Drastically increased expression of MYC and FOS protooncogenes during in vitro differentiation of chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia cells, representing a clonal population of resting B lymphocytes, were induced to differentiate into immunoglobulin-secreting lymphoblasts and plasmablasts by phorbol 12-myristate 13-acetate. The induction resulted in a rapid increase in the molar ratio of secreted/membrane-bound mu-chain mRNA. Immunoglobulin secretion was preceded by a transition of the cells from the G0 to G1 phase of the cell cycle, as indicated by an increase in RNA and protein synthesis, and an overall increase in cellular RNA. The cells, however, became blocked in G1 and did not enter S phase. The expression of MYC and FOS was rapidly induced by the phorbol 12-myristate 13-acetate treatment. The induction of FOS preceded the shift in secreted/membrane-bound mu-chain mRNA molar ratio, while that of MYC occurred concomitantly with the shift, but prior to induction of total RNA synthesis and immunoglobulin secretion. MYC expression remained at a relatively high level during the whole differentiation process. It is thus concluded that a decline of MYC expression is not a prerequisite for differentiation of the chronic lymphocytic leukemia cells. This suggests that MYC expression may play a different role during differentiation of nonproliferating B cells than in the myelomonocytic cell lines HL-60 and U-937, where MYC expression has been reported to decrease during induced differentiation. The results also show that the expression of the MYC and FOS genes does not result in the transition of these cells into the S phase of the cell cycle.     

Development of a synthetic tissue engineered three‐dimensional printed bioceramic‐based bone graft with homogenously distributed osteoblasts and mineralizing bone matrix in vitro

Over the last decade there have been increasing efforts to develop three‐dimensional (3D) scaffolds for bone tissue engineering from bioactive ceramics with 3D printing emerging as a promising technology. The overall objective of the present study was to generate a tissue engineered synthetic bone graft with homogenously distributed osteoblasts and mineralizing bone matrix in vitro, thereby mimicking the advantageous properties of autogenous bone grafts and facilitating usage for reconstructing segmental discontinuity defects in vivo. To this end, 3D scaffolds were developed from a silica‐containing calcium alkali orthophosphate, using, first, a replica technique – the Schwartzwalder–Somers method – and, second, 3D printing, (i.e. rapid prototyping). The mechanical and physical scaffold properties and their potential to facilitate homogenous colonization by osteogenic cells and extracellular bone matrix formation throughout the porous scaffold architecture were examined. Osteoblastic cells were dynamically cultured for 7 days on both scaffold types with two different concentrations of 1.5 and 3 × 10⁹ cells/l. The amount of cells and bone matrix formed and osteogenic marker expression were evaluated using hard tissue histology, immunohistochemical and histomorphometric analysis. 3D‐printed scaffolds (RPS) exhibited more micropores, greater compressive strength and silica release. RPS seeded with 3 × 10⁹ cells/l displayed greatest cell and extracellular matrix formation, mineralization and osteocalcin expression. In conclusion, RPS displayed superior mechanical and biological properties and facilitated generating a tissue engineered synthetic bone graft in vitro, which mimics the advantageous properties of autogenous bone grafts, by containing homogenously distributed terminally differentiated osteoblasts and mineralizing bone matrix and therefore is suitable for subsequent in vivo implantation for regenerating segmental discontinuity bone defects. Copyright © 2016 John Wiley & Sons, Ltd.     

Predictors for Employment Status in People With Multiple Sclerosis: A 10-Year Longitudinal Observational Study

Objective

To identify predictors for employment status after 10 years in a cohort of people with multiple sclerosis (MS), with the aim to increase knowledge concerning factors present at an early stage that are important for working life and work-life balance.

Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

AimsAZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR‐H067637, a potent, specific and reversible thrombin inhibitor. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR‐H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients.MethodsBlood samples were obtained from 601 AF patients randomized to one of four doses of AZD0837 (blinded treatment) or dose‐adjusted vitamin K antagonists (VKA, open treatment) for 3–9 months. A pharmacodynamic model was developed to describe the time course of the AR‐H067637 exposure dependent effects and the effect of VKA on fibrin D‐dimer. The thrombin generation measured ex vivo in venous plasma was also investigated.ResultsThe PK exposure of AR‐H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D‐dimer levels decreased with more rapid onset than for VKA. The decrease in D‐dimer levels correlated with steady‐state plasma concentrations (C _ss) of AR‐H067637, with a maximum decrease of baseline D‐dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR‐H067637.ConclusionsThe effects on thrombin generation and fibrin D‐dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well‐controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837.     

Is CEA analysis of value in screening for recurrences after surgery for colorectal carcinoma?

The progress of 139 patients operated upon for cure of colorectal carcinoma, was followed postoperatively with a standardized protocol. A CEA test was performed for comparison with other parameters. Median observation time was four years. When an upper limit for CEA of 7.5 μg/l was allowed, sensitivity was found to be 78 per cent, specificity 91 per cent, and predictive value of an elevated CEA concentration, 83 per cent. In general, CEA measurement traced, recurrence six months before clinical diagnosis. In only a few cases was recurrence first heralded by an abnormality in other blood chemistry test results. CEA may thus be used in postoperative screening for recurrence even though most recurrences, when detected, are not curable. Read at the meeting of the American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 5–9, 1983 Presented in part at The World Congresses of Gastroenterology (OMGE) and Coloproctology, Stockholm, Sweden, June 14–19, 1982.     

Asthma and asthma-like disorder,a 5-year follow-up study

Consecutive adult patients (n = 70) referred for investigation of suspected asthma were reinvestigated after 5 years with the same diagnostic procedures (airway symptom score, spirometry, methacholine test) as used at the initial investigation. The same diagnostic criteria for asthma, asthma-like disorder (current asthma-like symptoms but negative asthmatests)and chronicobstructive pulmonary disease (COPD) were used at both visits. At the first visit 39/70 patients (56%) fulfilled the asthma criteria, 21/70 (27%) fulfilled the asthma-like criteria and 5/70 (7%) the COPD criteria. Due to lack of current symptoms 5/70 (7%) could not be classified. 5/70 patients (7%) were smokers, however, in the majority (72%) smoke was not tolerated as it induced asthma-like symptoms. At the investigation, 5 years later, 30/39 patients (76%) still fulfilled the asthma criteria and 12/21 patients (57%) still fulfilled the asthma-like criteria. At the 5-year investigation, 10% of patients in the asthma group now fulfilled the asthma-like criteria and 10% of patients in the asthma-like group fulfilled the asthma criteria. It is concluded that asthma as well an asthma-like syndrome may persist for 5 years or more. It is also concluded thatthe two disorders are closely related as patients in the asthma group over time could move into the diagnostic criteria ofthe asthma-like disorder and vice versa.