Assessment of embolic cardiomyopathy from atrial myxoma on magnetic resonance imaging: A case report.

Atrial myxoma is the most common benign cardiac tumor, which can present with diverse symptoms. Systemic embolism is a frequent complication, affecting up to one-third of cases and frequently involving cerebral arteries. However, cardiac myxoma-induced myocardial infarction (MI) is rare. We report a case of a 56-year-old man presenting with predominant neurological symptoms and an unexplained elevation of hs-Trop T without clinical signs of acute MI. Computerized tomography of the head showed no acute lesions, but subsequent magnetic resonance imaging (MRI) revealed multiple small ischemic lesions and old microhemorrhage foci. A comprehensive cardiovascular investigation was performed. Ultrasonography revealed a left atrial mass. Cardiac MRI confirmed the mass was an atrial myxoma, and showed many old infarctions and scarring lesions in the cardiac muscle. The patient underwent tumor resection, but residual motor-neurological deficits were observed. This case emphasizes the importance of cardiac MRI in the diagnosis of multiple focal infarctions attributed to coronary embolism.

Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

Cardiac papillary fibroelastoma as a cause of acute coronary syndrome.

Cardiac papillary fibroelastoma (CPF) is a benign primary cardiac neoplasm, commonly found in men and above 40 years old. The clinical presentation of CPF ranges from asymptomatic to embolism-related complications such as stroke, myocardial ischemia, infarction, or ventricular fibrillation. Acute coronary syndrome is a rare complication of CPF, which was reported only in a few cases in medical literature. Hence, we report a case of a 50-year-old female with a CPF on the right coronary cusp of the aortic valve diagnosed with multi-modality imaging with definitive diagnosis through histopathologic confirmation. The patient presented with acute onset of fatigue, diaphoresis, and vomiting. Initial electrocardiogram (ECG) demonstrated T wave inversion in aVL. Repeated ECG two hours later showed persistent T wave inversion in aVL with new T wave inversions in lead I and ST depression in V2-V6. Troponin levels were elevated from 3.6 ng/L to 1503 ng/L but the patient did not report chest pain, abdominal pain, or dyspnea. Computed tomography coronary angiography did not show any significant coronary stenosis but revealed a low attenuation node with 7 × 6 mm in dimension attached to the right coronary cusp of the aortic valve. Treatment was discussed among a multidisciplinary team and the CPF was surgically removed. Learning objective: Acute coronary syndrome is a rare, but potentially fatal complication of cardiac papillary fibroelastoma (CPF). Multi-modality imaging is valuable in delineating the evaluation of exact position, dimensions, nature of cardiac masses, diagnostic workup, and preliminary assessment before the surgery. There are no clear guidelines for the treatment of CPF.

Trisubstituted ureas as potent and selective mPGES-1 inhibitors.

A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 µM) and in human whole blood assay (IC(50) of 2.1 µM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors.

Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors.

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.

Syntrophic Partners Enhance Growth and Respiratory Dehalogenation of Hexachlorobenzene by Dehalococcoides mccartyi Strain CBDB1.

This study investigated syntrophic interactions between chlorinated benzene respiring Dehalococcoides mccartyi strain CBDB1 and fermenting partners (Desulfovibrio vulgaris, Syntrophobacter fumaroxidans, and Geobacter lovleyi) during hexachlorobenzene respiration. Dechlorination rates in syntrophic co-cultures were enhanced 2-3 fold compared to H2 fed CBDB1 pure cultures (0.23 ± 0.04 µmol Cl- day-1). Syntrophic partners were also able to supply cobalamins to CBDB1, albeit with 3-10 fold lower resultant dechlorination activity compared to cultures receiving exogenous cyanocobalamin. Strain CBDB1 pure cultures accumulated ~1 µmol of carbon monoxide per 87.5 µmol Cl- released during hexachlorobenzene respiration resulting in decreases in dechlorination activity. The syntrophic partners investigated were shown to consume carbon monoxide generated by CBDB1, thus relieving carbon monoxide autotoxicity. Accumulation of lesser chlorinated chlorobenzene congeners (1,3- and 1,4-dichlorobenzene and 1,3,5-trichlorobenzene) also inhibited dechlorination activity and their removal from the headspace through adsorption to granular activated carbon was shown to restore activity. Proteomic analysis revealed co-culturing strain CBDB1 with Geobacter lovleyi upregulated CBDB1 genes associated with reductive dehalogenases, hydrogenases, formate dehydrogenase, and ribosomal proteins. These data provide insight into CBDB1 ecology and inform strategies for application of CBDB1 in ex situ hexachlorobenzene destruction technologies.

Correction: Validation of a Laboratory Method for Evaluating Dynamic Properties of Reconstructed Equine Racetrack Surfaces.

[This corrects the article DOI: 10.1371/journal.pone.0050534.].

Validation of a laboratory method for evaluating dynamic properties of reconstructed equine racetrack surfaces.

BACKGROUND: Racetrack surface is a risk factor for racehorse injuries and fatalities. Current research indicates that race surface mechanical properties may be influenced by material composition, moisture content, temperature, and maintenance. Race surface mechanical testing in a controlled laboratory setting would allow for objective evaluation of dynamic properties of surface and factors that affect surface behavior. OBJECTIVE: To develop a method for reconstruction of race surfaces in the laboratory and validate the method by comparison with racetrack measurements of dynamic surface properties. METHODS: Track-testing device (TTD) impact tests were conducted to simulate equine hoof impact on dirt and synthetic race surfaces; tests were performed both in situ (racetrack) and using laboratory reconstructions of harvested surface materials. Clegg Hammer in situ measurements were used to guide surface reconstruction in the laboratory. Dynamic surface properties were compared between in situ and laboratory settings. Relationships between racetrack TTD and Clegg Hammer measurements were analyzed using stepwise multiple linear regression. RESULTS: Most dynamic surface property setting differences (racetrack-laboratory) were small relative to surface material type differences (dirt-synthetic). Clegg Hammer measurements were more strongly correlated with TTD measurements on the synthetic surface than the dirt surface. On the dirt surface, Clegg Hammer decelerations were negatively correlated with TTD forces. CONCLUSIONS: Laboratory reconstruction of racetrack surfaces guided by Clegg Hammer measurements yielded TTD impact measurements similar to in situ values. The negative correlation between TTD and Clegg Hammer measurements confirms the importance of instrument mass when drawing conclusions from testing results. Lighter impact devices may be less appropriate for assessing dynamic surface properties compared to testing equipment designed to simulate hoof impact (TTD). POTENTIAL RELEVANCE: Dynamic impact properties of race surfaces can be evaluated in a laboratory setting, allowing for further study of factors affecting surface behavior under controlled conditions.

Wnt inhibitor screen reveals iron dependence of ß-catenin signaling in cancers.

Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/ß-catenin signaling, we identified a series of acyl hydrazones that act downstream of the ß-catenin destruction complex to inhibit both Wnt-induced and cancer-associated constitutive Wnt signaling via destabilization of ß-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans.

Diastereoselective palladium-catalyzed formate reduction of allylic carbonates en route to polypropionate systems.

Diastereoselective palladium-catalyzed formate reduction of allylic carbonates presents unique opportunities for applications in target-oriented organic synthesis provided that selectivity, in particular stereoselectivity, in the course of this metal-catalyzed reaction can be controlled. This article describes our recent developments on new and efficient metal-catalyzed processes exploiting resident stereocenters on the substrates as a means to control stereoselectivity en route to preparing propionate units containing an array of stereochemical patterns. In particular, the effect of the protecting group, the stereochemistry of the aldol adduct, neighboring substituents, and the olefin geometry were examined. Strategic choice of the above parameters provides entry into three of the four possible diastereomeric triads, namely syn-syn, anti-syn, and anti-anti. Preliminary results indicate that construction of the syn-anti triad is possible, albeit in moderate diastereoselectivity.

Remote electronic effects in the rhodium-catalyzed nucleophilic ring opening of oxabenzonorbornadienes.

We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to unsymmetrically arene-substituted oxabenzonorbornadienes. The regioselectivity of the ring opening was investigated using a variety of nucleophiles that led to a broad selection of dihydronaphthalene products. It was found that good to excellent regioselectivities are obtained using strongly pi-donating substituents, whereas sigma-donating and electron-withdrawing functionalities have a minimal effect. Post ring-opening manipulations of functional groups in the dihydronaphthalene products were shown to give efficient access to mono- and diamine tetrahydronaphthalene building blocks.