelephantopin attenuated lipopolysaccharide-induced decrease of superoxide dismutase and glutathione, and increase of malondialdehyde and myeloperoxidase in BEAS-2B and HPAEC. Moreover, deoxyelephantopin also weakened lipopolysaccharide-induced increase of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Finally, deoxyelephantopin decreased protein expression of p-p65 and p-signal transducer and activator of transcription 3 (STAT3) in lipopolysaccharide-treated BEAS-2B and HPAEC. In conclusion, deoxyelephantopin exhibited anti-oxidative and anti-inflammatory effects against lipopolysaccharide-treated BEAS-2B and HPAEC through inactivation of nuclear factor kappa B/STAT3 signaling.

Real-world experience of suture-based closure devices: Insights from the FDA Manufacturer and User Facility Device Experience.

OBJECTIVES: We analyzed post-marketing surveillance data from the United States Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for suture-based vascular closure devices (VCDs) - Perclose ProGlide (Abbott, Chicago, Illinois) and Prostar XL (Abbott). BACKGROUND: Suture-based VCDs are mostly used for large-bore femoral arterial access-site closure. Real-world, contemporary experience on the most commonly reported complications and modes of failure associated with these devices is limited. METHODS: Post-marketing surveillance data from the FDA MAUDE database, for the ProGlide system and for the Prostar XL system, were analyzed, yielding 827 Perclose ProGlide reports and 175 Prostar XL reports. RESULTS: Of the 827 reports of major complications involving the Perclose ProGlide devices, 404 reports involved injury, and one involved death related to the device. In the Prostar XL analysis, 94 reports involved injury, and one involved death. Bleeding from vessel injury was the most common adverse outcome described with both devices, followed by hematoma and thrombus. Surgical repair was the most commonly used treatment strategy. In terms of device malfunction, suture-related malfunction (212 reports) was most commonly seen in the Perclose ProGlide group, while failed deployment was most commonly seen in the Prostar XL group. CONCLUSIONS: Our analysis of the MAUDE database demonstrates that in real-world practice, suture-based VCDs were found to be associated with complications, including vascular injury, difficulties with the device itself, and even death. Ongoing user education and pre-procedural patient selection are important to minimize risks associated with suture-based vascular closure devices.

Impact of Intravascular Ultrasound on Outcomes Following PErcutaneous Coronary InterventioN in Complex Lesions (iOPEN Complex).

BACKGROUND: Clinical data support the use of intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) as being associated with improved outcomes. Nonetheless, global utilization of IVUS remains low. We hypothesize that, in the revascularization of complex lesions, IVUS use is associated with improved outcomes. METHODS: All patients with complex lesions treated with PCI at a single center from 2003 to 2016 were stratified by use of IVUS. Complex lesions were defined as follows: American College of Cardiology/American Heart Association type C lesions, in-stent restenosis, long lesions, bifurcations, severe calcification, left main lesions, and chronic total occlusions. The primary end point was the rate of major adverse cardiac events (MACE) at 1-year follow-up, defined as the composite of all-cause mortality, Q-wave myocardial infarction, and target vessel revascularization. Inverse probability weighting was used in the adjusted analysis. RESULTS: A total of 6,855 patients were included in the final analysis, of whom 67.3% had IVUS and 32.7% had angiography alone. The primary end point occurred in 13.4% of patients treated with IVUS and 18.3% of patients treated with angiography alone (P < .001). Inverse probability weighting-adjusted 1-year MACE rates demonstrated significant reduction with IVUS for each complex lesion type. CONCLUSIONS: Among patients with complex lesions, the use of IVUS was associated with lower MACE 1 year after PCI than angiography alone was. Because of the increased procedural risk in complex lesions, routine utilization of IVUS-guided PCI should be considered in this subset of patients.

Adverse events and modes of failure related to the FilterWire EZ Embolic Protection System: Lessons learned from an analytic review of the FDA MAUDE database.

OBJECTIVES: To assess the commonly reported complications and failure modes for FilterWire EZ Embolic Protection Devices (EPD) by analyzing the postmarketing surveillance data from the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. BACKGROUND: EPDs prevent distal embolization of atheroembolic materials during percutaneous interventions resulting in reduced microvascular obstruction and improved microcirculation while maintaining tissue perfusion. The FilterWire EZ EPD (Boston Scientific, Natick, MA) is approved for use in interventions of de novo saphenous vein grafts (SVG) and carotid artery stenosis. Robust data on the commonly reported complications and failure modes associated with the FilterWire EZ device are limited. METHODS: The MAUDE database was queried from September 1, 2008, through September 30, 2018, for FilterWire EZ system, yielding 474 reports. After exclusion of duplicate and incomplete reports, 464 device reports were included in the final analysis. RESULTS: Device-related adverse events were most commonly reported for carotid (n = 281) and SVG (n = 101) interventions. The most commonly reported major complications were: ischemic stroke (n = 57), vessel perforation or dissection (n = 12), death (n = 8), and myocardial infarction (n = 5). Minor complications included: hypotension (n = 68), bradycardia (n = 41), and vasospasm (n = 27). The most commonly reported failure modes were: detachment and/or damage of the device components (n = 118), device entrapment (n = 90), and stent-related issues (n = 46). CONCLUSIONS: Analysis of the MAUDE dataset is helpful in identifying the commonly reported adverse events and failure modes of FilterWire EZ devices. This platform serves as an important tool for both physicians and manufacturers to optimize device performance and clinical outcomes.

Reliability of temporal bone high-resolution CT in patients with facial paralysis in temporal bone fracture.

OBJECTIVE: This study aimed to investigate the reliability of temporal bone high-resolution CT (HRCT) in patients with traumatic facial paralysis. METHODS: HRCT with cross-sectional scanning and multi-planar reformation (MPR) was performed on 26 cases with traumatic facial paralysis, and the preoperative imaging manifestations were compared with surgical findings. RESULTS: Preoperative HRCT revealed fallopian canal damage at the posterior genu in 1 case, geniculate ganglion in 22 cases, labyrinthine segment in 4 cases, tympanic segment in 13 cases and mastoid segment in 0 case, while surgical findings confirmed fallopian canal damage at the posterior genu in 7 cases, geniculate ganglion in 23 cases, labyrinthine segment in 4 cases, tympanic segment in 17 cases and mastoid segment in 7 cases. The accuracy of temporal bone HRCT in revealing damage at those segments of fallopian canal was 14.3%, 95.7%, 100%, 76.5, and 0%, respectively. CONCLUSION: Temporal bone HRCT can generally estimate the extent of damage and provide important information for traumatic facial paralysis before surgery. However, it is unreliable in revealing the damage of fallopian canal at the posterior genu and mastoid segment.

CT differentiation of diffuse malignant peritoneal mesothelioma and peritoneal carcinomatosis.

BACKGROUND AND AIM: Diffuse malignant peritoneal mesothelioma (DMPM) and peritoneal carcinomatosis (PC) have similar imaging in computer tomography (CT). We aimed to distinguish them. METHODS: Computer tomography findings were evaluated in 48 DMPM and 47 PC for the peritoneal, mesenteric, omentum, lymph nodes, viscera infiltration, ascites and pleural plaques. RESULTS: Two groups had no difference in terms of thickness, clinical manifestation, diameter of lymph nodes, ascites, and viscera infiltration. But they showed differences in the following: Ratio of asbestos exposure in DMPM group was higher. Smooth and irregular peritoneal thickening were more seen in DMPM group; peritoneal nodules were more commonly detected in PC group. Forty-eight cases of peritoneum in DMPM showed mild enhanced, while 14 patients in PC showed severe enhanced. Nodular type of omentum was more common in PC group than in DMPM group; omental cake was more commonly detected in DMPM group. Mesentery involvement was more commonly seen in DMPM group. Location of enlarged lymph nodes in cardiophrenic region was more frequently identified in DMPM, whereas location of enlarged lymph nodes in retroperitoneal region was more frequently identified in PC. Lymph nodes fusion was more frequently visualized in PC. Fixation of the intestinal wall was more common in DMPM. Pleural plaque was more common in DMPM. PC had distant metastasis except primary foci and peritoneum. In PC, tumor origins were ovary in 10, digestive system in 21, breast in one. CONCLUSION: Using a combination of CT findings may increase our ability to distinguish PC from DMPM.

CT differentiation of malignant peritoneal mesothelioma and tuberculous peritonitis.

OBJECTIVE: The aim of this study was to determine which computed tomography (CT) findings were useful in differentiating malignant peritoneal mesothelioma (MPM) and tuberculous peritonitis (TBP). METHODS: CT scans performed in 53 patients with MPM and 27 patients with TBP confirmed by pathology were retrospectively reviewed. The CT findings were evaluated for the morphologic appearance of ascites, peritoneum, mesenterium and omentum involvement, enlarged lymph nodes, solid abdominal viscera infiltration and metastases, and thoracic changes. The Pearson χ (2) test was used to compare differences between groups. RESULTS: Patients in both groups displayed a high proportion of peritoneum and mesenterium thickening. However, there were no obvious differences observed for ascites or swollen lymph nodes. There were significant differences in the following aspects between the two groups: (1) smooth peritoneal thickening was more frequent in patients with TBP, while irregular thickening was more frequently observed in patients with MPM; (2) caked omentum stratification was more common in patients with MPM; (3) mesentery involvement was less commonly observed in patients with TBP; (4) abdominal viscera infiltration and pleural plaques were more common in patients with MPM (46/53 and 48/53, respectively) than in those with TBP (0/27 and 0/27); and (5) more patients in the TBP group (14/27) displayed pleural effusion, and extraperitoneal tuberculosis was more common in patients with TBP (20/27). CONCLUSION: Although most CT findings analyzed are observed in both diseases, each disease has its own several unique characteristics. Therefore, using a combination of CT findings may increase our ability to distinguish TBP from MPM.

Impact of subtropical climate on frequency of ambulance use for trauma patients in a coastal area of China.

PURPOSE: To explore the impact of subtropical maritime monsoon climate on the frequency of ambulance use for trauma patients in a coastal region in China. METHOD: Statistical analysis of data on ambulance use from the 120 Emergency Command Center in Shantou City, Guangdong Province, from January to December 2012 as well as daily meteorological data from a Shantou observatory was performed to determine how climatic factors (seasons, time, and weather) affect the frequency of ambulance use for trauma patients. RESULTS: The daily ambulance use for trauma patients differed between spring and summer or autumn (p<0.05), between sunny and rainy days (p<0.05), and between cloudy and lightly or moderately rainy days (p<0.05).We found a linear correlation between daily maximum temperature and daily ambulance use for trauma patients (R² =0.103, p<0.05). In addition, there was significant difference in ambulance use between good and bad weather (p<0.05). CONCLUSION: Frequency of ambulance use for trauma patients is affected by the subtropical maritime monsoon climate in the coastal region. Better weather contributes to increased daily frequency of ambulance use, which is the highest in autumn and lowest in spring.

Low-dose T3 replacement restores depressed cardiac T3 levels, preserves coronary microvasculature and attenuates cardiac dysfunction in experimental diabetes mellitus.

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 µg/mL T3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T3 and T4: 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T3 replacement largely restored cardiac tissue TH levels (T3 and T4: 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Synthesis of metal-organic frameworks with multiple nitrogen groups for selective capturing Ag(I) from wastewater.

As a noble metal with extremely high economic benefits, the recovery of silver ions has attracted a particular deal of attention. However, it is a challenge to recover silver ions efficiently and selectively from aqueous solutions. In this research, the novel metal-organic frameworks (MOFs) adsorbent (Zr-DPHT) is prepared for the highly efficient and selective recovery of silver ions from wastewater. Experimental findings reveal that Zr-DPHT's adsorption of Ag(I) constitutes an endothermic process, with an optimal pH of 5 and exhibits a maximum adsorption capacity of 268.3 mg·g-1. Isotherm studies show that the adsorption of Ag(I) by Zr-DPHT is mainly monolayer chemical adsorption. Kinetic studies indicate that the internal diffusion of Ag(I) in Zr-DPHT may be the rate-limiting step. The mechanism for Ag(I) adsorption on Zr-DPHT involves electrostatic interactions and chelation. In competitive adsorption, Ag(I) has the largest partition coefficient (9.64 mL·mg-1), indicating a strong interaction between Zr-DPHT and Ag(I). It is proven in the adsorption-desorption cycle experiments that Zr-DPHT has good regeneration performance. The research results indicate that Zr-DPHT can serve as a potential adsorbent for efficiently and selectively capturing Ag(I), providing a new direction for MOFs in the recycling field of precious metals.

The design of high-efficient MOFs for selective Ag(I) capture: DFT calculations and practical applications.

Recovering silver from wastewater not only significantly reduces environmental harm but also meets the growing demand for silver in modern industry. Here, a novel metal-organic framework adsorbent (MOF-RD) using rhodanine derivatives as linkers is introduced for the efficient and selective capture of silver ions in real wastewater. The adsorption of MOF-RD followed pseudo-second-order and Sips models, and thermodynamic investigations revealed the process to be endothermic. MOF-RD demonstrated a remarkable adsorption capacity of 707.2 mg·g-1 for Ag(I) at pH 5 and 318 K. The interaction between silver ions and MOF-RD was mainly electrostatic attraction and coordination, with coordination primarily occurring at the CO and CS sites within the rhodanine motif. The practical applicability of MOF-RD for selective adsorption of Ag(I) was validated in actual wastewater with high-concentration competing metal ions. Furthermore, after 10 adsorption-desorption cycle experiments, MOF-RD still retained a strong regenerative capability. The results reveal the good potential of MOF-RD as an adsorbent for selectively recovering Ag(I) from industrial wastewater. Additionally, the strategies and methods adopted in this article also provide new perspectives and technical paths for the separation and recovery of other metal ions in wastewater.

One-step functionalization of chitosan with rich sulfur and nitrogen adsorption sites for efficient recovery of silver ions from actual wastewater.

The recovery of silver ions from wastewater is of great importance due to their adverse environmental impact and significant economic value. This paper introduces a novel adsorbent (CS-AHMT) that can be easily synthesized via a one-step functionalization of chitosan with 4-Amino-3-hydrazino-1,2,4-triazol-5-thiol to efficiently recover silver ions from actual wastewater. CS-AHMT demonstrated superior adsorption performance, achieving an adsorption capacity of 241.4 mg·g-1 at pH 5 and 318 K, and the adsorption equilibrium was rapidly attained within 60 to 120 min. Kinetic and isotherm studies indicate that the adsorption process conforms to the pseudo-nth-order (PNO) and Sips models, suggesting a monolayer adsorption that incorporates both physical and chemical processes, with internal mass transfer being the primary rate-limiting step. Electrostatic and coordination interactions are primarily involved in the adsorption mechanism of silver ions on CS-AHMT, as further validated by density functional theory (DFT) calculations. The selectivity and practical applicability of CS-AHMT were confirmed in real wastewater containing high concentrations of competing ions. The findings underscore the potential of CS-AHMT as an effective adsorbent for silver ion recovery in wastewater treatment applications.

Improvement of left ventricular remodeling after myocardial infarction with eight weeks L-thyroxine treatment in rats.

BACKGROUND: Left ventricular (LV) remodeling following large transmural myocardial infarction (MI) remains a pivotal clinical issue despite the advance of medical treatment over the past few decades. Identification of new medications to improve the remodeling process and prevent progression to heart failure after MI is critical. Thyroid hormones (THs) have been shown to improve LV function and remodeling in animals post-MI and in the human setting. However, changes in underlying cellular remodeling resulting from TH treatment are not clear. METHODS: MI was produced in adult female Sprague-Dawley rats by ligation of the left descending coronary artery. L-thyroxine (T4) pellet (3.3 mg, 60 days sustained release) was used to treat MI rats for 8 weeks. Isolated myocyte shape, arterioles, and collagen deposition in the non-infarcted area were measured at terminal study. RESULTS: T4 treatment improved LV ±dp/dt, normalized TAU, and increased myocyte cross-sectional area without further increasing myocyte length in MI rats. T4 treatment increased the total LV tissue area by 34%, increased the non-infarcted tissue area by 41%, and increased the thickness of non-infarcted area by 36% in MI rats. However, myocyte volume accounted for only ~1/3 of the increase in myocyte mass in the non-infarct area, indicating the presence of more myocytes with treatment. T4 treatment tended to increase the total length of smaller arterioles (5 to 15 µm) proportional to LV weight increase and also decreased collagen deposition in the LV non-infarcted area. A tendency for increased metalloproteinase-2 (MMP-2) expression and tissue inhibitor of metalloproteinases (TIMPs) -1 to -4 expression was also observed in T4 treated MI rats. CONCLUSIONS: These results suggest that long-term T4 treatment after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.

MaxMatch: Semi-Supervised Learning With Worst-Case Consistency.

In recent years, great progress has been made to incorporate unlabeled data to overcome the inefficiently supervised problem via semi-supervised learning (SSL). Most state-of-the-art models are based on the idea of pursuing consistent model predictions over unlabeled data toward the input noise, which is called consistency regularization. Nonetheless, there is a lack of theoretical insights into the reason behind its success. To bridge the gap between theoretical and practical results, we propose a worst-case consistency regularization technique for SSL in this article. Specifically, we first present a generalization bound for SSL consisting of the empirical loss terms observed on labeled and unlabeled training data separately. Motivated by this bound, we derive an SSL objective that minimizes the largest inconsistency between an original unlabeled sample and its multiple augmented variants. We then provide a simple but effective algorithm to solve the proposed minimax problem, and theoretically prove that it converges to a stationary point. Experiments on five popular benchmark datasets validate the effectiveness of our proposed method.

Effect of Nb Content and Second Heat Cycle Peak Temperatures on Toughness of X80 Pipeline Steel.

The microstructure evolution and variation of impact toughness in the heat-affected zone (HAZ) of X80 pipeline steel with different Nb content under different peak temperatures in the secondary thermal cycle were studied through welding thermal simulation, the Charpy impact test, EBSD analysis, SEM observation, and TEM observation in this study. The results indicate that when the peak temperatures of the second pass were lower than Ac1, both X80 pipeline steels had high impact toughness. For secondary peak temperatures in the range of Ac1 to Ac3, both X80 pipeline steels had the worst impact toughness, mainly due to the formation of massive blocky M-A constituents in chain form on grain boundaries. When the secondary peak temperatures were higher than Ac3, both X80 pipeline steels had excellent impact toughness. Smaller grain size and higher proportions of HAGBs can effectively improve the impact toughness. Meanwhile, high Nb X80 pipeline steel had higher impact absorption energy and smaller dispersion. Adding an appropriate amount of Nb to X80 pipeline steel can ensure the impact toughness of SCCGHAZ and SCGHAZ in welded joints.

Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRß, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.