Medication adherence and stroke/TIA risk in treated hypertensives: Results from the REGARDS study

BackgroundThe extent to which low medication adherence in hypertensive individuals contributes to disparities in stroke and transient ischemic attack (TIA) risk is poorly understood.MethodsInvestigators examined the relationship between self-reported medication adherence and blood pressure (BP) control (<140/90 mm Hg), Framingham Stroke Risk Score, and physician-adjudicated stroke/TIA incidence in treated hypertensive subjects (n = 15,071; 51% black; 57% in Stroke Belt) over 4.9 years in the national population-based REGARDS cohort study.ResultsMean systolic BP varied from 130.8 ± 16.2 mm Hg in those reporting high adherence to 137.8 ± 19.5 mm Hg in those reporting low adherence (P for trend < .0001). In logistic regression models, each level of worsening medication adherence was associated with significant and increasing odds of inadequately controlled BP (≥140/90 mm Hg; score = 1, odds ratio [95% confidence interval], 1.20 [1.09–1.30]; score = 2, 1.27 [1.08–1.49]; score = 3 or 4, 2.21 [1.75–2.78]). In hazard models using systolic BP as a mediator, those reporting low medication adherence had 1.08 (1.04–1.14) times greater risk of stroke and 1.08 (1.03–1.12) times greater risk of stroke or TIA.ConclusionLow medication adherence was associated with inadequate BP control and an increased risk of incident stroke or TIA.     

Assessment of Apoptosis Regulating Factors BCL-2 and Fas Antigens on Malignant and Normal Plasma Cells

Multiple myeloma (MM) is characterised by slow proliferation of malignant plasma cells and their accumulation within the bone marrow. The dysregulation of programmed cell death (apoptosis) is a very important mechanism in the pathogenesis of this tumour. It prompted us to investigate the apoptosis regulating factors such as the pro-apoptotic Fas antigen and the anti-apoptotic protein BCL-2 on bone marrow malignant plasma cells in untreated patients with newly diagnosed MM and to compare them with their normal counterparts—plasma cells isolated from bone marrow of healthy individuals. Twenty-nine MM patients and 16 healthy persons were studied. Bone marrow mononuclear cells were isolated, indicated by monoclonal antibodies and analysed using the flow cytometry method. There was no statistically significant difference in BCL-2 expression in plasma cells between patients and control groups. However the percentage of BCL-2 positive cells was significantly related to the clinical stage of the disease. We detected statistically significant lower percentage of Fas positive cells in the patient group than in control.

We concluded that in MM at diagnosis the expression of BCL-2 in bone marrow malignant plasma cells was comparable to normal plasma cells but expression of Fas antigen on these cells was lower. It suggests that down regulation of Fas and normal regulation of BCL-2 may be implicated for myeloma cell survival and their escape from apoptosis in vivo.     

Pulmonary thromboembolism in congenital heart defects with severe pulmonary arterial hypertension

IntroductionCongenital heart defect (CHD) with shunt can lead to severe, even irreversible pulmonary arterial hypertension (PAH); in extreme form to Eisenmenger syndrome (ES). Despite relatively good long-term survival, these patients often suffer from cyanosis and multisystemic dysfunction, where pulmonary artery thrombosis can be a potentially fatal complication. Together with bleeding these are the most frequent causes of non-cardiac death in patients with severe PAH due to CHD.Patients and methodsProspective study of 40 patients with severe PAH due to CHD (28 female/12 male, median age 41.5 years) was performed, with the aim to analyze the presence of pulmonary artery thrombosis and correlating anatomical and laboratory risk factors.ResultsPrevious thrombosis and/or thromboembolic event was found in 7 patients (17.5%). Significant differences in cyanotic vs non-cyanotic patients were in red blood count parameters: median hemoglobin level 195 vs 141 (p<0.0001), median erythrocytes count 6.62 vs 4.88×10¹²/l (p<0.0001), median hematocrit 0.58 vs 0.44 (p<0.0001). Laboratory findings causing increased risk for thrombosis were increased thrombocytes aggregation in 15 patients (37.5%), hypercoagulation in 5 patients (12.5%) and endothelial dysfunction in 8 patients (20%). Anatomical risk factor—severe pulmonary artery dilatation (>40 mm in female and >45 mm in male) was found in 19 patients (51.4%).ConclusionsPatients with severe PAH due to CHD represent a high-risk group for pulmonary artery thrombosis with morphological and flow pathology combined with secondary erythrocytosis and coagulation abnormalities. A relatively high incidence of platelet hyperaggregability shown in our study would propose that aspirin therapy might be considered in some highly selected patients with severe PAH due to CHD. Further studies though are needed to support this data.     

APBB2 genetic polymorphisms are associated with severe cognitive impairment in centenarians

APBB2 gene encodes for β-amyloid precursor protein-binding family B member 2, (APBB2, FE65-like, FE65L1), an adaptor protein binding to the cytoplasmatic domain of β-amyloid precursor protein (βAPP). Over-expression of APBB2 promotes formation of β-amyloid (Aβ), the main constituent of senile plaques. Polymorphisms within APBB2 gene have been proposed as candidate risk factors for Alzheimer's disease. However, their association with longevity has never been investigated. Here we present the first attempt to analyze APBB2 polymorphisms in centenarians. We used a PCR-RFLP method to analyze two intronic nucleotide substitutions: hCV1558625 (rs17443013) and rs13133980. We found no differences in genotype or allele distribution between centenarians and young controls. After stratification of centenarians upon their cognitive performance, the APBB2 rs13133980 G allele was over-represented in centenarians with severe cognitive impairment compared to individuals without this disability. Also the hCV1558625-rs13133980 AG haplotype increased relative risk for severe cognitive impairment in centenarians. Our results support the concept of APBB2 polymorphism association with cognitive performance in the oldest age.     

Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins

The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non–small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1^G2032R mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.Receptor tyrosine kinases (RTKs) are critical mediators of extracellular signals that control key cell growth, survival, and motility pathways. Conversely, deregulated and constitutive RTK activation is responsible for the initiation and progression of many cancers. Multiple mechanisms contribute to aberrant RTK activation including chromosomal rearrangements, point mutations, and gene amplification. Oncogenic activation of the orphan RTK c-ros oncogene 1 (ROS1) is observed in a subset of patients with glioblastoma, non–small-cell lung cancer (NSCLC), and cholangiocarcinoma (1–5). In most cases, ROS1 signaling is activated by interchromosomal translocation or intrachromosomal deletion that results in N-terminal ROS1 fusion genes. Several ROS1 kinase fusion proteins have been identified, including the Fused in Glioblastoma–ROS1 (FIG–ROS) that was first discovered in a human glioblastoma cell line (2) and more recently in patients with NSCLC (4), cholangiocarcinoma (3), and serous ovarian carcinoma (6). The SLC34A2–ROS1 (SLC–ROS) fusion is present in a subset of patients with NSCLC (1, 7) and gastric cancer (8). Other ROS1 fusions include CD74–ROS1, EZR–ROS1, LRIG3–ROS1, SDC4–ROS1, and TPM3–ROS1 (5).Given the recent success of molecularly targeted therapies in treating cancers driven by oncogenic kinases, there is acute clinical momentum to identify inhibitors that selectively target ROS1 fusions. Because the ROS1 and Anaplastic Lymphoma Kinase (ALK) domains are partially homologous, the Food and Drug Administration (FDA)-approved ALK/MET kinase inhibitor crizotinib is being investigated via phase I/II clinical trials for its efficacy in ROS1-driven lung cancer patients (9). Although early results appear promising, consistent with the clinical experience of crizotinib in patients with ALK-positive lung cancer to date, as well as prior experience with kinase inhibitors in many other malignancies (10–13), recent evidence suggests that a subset of patients with crizotinib-treated ROS1 fusion-positive may acquire ROS1 kinase domain mutations that confer drug resistance, thus necessitating alternative therapeutic approaches.To identify additional and potentially more efficacious ROS1 inhibitors, we used an unbiased, high-throughput kinase inhibitor screening assay and discovered that foretinib (GSK1363089) and Gö6976 are potent inhibitors of ROS1. Foretinib selectively suppresses the growth of the SLC–ROS-driven human NSCLC cell line HCC78 and of FIG–ROS-driven murine cholangiocarcinoma, but not of EGFR-driven NSCLC or phosphatase and tensin homolog (PTEN)-suppressed murine cholangiocarcinoma cells. Further, treatment of tumor-bearing mice with foretinib resulted in specific and dramatic regression of FIG–ROS-driven tumors in contrast to non-FIG–ROS tumors that share similar histopathological features. Importantly, we also use a cell-based in vitro resistance screen to preemptively identify several ROS1 kinase domain point mutations that confer resistance to crizotinib and show that these crizotinib-resistant ROS1 mutants remain sensitive to foretinib. These data suggest that foretinib may provide an alternative front-line treatment for ROS1-positive tumors and an effective second-line approach for patients that develop crizotinib-resistant disease.