Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells

The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth- factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13-259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G- protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.     

Lymphangiomas in children: MR imaging

Seventeen lymphangiomas in 15 patients were imaged with magnetic resonance (MR) to define the nature, extent, and anatomic relationships of these lesions. The MR and pathologic findings were then compared to determine the histologic basis for the signal-intensity characteristics of these lesions. The signal intensity of 13 lesions was similar to or slightly less than that of muscle on T1-weighted images and greater than that of fat on T2-weighted images. This appearance correlated with the presence of ectatic lymphatic channels containing clear fluid on histologic section. Four lymphangiomas had high signal intensity, approximately equal to that of fat, on T1-weighted images, reflecting the presence of clotted blood or small cystic spaces with a higher ratio of fat to fluid. Sixteen of 17 lesions had visible septations on MR images. The authors' experience suggests that most lymphangiomas have a characteristic appearance on MR images. The information obtained with MR imaging can help in providing a preoperative diagnosis, in planning surgical resection, and in defining recurrence.     

The relationship between bicultural identity,acculturative stress,and psychological well‐being in multicultural adolescents: Verification using multivariate latent growth modelling

This study aimed to examine causal relationships between bicultural identity, acculturative stress, and subjective well‐being among multicultural adolescents. Secondary longitudinal data that were obtained from 1,635 multicultural adolescents were analysed. The results showed that bicultural identity had a positive effect on psychological well‐being and a negative impact on acculturative stress; in addition, greater acculturative stress was associated with lower psychological well‐being. Finally, bicultural identity indirectly affected psychological well‐being by mediating the effects of acculturative stress. These findings underscore the need to facilitate the adaptation of multicultural adolescents by reducing acculturative stress and promoting bicultural acceptance in educational institutions.     

Adoptive Transfer of Human Papillomavirus E7-specific CTL Enhances Tumor Chemoresponse Through the Perforin/Granzyme-mediated Pathway

Adoptive cytotoxic T lymphocyte (CTL) therapy has an important implication in treating cancer patients. Here, we investigate whether adoptive transfer of human papillomavirus (HPV) E7-specific CTL can enhance tumor chemoresponse using an established cervical cancer animal model. Cisplatin-based chemotherapy plus CTL therapy showed an improved therapeutic effectiveness, along with antitumor protective responses to a parental tumor cell rechallenge. Cisplatin treatment dose-dependently increased the expression of Fas, intercellular adhesion molecule (ICAM)-1, and major histocompatibility complex (MHC) class I antigens (Ags) on tumor cells in vitro. However, CTL-expressing FasL failed to improve antitumor activity in vitro and in animals, resulting from nonfunctional Fas expressed on tumor cells. In contrast, ethylene glycol tetraacetic acid (EGTA) treatment blocked increased sensitivity of cisplatin-treated tumor cells to CTL-mediated killing in vitro, suggesting an important role of the perforin/granzyme-mediated pathway for improved therapeutic effectiveness. This notion was further confirmed by perforin knockout animal studies. Thus, this study shows that (i) modulation of Ag (Fas, ICAM-1) expression by tumor cells has little effect on their increased sensitivity to CTL-mediated killing, (ii) improved therapeutic effectiveness is mediated mainly through the perforin/granzyme-mediated tumor killing pathway, and (iii) a combination of chemotherapy and adoptive E7-specific CTL transfer augments antitumor therapeutic activity in vivo. This finding may have important implications for treating HPV-associated cervical cancer.     

Accumulation of coronary artery disease risk factors over three years: data from an international inception cohort

OBJECTIVE: To examine the accumulation of risk factors over 3 years in a multicenter, international inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: The Systemic Lupus International Collaborating Clinics registry for atherosclerosis comprises 27 centers from 11 countries. An inception cohort of 935 patients with SLE was assembled, according to a standardized protocol, from 2000 to 2006 to study risk factors for atherosclerosis. Both classic and other coronary artery disease (CAD) risk factors were collected at entry and through 3 years of followup. Therapy was documented over the 3 years. The Framingham 10-year risk factor profile was calculated for each patient at year 1 and year 3. RESULTS: A total of 278 patients from the inception cohort were followed for 3 years and constituted the population for this study. At enrollment a substantial number of patients already demonstrated several risk factors for CAD, both classic and other. All risk factors increased from enrollment over the 3 years of followup. Treatment of hypertension and hypercholesterolemia also increased over 3 years, but less so for hypercholesterolemia. The Framingham 10-year CAD risk profile was higher in men than in women both at entry and at 3 years, and remained unchanged over the 3 years. Corticosteroid use increased only slightly over 3 years, but use of antimalarials and immunosuppressive agents increased to a greater extent. CONCLUSION: Patients with SLE should be monitored for CAD risk factors from the time of diagnosis and appropriate treatment should be instituted early.     

Males seropositive for hepatitis B surface antigen are at risk of lower bone mineral density: the 2008–2010 Korea National Health and Nutrition Examination Surveys

Background

Hepatic osteodystrophy has been reported in patients with various chronic liver diseases, including liver cirrhosis. However, it has not been well investigated in patients with hepatitis B virus infection. The aim of this study was to investigate the association between hepatitis B surface antigen (HBsAg) seropositivity and bone mineral density (BMD) in a population representative of normal Koreans.

Methods

Subjects with both HBsAg and BMD levels examined during the 2008–2010 Korea National Health and Nutrition Examination Surveys were included. HBsAg-seropositive (+) subjects were compared with those who were HBsAg-seronegative (?). BMD was measured at the lumbar spine and femur by dual-energy X-ray absorptiometry. Multivariable logistic regression was performed for BMD.

Results

In total, 11,306 participants were included in this study, among which 423 (3.7 %) were HBsAg(+): 153 premenopausal female (3.4 %), 83 postmenopausal female (3.5 %), and 187 male (4.2 %). Multivariable logistic regression analysis adjusted for age and body mass index showed that HBsAg(+) male had significantly lower BMD of the femoral neck than HBsAg(?) male (0.810 ± 0.009 vs. 0.827 ± 0.002 g/cm², p = 0.035). Further adjustment for waist circumference, smoking, drinking, exercise, income, occupation, and vitamin D levels showed that HBsAg(+) male had significantly lower BMD of the femur neck (0.810 ± 0.010 vs. 0.831 ± 0.002 g/cm², p = 0.032) and lumbar spine (0.953 ± 0.011 vs. 0.974 ± 0.003 g/cm², p = 0.049) than HBsAg(?) male.

Conclusions

HBsAg seropositivity was significantly associated with lower BMD in male. Future long-term prospective studies investigating bone turnover markers and hormones are needed to better understand the pathophysiology and clinical significance of chronic hepatitis B virus-related hepatic osteodystrophy.

     

Intracranial hemorrhage after carotid angioplasty: a pooled analysis.

PURPOSE: To use a pooled analysis of the literature to find the incidence of and characteristics common to intracranial hemorrhage (ICH) associated with carotid artery stenting (CAS). METHODS: A search of the English-language literature (1996-2005) was performed in PubMed to find cases of CAS-associated ICH. Information was derived from the identified case studies in 5 categories and 19 aspects: (1) incidence of CAS-associated ICH; (2) demographic data (sex, age, symptom presentation, and presence of preexisting hypertension); (3) imaging data (side of lesion, degree of maximal stenosis, lesion location, status of the contralateral carotid artery, collateral circulation, and preprocedural imaging features); 4) procedure-related characteristics (antithrombotic medication, use of cerebral protection devices, residual stenosis, symptoms, interval from the procedure to ICH, type of ICH, and blood pressure changes); and (5) clinical outcome. RESULTS: Fifty-four cases of CAS-associated ICH were reviewed: 51 cases from 36 published articles and our own 3 cases. The incidence of CAS-associated ICH was 0.63% (95% CI 0.38% to 0.97%) in studies consisting of >100 cases, which was significantly lower (p<0.0001) than that of case series consisting of <100 cases (2.69%, 95% CI 1.75% to 3.94%). Distinctive features included symptomatic lesions, severe stenosis (> or =90%), maximal stenosis in the internal carotid artery (ICA) distal to the bifurcation, and preexisting cerebral infarction. CONCLUSION: The incidence of CAS-associated ICH was significantly lower in series consisting of >100 cases. More caution should be directed toward patients with symptomatic lesions, severe stenosis, maximal ICA stenosis distal to the carotid bifurcation, and preexisting cerebral infarction.