Type A aortic intramural haematoma--clinical course in two patients

Aortic intramural haematoma (AIH) is a variation of aortic dissection where blood collects within the aortic media without the presence of an intimal flap. The natural history of the disease has not yet been definitely established. Two cases of AIH type A are presented--an 81-year-old hypertensive male, and a 60-year-old male, both admitted to the hospital with sudden-onset severe chest pain. In both cases AIH type A was confirmed using computed tomography. One patient underwent successful conservative treatment, whereas another one had urgent surgery.     

Pharmacological versus invasive treatment in patients with atrial fibrillation

Aim of this prospective study was to assess quality of life (QoL), left ventricular (LV) function and exercise performance in two groups of patients (pts) with atrial fibrillation (Af) treated with: radiofrequency catheter ablation (RFA) and antiarrhythmic drugs (AA). Between 1996 and 2000 - 74 patients, 28 women, with drug refractory Af were enrolled by clinical indications for two modes of therapy: RFA and AA. RFA group consisted of 38 pts, 63.7 +/- 11.5 years old: 28 pts with RF AV Node ablation and pacemaker implantation (PI) and 10 pts with AV Node modification or right atrial isthmus RF ablation due to Af conversion to atrial flutter (Aflu) during medical therapy. AA group consisted of 36 pts, aged 59.7 +/- 13.8 years. Patients from RFA group suffered significantly more serious diseases than pts from AA group. No significant (sign.) differences between two groups were found in age, gender, arrhythmia history and number of AA taken. Pts were analyzed before entry, after 3 and 12 months of follow-up (3 mo. FU, 12 mo. FU) with following indices: LV function (Echo: EF & FS), exercise performance (treadmill test), QoL questionnaires, number of hospital admissions connected to arrhythmia or procedures (RFA & PI), number of AA drugs taken in RFA group. RFA group: Two deaths occurred due to end stage respiratory insufficiency (COPD), one pt required reposition of pacemaker lead. AA group: 3 pts required RFA due to uncontrolled Af/Aflu (AV Node ablation with PI - 1 pt, right atrial isthmus ablation - 2 pts). Analysis of two patients groups: LV function: Sign. improvement (EF & FS) in both groups in 12 mo. FU; Exercise performance: no sign. changes in 3 and 12 mo. FU. QoL: Arrhythmia scale: 3 mo. FU sign. reduction in both groups; 12 mo. FU reduction in RFA group only; Anxiety scale: 3 and 12 mo. FU sign. reduction of anxiety level in RFA group; Exercise and activity scales: 3 and 12 mo. FU sign. improvement in RFA group. During 3 and 12 mo. FU sign. less pts from RFA group required hospital admission versus pts from AA group. Sign. reduction in AA was noted in RFA group. Patients with symptomatic Af treated with RFA benefit from this kind of therapy more than patients treated with AA. Quality of life improvement visible in short term observation in patients from RFA group is still present after one year observation. Improvement in LV function is observed after one year in both groups of pts with Af.     

An evaluation of RVX-208 for the treatment of atherosclerosis

Introduction: RVX-208 is a first-in-class, orally active, novel small molecule in development by Resverlogix Corporation (Calgary, AB, Canada). It acts through an epigenetic mechanism by inhibiting the bromodomain and extraterminal (BET) family of proteins, increasing apolipoprotein A-I (apoA-I) and targeting high-density lipoprotein (HDL) metabolism, including generating of nascent HDL and increased larger HDL particles, resulting in the stimulation of reverse cholesterol transport. RVX-208 also has a beneficial effect on inflammatory factors known to be involved in atherosclerosis and plaque stability. New therapeutic strategies are needed for patients with atherosclerosis.

Areas covered: In this review, the authors evaluate the use of RVX-208 as an agent for the treatment of atherosclerosis. The article is based on a literature search considering both animal and human studies available on PubMed as well as Media Releases from the Resverlogix Corporation.

Expert opinion: The current evidence suggests promising beneficial effects of this novel drug in the prevention and treatment of atherosclerosis and other metabolic disorders. Its unique mechanism of action is encouraging; it affects several pathways and has a modest effect on HDL levels. There is also a shift in particle size to larger HDL particles, which may have potent atheroprotective effects. Future clinical development is needed, including safety assessment.     

The PCBP1 gene encoding poly(rc) binding protein i is recurrently mutated in Burkitt lymphoma

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG‐MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole‐genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron‐less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K‐Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre‐mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20–40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis. © 2015 Wiley Periodicals, Inc.     

Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.     

Functionalization of α-hydroxyphosphonates as a convenient route to N-tosyl-α-aminophosphonates

Direct conversion of the α-hydroxyl group by para-toluenesulfonamide to yield α-(N-tosyl)aminophosphonates is reported. α-Aminophosphonates 23a,b–37a,b were obtained from the corresponding α-hydroxyphosphonates 6a,b–21a,b in the presence of K₂CO₃, via the retro-Abramov reaction of the appropriate aldehydes, 1–5. The subsequent formation of imines with simultaneous addition of diethyl phosphite provided access to the α-sulfonamide phosphonates 23a,b–37a,b with better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue 12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38 as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not observed in the case of proline 18a,b and serine 21a,b derivatives.

The reaction mechanism and diastereoselectivity of the direct transformation of α-hydroxyphosphonates 6a,b–21a,b by para-toluenesulfonamide, yielding α-(N-tosyl)aminophosphonates 23a,b–37a,b under K₂CO₃ conditions are presented.     

Towards potent but less toxic nanopharmaceuticals – lipoic acid bioconjugates of ultrasmall gold nanoparticles with an anticancer drug and addressing unit

Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units. The application of lipoic acid enabled the control of the gold nanoparticle functionalities leading to enhanced solubility and allowing for attachment of both the folic acid and the cytotoxic drug, doxorubicin. More robust attachment of doxorubicin to the nanoparticle through the amide bond resulted in toxicity comparable with that of the drug alone, opening a new perspective for designing more potent, but less toxic nanopharmaceuticals. The increased uptake was accompanied by pronounced nuclear accumulation and observable cytotoxicity. Doxorubicin binding via covalent amide bonds enhanced stability of the whole drug vehicle and provided much better control over doxorubicin release in the cell environment, as compared to physical adsorption or pH sensitive bonding commonly used for anthracycline carriers. Confocal microscopy revealed that the bond was stable in the cytoplasm for 22 h. The ability to slow down the rate of drug release may be crucial for the application in sustained anticancer drug delivery. Biological analyses performed using MTT assay and confocal microscopy confirmed that the ultrasmall AuNPs with the lipoic acid derivative of folic acid exhibit relatively low cytotoxicity, however when loaded with a chemotherapeutic, they cause a significant reduction in the cell viability.

Modification of ultrasmall gold nanoparticles (AuNPs) with the lipoic acid derivative of folic acid was found to enhance their accumulation in the cancer cell, as compared to AuNPs without addressing units.