c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun.

c-Jun N-terminal kinase (JNK) plays a vital role in malignant transformation of different cancers, and JNK is highly activated in basal-like triple-negative breast cancer (TNBC). However, the roles of JNK in regulating cancer stem-like cell (CSC) phenotype and tumorigenesis in TNBC are not well defined. JNK is known to mediate many cellular events via activating c-Jun. Here, we found that JNK regulated c-Jun activation in TNBC cells and that JNK activation correlated with c-Jun activation in TNBC tumors. Furthermore, the expression level of c-Jun was significantly higher in TNBC tumors than in non-TNBC tumors, and high c-Jun mRNA level was associated with shorter disease-free survival of patients with TNBC. Thus, we hypothesized that the JNK/c-Jun signaling pathway contributes to TNBC tumorigenesis. We found that knockdown of JNK1 or JNK2 or treatment with JNK-IN-8, an adenosine triphosphate-competitive irreversible pan-JNK inhibitor, significantly reduced cell proliferation, the ALDH1+ and CD44+/CD24- CSC subpopulations, and mammosphere formation, indicating that JNK promotes CSC self-renewal and maintenance in TNBC. We further demonstrated that both JNK1 and JNK2 regulated Notch1 transcription via activation of c-Jun and that the JNK/c-Jun signaling pathway promoted CSC phenotype through Notch1 signaling in TNBC. In a TNBC xenograft mouse model, JNK-IN-8 significantly suppressed tumor growth in a dose-dependent manner by inhibiting acquisition of the CSC phenotype. Taken together, our data demonstrate that JNK regulates TNBC tumorigenesis by promoting CSC phenotype through Notch1 signaling via activation of c-Jun and indicate that JNK/c-Jun/Notch1 signaling is a potential therapeutic target for TNBC.

Does left ventricular shape influence clinical outcome in heart failure?

BACKGROUND: Left ventricular (LV) shape tends to become spherical in patients with dilated cardiomyopathy of diverse etiology. Clinical and echocardiographic factors which affect the degree of LV spherical distortion and the impact of altered LV shape on prognosis have not been studied adequately. HYPOTHESIS: This study was undertaken to investigate the prognostic implications of altered LV shape on clinical outcome in dilated cardiomyopathy. METHODS: In 112 patients with depressed LV ejection fraction (19 +/- 9%) and symptomatic heart failure, and in 10 age- and gender-matched normal controls, we performed 2-dimensional echocardiography to assess LV shape using the eccentricity index. Eccentricity index was defined as the ratio of the LV long axis to the LV transverse diameter, measured at end systole and end diastole in the apical four-chamber view. We sought univariate and multivariate clinical and echocardiographic correlates of LV shape. Further, we sought correlations between eccentricity index and clinical outcomes (death and composite outcome of death or emergent heart transplant). RESULTS: Compared with controls, patients with cardiomyopathy had significantly lower systolic (2.04 vs. 1.56; p = 0.001) and diastolic (1.75 vs. 1.53; p = 0.003) eccentricity index, implying a more spherical LV shape. Of all clinical and echocardiographic variables tested, mitral regurgitation, right ventricular dysfunction, and increased LV mass were independently associated with spherical LV shape. At a follow-up period of 17 +/- 12 months, no correlation was found between eccentricity index and the occurrence of death or the combined endpoint of death or emergent heart transplant, in univariate or multivariate analysis. CONCLUSIONS: In patients with dilated cardiomyopathy, the degree of spherical distortion of the LV does not correlate with prognosis.

Acute coronary occlusion and in-stent thrombosis in a patient with essential thrombocythemia.

We describe a case of essential thrombocythemia in a 34-year-old male who presented with acute anterior wall myocardial infarction and a platelet count of 2,100,000/mm3. Primary percutaneous coronary angioplasty and stenting were performed. Postangioplasty course was complicated by stent thrombosis requiring repeat coronary angioplasty and persistent femoral arterial bleeding that was treated with surgical exploration and repair. The patient was subsequently treated with platelet pheresis, acetylsalicylic acid, ticlopidine, hydroxyurea, and anagrelide without further complications.