Oncogenic AKTivation of translation as a therapeutic target.

The AKT signalling pathway is a major regulator of protein synthesis that impinges on multiple cellular processes frequently altered in cancer, such as proliferation, cell growth, survival, and angiogenesis. AKT controls protein synthesis by regulating the multistep process of mRNA translation at every stage from ribosome biogenesis to translation initiation and elongation. Recent studies have highlighted the ability of oncogenic AKT to drive cellular transformation by altering gene expression at the translational level. Oncogenic AKT signalling leads to both global changes in protein synthesis as well as specific changes in the translation of select mRNAs. New and developing technologies are significantly advancing our ability to identify and functionally group these translationally controlled mRNAs into gene networks based on their modes of regulation. How oncogenic AKT activates ribosome biogenesis, translation initiation, and translational elongation to regulate these translational networks is an ongoing area of research. Currently, the majority of therapeutics targeting translational control are focused on blocking translation initiation through inhibition of eIF4E hyperactivity. However, it will be important to determine whether combined inhibition of ribosome biogenesis, translation initiation, and translation elongation can demonstrate improved therapeutic efficacy in tumours driven by oncogenic AKT.

Antibiotics and open fractures of the lower extremity: less is more.

PURPOSE: Infectious complications in open lower extremity fractures contribute to significant morbidity. Historically, orthopedic guidelines have recommended Grade III fractures receive a first generation cephalosporin and an aminoglycoside. Despite these guidelines, few studies have evaluated the utility of adding an aminoglycoside in this patient population. At our trauma center, we have a unique trauma service where half of our surgeons treat Grade III open fractures with a cephalosporin alone and half use a cephalosporin + aminoglycoside. We hypothesized that our outcomes were the same between the two groups. METHODS: We identified all Grade III fractures of the lower extremity admitted to our urban Level I Trauma Center over the 5-year study period. Charts were retrospectively reviewed to identify demographic information, injury severity score (ISS), fracture location, grade of fracture, type of antibiotic administered, incidence of acute kidney injury (AKI), surgical site infection (SSI), hardware removal, hospital length of stay (HLOS), and disposition. Patients were classified into two groups: those treated with a cephalosporin alone (CEPH) or cephalosporin + an aminoglycoside (CEPH + AG). RESULTS: A total of 126 grade III fractures of the lower extremity were admitted our Trauma Center during the 5-year study period. There were 65 (52%) patients in the CEPH group and 61 (48%) in the CEPH + AG group. Demographics, ISS, fracture location, grade of fracture, rate of SSI, need for hardware removal, and disposition were not different between the two groups. In contrast, patients in the CEPH group had a 4% incidence of AKI, while the incidence was 10% of patients in the CEPH + AG group (p < 0.05). CONCLUSION: The addition of an AG to antibiotic prophylaxis in open lower extremity fractures was associated with a significant increase in AKI with no change in the incidence of wound infection or hardware removal. Cephalosporins alone may be sufficient for prophylaxis in Grade III open fractures of the lower extremity. A large-scale prospective randomized trial is needed to confirm these findings and inform clinical practice.

Vena cava filters: a synopsis of complications and related topics.

Deep venous thrombosis and pulmonary embolism constitute common preventable causes of morbidity and mortality. The incidence of venous thromboembolism (VTE) continues to increase. Standard anticoagulation therapy may reduce the risk of fatal PE by 75% and that of recurrent VTE by over 90%. For patients who are not candidates for anticoagulation, a vena cava filter (VCF) may be beneficial. Despite a good overall safety record, significant complications related to VCF are occasionally seen. This review discusses both procedural and non-procedural complications associated with VCF placement and use. We will also discuss VCF use in the settings of pregnancy, malignancy, and the clinical need for more than one filter.

Characterization of mouse mammary tumor viruses from primary tumor cell cultures.I. Immunologic and structural studies.

Primary cell cultures of mammary tumors from Rill, GR, DD, BALB/cfC3H, and BALB/c mice were prepared by trypsin-EDTA dissociation of tumors. Cultures from these strains contained predominantly cells of epithelial morphology which formed three-dimensional domelike structures. Cultures from Rill, GR, DD, and BALB/cfC3H tumors produced extra-cellular type-B mouse mammary tumor virus(es) (MuMTV), either in the absence of detectable type-C virus or with less than 1% contamination with type-C virus. This was determined by radioimmunoassays for MuMTV and murine leukemia virus (MuLV) antigens. Only BALB/c cultures produced MuMTV with as much as 3% contaminating MuLV. High levels of MuMTV surface antigen were also found in soluble form in culture supernatants. Virus polypeptide analyses by electrophoresis on polyacrylamide gels showed that the Rill BALB/cfC3H, DD, and BALB/c viruses all contained polypeptides characteristic of MuMTV. Primary cultures of mammary tumor cells make available a source of purified MuMTV antigens, structural proteins, and nucleic acids for comparative studies of MuMTV from various mouse strains.

Antigenic analysis of the major structural protein of the Mason-Pfizer monkey virus.

The major internal protein, p27 (m.w. 27,000 daltons) of the Mason-Pfizer monkey virus (MPMV) was purified by gel filtration and ion-exchange chromatography and then used to develop a radioimmunoassay (RIA). This RIA was specific for MPMV because no immunologic cross-reactivity was observed between p27 of MPMV and 13 different RNA tumor viruses of mammalian and avian origin. However, the p27 of MPMV grown in three different primate cells exhibited identical antigenic cross-reactivity. In addition, significant levels of p27 were found only in MPMV-infected cells. These results indicate that synthesis of p27 is induced after virus infection and that p27 represents a viral-coded protein.

Demonstration of activation of B lymphocytes in New Zealand black mice at birth by an immunoradiometric assay for murine IgM.

We have developed a highly specific and sensitive "two-site" immunoradiometric assay for murine IgM in which antigen bound to immobilized antibody reacts with affinity-purified radiolabeled antibody. We utilized the sensitivity of this assay to study the rate of IgM secretion in short-term cultures by spleen cells from the autoimmune strains, New Zealand Black (NZB) and New Zealand Black by New Zealand White F1 hybrid (BW), and from normal (C57BL/6, DBA/2, NZW) mice. The temperature dependence of IgM secretion in short-term cultures, its pentameric structure, and the similar viability of NZB and normal strain spleen cells indicate that active IgM synthesis is being measured. We observed that the splenic B lymphocytes of NZB and BW mice, in contrast to normal strains, produce IgM in vitro at birth. By 6 to 8 weeks of age NZB and BW spleen cells produce 40 times more IgM than spleen cells from normal strains of mice. The IgM produced in vitro by splenic lymphocytes from NZB and BW mice is not absorbed by synegeneic or allogeneic thymocytes or erythrocytes.