Reference values of the carotid elastic modulus using shear wave elastography and arterial stiffness change in coronary slow flow.

PURPOSE: Shear wave elastography (SWE) accurately and sensitively evaluates arterial wall stiffness by quantifying the elastic modulus (EM); however, the absence of reference values has precluded its widespread clinical application. This prospective cohort study aimed to establish reference values for the carotid EM using SWE; investigate the main determinants of the EM; and evaluate EM changes in coronary slow flow (CSF), which is characterized by delayed coronary opacification without evident obstructive lesion in epicardial coronary artery on angiography. METHOD: This study enrolled 169 healthy volunteers and 30 patients with CSF. The carotid maximum EM (EMmax), mean EM, and minimum EM were measured using SWE. CSF was diagnosed by thrombolysis in the myocardial infarction frame count during coronary angiography. RESULTS: No differences were found in the EM between the left and right carotid arteries and between men and women. Multiple linear regression analysis revealed that age was independently correlated with the EMmax, which progressively increased with age. Moreover, smoking had an independent influence on the EM after adjusting for age; smokers had higher EM than non-smokers. Age-specific reference values for the carotid EM were established. The EM was higher in patients with CSF than in controls after adjusting for age and smoking status. CONCLUSIONS: This study first established the reference values for the carotid EM using SWE. Age and smoking status were the main determinants of the EM. Patients with CSF had high EM. SWE can effectively and noninvasively evaluate arterial stiffness in patients with CSF.

Validation of estimating left ventricular ejection fraction by mitral annular displacement derived from speckle-tracking echocardiography: A neglected method for evaluating left ventricular systolic function.

PURPOSE: The echocardiographic measurement of left ventricular (LV) ejection fraction (EF) is dependent on professional experience and adequate visualization. Tissue motion of mitral annular displacement (TMAD) can be easily assessed using speckle-tracking echocardiography (STE), even in patients with poor acoustic windows. Therefore, this study aimed to assess whether left ventricular ejection fraction (LVEF) can be estimated using STE-derived TMAD when LVEF is not available. METHODS: Four-hundred fifty-six outpatients were enrolled after excluding the patients whose LVEF measurements remained challenging or TMAD value could be confounded. An optimized regression model for LVEF-TMAD was developed in the derivation set (n = 287), and its reliability was verified in the validation set (n = 123) and regional wall motion abnormalities (RWMA) set (n = 46). RESULTS: In the derivation set, the power models had the highest F-value. Therefore, the power equations were chosen to estimate LVEF by TMAD in the validation set. There was a near-zero bias and a narrow range between the observed and estimated LVEF. The highest intra-class correlation coefficient was found between the observed and the estimated LVEF by normalized TMAD at the midpoint of mitral annular (nTMADmid). Moreover, there were no significant differences between the observed and the estimated LVEF in the RWMA set. CONCLUSION: The LVEF can be estimated with STE-derived TMAD, even for patients with RWMA, and nTMADmid may be the optimal parameter.

Left ventricular systolic dysfunction potentially contributes to the symptoms in heart failure with preserved ejection fraction.

AIMS: Left ventricular diastolic dysfunction (LVDD) is considered a key factor associated with heart failure (HF) symptoms in patients with preserved ejection fraction (HFpEF). However, LV systolic performance, including LV systolic function and synchrony, has not been well characterized in these patients. The aims of this study were to assess to investigate the underlying relationship and differences between subclinical LVDD and HFpEF. METHODS: Eighty-six patients with LVDD were recruited (58 with HFpEF and 28 with subclinical LVDD). Systolic left ventricular (LV) longitudinal strain (LS), systolic longitudinal strain rate (LSrS), early diastolic longitudinal strain rate (LSrE), and late diastolic longitudinal strain rate (LSrA) were measured using speckle tracking echocardiography. LV diastolic and systolic dyssynchrony (Te-SD and Ts-SD) were calculated. Forty age- and sex-matched healthy individuals were enrolled as a control group. RESULTS: LV global LS and LSrS were decreased in patients with HFpEF than in normal controls and subclinical LVDD patients (P < .05). Te-SD and Ts-SD were significantly more prolonged in subclinical LVDD and HFpEF patients than in the control group (P < .05). Reduced LS was associated with HF symptoms in LVDD patients, and a cutoff value of -18% for LS could differentiate HFpEF from subclinical LVDD with 73% sensitivity and 69% specificity. CONCLUSION: LV systolic function and mechanical dyssynchrony were impaired in HFpEF patients. Deteriorated LV longitudinal systolic function was likely correlated with the symptoms of HFpEF.

Synthesis of Ag/BiVO4/rGO composite with enhanced photocatalytic degradation of triclosan.

A ternary visible-light driven photocatalyst, Ag/BiVO4/reduced graphene oxide (rGO) composite was manufactured by hydrothermal strategy. The optimized products were characterized by XRD, SEM, HRTEM, EDS, XPS, DRS, Raman spectra, PL, BET, photocurrent density and EIS analysis. Compared to pure BiVO4, the fabricated ternary composite showed enhanced photocatalytic ability to decompose pollutant under visible light. Triclosan was completely removed after 100 min in solution with 1 mg/mL photocatalyst under visible light irradiation. Repeated cycle tests demonstrated the photo-stability and reusability of composite to decompose triclosan, indicating that this material could be utilized repeatedly. The upgraded photocatalytic ability was attributed to the addition of Ag and rGO, which enhanced the charge separation and inhibited the recombination of photogenerated electrons and holes. The EPR spin-trap technique (with DMPO) was performed to identify the radicals produced in Ag/BiVO4/rGO under the visible light, and trapping experiments were conducted to determine the main active species in the photocatalytic process of decomposing triclosan. Finally, seven reaction intermediates of triclosan were detected by LC-MS/MS and possible degradation routes were proposed.

Predictive Value of Septal Flash for Reduction of Left Ventricular Systolic Function as Reflected by Global Longitudinal Strain Using Echocardiography in Patients With Isolated Complete Left Bundle-Branch Block.

BACKGROUND: Septal leftward motion followed by a counter motion during early systole is known as septal flash (SF) in patients with isolated complete left bundle-branch block (cLBBB). This study aimed to determine the predictive value of SF for reduction of left ventricular (LV) global systolic function using 2D speckle-tracking echocardiography (2D STE) in cLBBB patients.Methods and Results:The study group of 41 patients with isolated cLBBB and preserved LV ejection fraction and 41 age- and sex-matched control subjects were studied. The presence of SF and LV global longitudinal strain (GLS) were defined and measured using 2D STE. Multivariate logistic regression analysis identified the presence of SF as an independent factor predicting LV GLS >-20% in isolated cLBBB patients (odds ratio, 1.38; 95% confidence interval, 1.10-1.72; P=0.005). LV GLS in cLBBB patients with SF further decreased over time, whereas LV GLS did not decrease in patients without SF. The presence of SF was shown to be an independent factor predicting the reduction of LV global systolic function (relative reduction in LV GLS >15% from baseline to 2-year follow-up) (odds ratio, 1.27; 95% confidence interval, 1.06-1.50; P=0.008). CONCLUSIONS: Assessment of SF by 2D STE may be an easy and effective method of predicting the reduction in LV global systolic function in isolated cLBBB patients.

Incremental Value of the Tissue Motion of Annular Displacement Derived From Speckle-Tracking Echocardiography for Differentiating Chronic Constrictive Pericarditis From Restrictive Cardiomyopathy.

OBJECTIVES: The tissue motion of annular displacement provides an accurate and rapid assessment of left ventricular (LV) systolic function. However, it has rarely been used in patients with chronic constrictive pericarditis and restrictive cardiomyopathy. This study aimed to assess the differences in LV systolic function in patients with constrictive pericarditis and restrictive cardiomyopathy using tissue motion of annular displacement derived from speckle-tracking echocardiography. METHODS: Twenty-four patients with constrictive pericarditis, 24 with restrictive cardiomyopathy, and 25 healthy volunteers (controls) were enrolled. The septal and lateral mitral annular longitudinal displacements, displacement at the midpoint, and normalized midpoint displacement of the mitral ring were calculated. RESULTS: Mitral annular tracking and quantification of the tissue motion of annular displacement were achieved within 10 seconds. In patients with constrictive pericarditis, the lateral mitral annular longitudinal displacement, displacement at the midpoint, and midpoint displacement of the mitral ring were decreased, whereas the septal mitral annular longitudinal displacement was preserved compared to controls, indicating that the reduction of systolic function in constrictive pericarditis was caused by pericardial adhesion and calcium. In patients with restrictive cardiomyopathy, tissue motion of annular displacement was more reduced compared to patients with constrictive pericarditis and controls. The correlation between the septal mitral annular longitudinal displacement and left ventricular ejection fraction was 0.67 (P < .001). A cutoff value of 8.45 mm for the septal mitral annular longitudinal displacement could effectively differentiate constrictive pericarditis from restrictive cardiomyopathy with 95.2% sensitivity and 91.7% specificity. CONCLUSIONS: The tissue motion of annular displacement was decreased in patients with constrictive pericarditis, which indicated early impairment of longitudinal function in constrictive pericarditis; adhesion and calcium in the pericardium might account for the reduction. The septal mitral annular longitudinal displacement provides a fast and effective method for the assessment of LV systolic function in patients with constrictive pericarditis and restrictive cardiomyopathy.

Impaired left atrial systolic function and inter-atrial dyssynchrony may contribute to symptoms of heart failure with preserved left ventricular ejection fraction: A comprehensive assessment by echocardiography.

AIMS: To assess LA diastolic and systolic function and atrial dyssynchrony in patients with heart failure with preserved ejection fraction (HFpEF) and to examine whether LA dysfunction and dyssynchrony account for the patients' symptoms of HFpEF. METHODS: Fifty-five patients with HFpEF, 31 asymptomatic patients with left ventricular diastolic dysfunction (LVDD) and 33 healthy individuals were enrolled in the study. The LA active ejection fraction (LAAEF) was calculated. The peak atrial longitudinal systolic strain (PALS) and peak atrial contraction strain (PACS) were measured using speckle tracking echocardiography (STE). Atrial dyssynchrony including inter-atrial dyssynchrony, LA dyssynchrony and right atrial dyssynchrony were calculated by tissue Doppler imaging (TDI). RESULTS: The PALS and PACS were deteriorated, whereas inter-atrial dyssynchrony was prolonged in patients with HFpEF (20.41±7.41%, 10.83±4.19%, 31±15ms, respectively) compared with the values obtained in asymptomatic LVDD patients (26.61±6.30%, 13.23±4.52%, 19±12ms, respectively) and those found in normal individuals (33.51±6.74%, 14.17±2.88%, 17±12ms, respectively) (P<0.05). However, PACS and inter-atrial dyssynchrony did not reach statistical significance between asymptomatic LVDD and normal individuals (P>0.05). Moreover, patients with deteriorated clinical symptoms (NYHA>II) presented worse LA systolic function and prolonged dyssynchrony compared with those with NYHA=II. Inter-atrial dyssynchrony and LAAEF are independently associated with worse NYHA functional classes in patients with HFpEF. CONCLUSIONS: LA diastolic and systolic function were significantly impaired, and inter-atrial dyssynchrony was prolonged in patients with HFpEF. Decreased LA systolic function and prolonged inter-atrial dyssynchrony were possibly associated with deteriorated clinical symptoms.

Left ventricular diastolic and systolic dyssynchrony and dysfunction in heart failure with preserved ejection fraction and a narrow QRS complex.

Aims: Mechanical dyssynchrony has been reported in heart failure with preserved ejection fraction (HFpEF), with a majority of patients having a narrow QRS complex; however, whether any benefit is observed with restoration of dyssynchrony remains unclear. We sought to assess left ventricular (LV) dyssynchrony and function in HFpEF and elucidate the underlying mechanisms that may account for HFpEF. Methods: Seventy-eighty patients with a narrow QRS complex including 47 with HFpEF, 31 with heart failure with reduced ejection fraction (HFrEF) patients, and 29 with asymptomatic left ventricular diastolic dysfunction (LVDD) were recruited. Forty-five normal subjects acted as controls. Systolic LV longitudinal strain (LS), systolic longitudinal strain rate (LSrS), early diastolic longitudinal strain rate (LSrE), and late diastolic longitudinal strain rate (LSrA) were measured using speckle tracking echocardiography. LV diastolic and systolic dyssynchrony (Te-SD and Ts-SD) were calculated. Results: Te-SD and Ts-SD were prolonged in HFpEF and HFrEF patients than in the control group (p<0.05). However, Ts-SD was shorter in HFpEF patients compared to HFrEF patients despite a narrow QRS complex (p<0.05). LV global LS, LSrS, and LSrE were decreased in patients with HFpEF and HFrEF compared to other groups, with HFrEF being even more reduced than HFpEF (p<0.05). Reduced LS, LSrS, and LSrE could effectively differentiate HF from asymptomatic LVDD patients (p<0.05). Conclusion: HFrEF exhibited increased systolic dyssynchrony compared to HFpEF despite a narrow QRS complex in addition to the more reduced diastolic and systolic function. Therefore, targeting to improve diastolic and systolic function instead of managing systolic dyssynchrony might be of great importance in the treatment of HFpEF.

Effect of septal flash on right ventricular systolic function in left bundle-branch block patients with preserved left ventricular ejection fraction.

A leftward motion of the ventricular septum prior to ejection, known as the septal flash (SF), is frequently observed in patients with left bundle-branch block (LBBB). We investigated whether the abnormal motion of the ventricular septum affects right ventricle (RV) contractile performance in LBBB patients with preserved left ventricular ejection fraction (LVEF). Forty-four patients with complete LBBB were selected using standard 12-lead electrocardiograms (ECGs), with 30 healthy individuals serving as controls. According to the presence of SF, patients with LBBB were allocated to two subgroups: those with SF (LBBB-SF, n = 24) and those without SF (LBBB-NSF, n = 20). RV longitudinal strain (LS) decreased in LBBB patients with preserved LVEF compared to control subjects (p = 0.002). And RV LS decreased significantly in LBBB-SF patients compared to NSF-LBBB patients (p = 0.04). RV LS correlated negatively with involved septal myocardial segments of SF (r = -0.36, p = 0.02), but did not correlate with the magnitude of SF. RV contractile performance deceased in LBBB patients with preserved LVEF. SF, particularly the extent of this phenomenon, may further affect RV contractile performance.

Cardiac involvements in hypereosinophilia-associated syndrome: Case reports and a little review of the literature.

Hypereosinophilia-associated syndrome is a rare group of systemic diseases without certain underlying causes. Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (CSS), are initial considerations, when underlying causes remains unexplained despite of complete evaluation of hypereosinophilia. In this study, we report two rare cases, one case of HES with Loeffler endocarditis, and the other one of EGPA with restrictive cardiomyopathy mimicking myocardial infarction, to further address differential chief cardiac manifestations between HES and EGPA. Key roles of echocardiography played in detection of cardiac involvements, diagnosis, and prognosis prediction are also highlighted.

The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

Layer-specific analysis of left ventricular myocardial contractility in patients with coronary slow-flow phenomenon.

PURPOSE: Coronary slow-flow phenomenon (CSFP) is an angiographic diagnosis characterized by delayed coronary opacification in the absence of significant epicardial coronary stenosis. We previously reported impaired left ventricular (LV) function in patients with CSFP. However, the LV wall comprises three myocardial layers whose contractility can be differently affected. Therefore, we evaluated layer-specific (endocardial, mid-myocardial, and epicardial) LV myocardial contractility and assessed its relationships with the number of affected coronary arteries and their flow. METHODS: We studied 60 patients with CSFP and 46 controls. CSFP was diagnosed by thrombolysis in myocardial infarction frame count. Echocardiography was performed within 72 hours after the coronary angiography. LV layer-specific longitudinal strain (LS) was measured using two-dimensional speckle-tracking echocardiography. RESULTS AND CONCLUSIONS: The LS of all three myocardial layers was lower in patients with CSFP than in controls. In patients with CSFP, LS of all three myocardial layers and transmural LS gradient correlated negatively with the number of affected coronary arteries and the mean thrombolysis in myocardial infarction frame count. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:429-436, 2016.

Evaluation of Left and Right Atrial Function in Patients with Coronary Slow-Flow Phenomenon Using Two-Dimensional Speckle Tracking Echocardiography.

BACKGROUND: Coronary slow-flow phenomenon (CSFP) is an angiographic diagnosis characterized by delayed coronary opacification in the absence of obstructive coronary artery disease. Currently, several investigators are focusing on ventricular function assessment in patients with CSFP; however, there is a paucity of data on their atrial function. This study was performed to evaluate left atrial (LA) and right atrial (RA) function in patients with CSFP. MATERIALS AND METHODS: Eighty-two patients with CSFP and 55 controls without CSFP were enrolled in the study. Diagnosis of CSFP was made by thrombolysis in myocardial infarction frame count (TFC). The LA and RA global longitudinal strain and strain rate during systole (Ss, SRs), during early diastole (Se, SRe), and during late diastole (Sa, SRa) were measured using two-dimensional speckle tracking echocardiography. RESULTS: In the CSFP group, LA Se and SRe decreased, while LA Sa and SRa increased, compared with the control group. RA Se and SRe were lower in patients with CSFP than in the controls. CONCLUSIONS: LA conduit function decreased in patients with CSFP, while contractile function increased. RA conduit function also decreased in patients with CSFP.

Assessment of risk factors and left ventricular function in patients with slow coronary flow.

Slow coronary flow (SCF) is characterized by delayed distal vessel opacification in the absence of significant epicardial coronary disease. Life-threatening arrhythmias and sudden cardiac death can occur; however, the pathological mechanism and influence on left ventricular function remain undetermined. We aimed to assess the risk factors and left ventricular (LV) function in SCF and evaluate the relationships between thrombolysis in myocardial infarction frame count (TFC) and the number of involved coronary arteries with LV function in patients with SCF. We included 124 patients who underwent coronary angiography because of symptoms of angina; 71 patients with angiographically proven SCF and 53 cases with normal coronary flow pattern. SCF was diagnosed as TFC >27 in at least one coronary artery. Complete blood count and biochemical parameters were compared between the two groups. Conventional echocardiography and tissue Doppler imaging were used to assess LV systolic and diastolic function. Platelet aggregation rate induced by ADP was an independent predictor of SCF and positively correlated with coronary artery mean TFC (mTFC) (r = 0.514, P < 0.001) and the number of coronary arteries with SCF (r = 0.628, P < 0.001). Early diastolic mitral inflow velocity (E) (0.66 ± 0.15 vs. 0.74 ± 0.17, P = 0.008), ratio of early to late diastolic mitral inflow velocity (E/A) (0.95 ± 0.29 vs. 1.15 ± 0.35, P = 0.002), global myocardial peak early diastolic velocity (gVe) (4.41 ± 1.25 vs. 4.96 ± 1.45, P = 0.037), and ratio of global myocardial peak early to late diastolic velocity (gVe/gVa: 1.09 ± 0.45 vs. 1.36 ± 0.58, P = 0.006) were decreased in patients with SCF compared with controls. gVe (3 vs. 0 branches, 4.08 ± 1.14 vs. 4.97 ± 1.45, respectively, P = 0.008) deteriorated significantly in patients with SCF involving three coronary arteries. mTFC negatively correlated with E and E/A (r = -0.22, P = 0.02; r = -0.20, P = 0.04, respectively). The number of coronary arteries with SCF negatively correlated with E, E/A, gVe and gVe/gVa (r = -0.23, P = 0.02; r = -0.25, P = 0.009; r = -0.25, P = 0.008; r = -0.21, P = 0.03, respectively). Platelet aggregation rate induced by ADP was an independent predictor of SCF and positively correlated with coronary artery TFC and the number of affected coronary arteries. Left ventricular global and regional diastolic function was impaired in SCF patients. Furthermore, the number of coronary arteries involved rather than coronary artery TFC determined the severity of left ventricular dysfunction in patients with SCF.

Assessment of left and right ventricular diastolic and systolic functions using two-dimensional speckle-tracking echocardiography in patients with coronary slow-flow phenomenon.

OBJECTIVE: Coronary slow-flow phenomenon (CSFP) is an angiographic diagnosis characterised by a low rate of flow of contrast agent in the normal or near-normal epicardial coronary arteries. Many of the patients with CSFP may experience recurrent acute coronary syndromes. However, current clinical practice tends to underestimate the impact of CSFP due to the yet unknown effect on the cardiac function. This study was performed to evaluate left ventricular (LV) and right ventricular (RV) diastolic and systolic functions, using two-dimensional (2D) longitudinal strain and strain rate, in patients with CSFP, and to determine the relationships between the thrombolysis in myocardial infarction (TIMI) frame count (TFC) and LV and RV diastolic and systolic functions. METHODS: Sixty-three patients with CSFP and 45 age- and sex-matched controls without CSFP were enrolled in the study. Diagnosis of CSFP was made by TFC. LV and RV diastolic and systolic functions were assessed by 2D speckle-tracking echocardiography. RESULTS: LV peak early diastolic longitudinal strain rate (LSRe) was lower in patients with CSFP than in controls (P = 0.01). LV peak systolic longitudinal strain (LS) and LV peak systolic longitudinal strain rate (LSRs) were lower in patients with CSFP than in controls (P = 0.004 and P = 0.03, respectively). There was no difference in LV ejection fraction. RV peak early diastolic longitudinal strain rate (RSRe) was lower in patients with CSFP than in controls (P = 0.03). There were no differences in RV peak systolic longitudinal strain (RS), RV peak systolic longitudinal strain rate (RSRs), or RV fractional area change among the groups. The mean TFC correlated negatively with LSRe and RSRe in patients with CSFP (r = -0.26, P = 0.04 and r = -0.32, P = 0.01, respectively). CONCLUSIONS: LV diastolic and systolic functions were impaired in patients with CSFP. CSFP also affected RV diastolic function, but not RV systolic function.

Libman-sacks endocarditis exclusively involving the tricuspid valve in a patient with systemic lupus erythematosus.

Libman-Sacks endocarditis, characterized by sterile verrucous vegetations, is a rare but typical cardiac manifestation of systemic lupus erythematosus. It primarily leads to lesions of the mitral and aortic valves, but isolated tricuspid valve involvement is exceptional. We report the case of a 40-year-old woman with large tricuspid valve vegetations, thickening, and regurgitation. Clinical findings and laboratory tests confirmed the diagnosis of systemic lupus erythematosus. The patient successfully recovered following tricuspid valve replacement. Echocardiography is the definitive imaging modality for assessing cardiac valvular involvement, choosing appropriate therapy, and evaluating the prognosis of Libman-Sacks endocarditis in systemic lupus erythematosus. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:265-267, 2015.

Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models.

PURPOSE: We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers. EXPERIMENTAL DESIGN: The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents. RESULTS: GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents. CONCLUSIONS: GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling.

[Collagen changes of allografting an acellular dermal matrix].

OBJECTIVE: To evaluate the collagen changes of allografting an acellular dermal matrix (allo-ADM). METHODS: The allo-ADM was grafted underneath the skin of SD rats. The content of collagen and the proportion of type I to III collagen was examined with a biochemical assay. RESULT: The content of collagen and the proportion of type I to III collagen in the allo-ADM group showed no significant changes. CONCLUSION: The allo-ADM could keep long time in the body and it may be an ideal material for soft tissue filling.

Prion and doppel proteins bind to granule cells of the cerebellum.

We reported that expression of the cellular prion protein (PrPC) rescues doppel (Dpl)-induced cerebellar degeneration in mice. To search for protein(s) that mediate this process, we fused the C-termini of mouse (Mo) PrP and Dpl to the Fc portion of an IgG. Although both MoPrP-Fc and MoDpl-Fc bound to many regions of the brain, we observed restricted binding to granule cells in the cerebellum, suggesting a scenario in which granule cells express a protein that mediates Dpl-induced neurodegeneration. Because granule cells do not express PrPC, it seems unlikely that MoPrP-Fc binding reflects a ligand that is involved in the conversion of PrPC into PrPSc, the disease-causing isoform. In contrast, the dominant-negative MoPrP(Q218K)-Fc not only binds to granule cells but also binds to neurons of the molecular layer where PrPC is expressed. These findings raise the possibility that the cells of the molecular layer express an auxiliary protein, provisionally designated protein X, which is involved in prion formation and is likely to be distinct from the protein that mediates Dpl-induced degeneration. Although the binding of the dominant-negative MoPrP(Q218K)-Fc to cells in the molecular layer expressing PrPC is consistent with a scenario for the binding of MoPrP(Q218K)-Fc to protein X, the absence of PrPSc deposition in the molecular layer requires that PrP(Sc), once formed there, be readily transported to the cerebellar white matter where PrPSc is found. Identifying the ligands to which PrP-Fc, Dpl-Fc, and dominant-negative PrP bind may provide new insights into the functions of PrPC and Dpl as well as the mechanism of PrPSc formation.