A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia

Activated tyrosine kinases have been frequently implicated in the pathogenesis of cancer, including acute myeloid leukemia (AML), and are validated targets for therapeutic intervention with small-molecule kinase inhibitors. To identify novel activated tyrosine kinases in AML, we used a discovery platform consisting of immunoaffinity profiling coupled to mass spectrometry that identifies large numbers of tyrosine-phosphorylated proteins, including active kinases. This method revealed the presence of an activated colony-stimulating factor 1 receptor (CSF1R) kinase in the acute megakaryoblastic leukemia (AMKL) cell line MKPL-1. Further studies using siRNA and a small-molecule inhibitor showed that CSF1R is essential for the growth and survival of MKPL-1 cells. DNA sequence analysis of cDNA generated by 5'RACE from CSF1R coding sequences identified a novel fusion of the RNA binding motif 6 (RBM6) gene to CSF1R gene generated presumably by a t(3;5)(p21;q33) translocation. Expression of the RBM6-CSF1R fusion protein conferred interleukin-3 (IL-3)-independent growth in BaF3 cells, and induces a myeloid proliferative disease (MPD) with features of megakaryoblastic leukemia in a murine transplant model. These findings identify a novel potential therapeutic target in leukemogenesis, and demonstrate the utility of phosphoproteomic strategies for discovery of tyrosine kinase alleles.     

Enhancing repair of the mammalian heart

The injured mammalian heart is particularly susceptible to tissue deterioration, scarring, and loss of contractile function in response to trauma or sustained disease. We tested the ability of a locally acting insulin-like growth factor-1 isoform (mIGF-1) to recover heart functionality, expressing the transgene in the mouse myocardium to exclude endocrine effects on other tissues. supplemental mIGF-1 expression did not perturb normal cardiac growth and physiology. Restoration of cardiac function in post-infarct mIGF-1 transgenic mice was facilitated by modulation of the inflammatory response and increased antiapoptotic signaling. mIGF-1 ventricular tissue exhibited increased proliferative activity several weeks after injury. The canonical signaling pathway involving Akt, mTOR, and p70S6 kinase was not induced in mIGF-1 hearts, which instead activated alternate PDK1 and SGK1 signaling intermediates. The robust response achieved with the mIGF-1 isoform provides a mechanistic basis for clinically feasible therapeutic strategies for improving the outcome of heart disease.     

Impact of a primary care intervention on smoking, drinking, diet, weight, sun exposure, and work risk in families with cancer experience

Background

Modifying multiple behavior risks is a promising approach to reduce cancer risk. Primary prevention advices of the European Code against Cancer were included in an educational intervention (EI) using social cognitive theories for motivating families with cancer experiences to adopt six cancer prevention behaviors.

Methods

A randomized clinical controlled trial recruited 3,031 patients from Primary Care among cancer patients’ relatives. The experimental group (EG) received four EI, one EI every six months, focused on tobacco, alcohol, diet, weight, sun and work, and based on social cognitive models. The impact of the first three EI was calculated measuring at baseline and 18 months later: (a) The percentage of people with each risk behavior; (b) The score reached in a Total Cancer Behavioral Risk (TCBR) indicator; (c) The Odds Ratios at the post-test.

Results

Five risk behaviors decreased significantly more (p < 0.01) in the EG than in the CG: Smoking (OR = 0.662), drinking (OR = 0.504), diet (OR = 0.542), weight (OR = 0.698), and sun (OR = 0.389). The TCBR indicator also decreased an average of nearly 5 points (28.42 vs. 23.82), significantly more (p < 0.001) in the EG.

Conclusion

Families with cancer experiences changed five cancer risk behaviors when approached in Primary Care with interventions based on social cognitive models.     

Arthroscopic versus open dorsal ganglion excision: a prospective, randomized comparison of rates of recurrence and of residual pain

PURPOSE: The purpose of this study was to compare the postoperative rates of ganglion recurrence between arthroscopic and open techniques of dorsal ganglion (DG) excision. METHODS: A total of 72 patients had either arthroscopic or open excision of a primary, simple DG by 1 of 2 senior hand surgeons. Three prospective postoperative assessments were performed. The first examination was performed at 5 to 7 days, the second at 4 to 8 weeks, and the third assessment was performed at a minimum of 1 year after surgery. Percentages of ganglion recurrence at the second and third assessments were recorded. RESULTS: Forty-one patients had arthroscopic excision, and 31 patients had open excision. Baseline patient age, gender, and surgical side were similar between the 2 groups. Recurrence of the DG at the second postoperative assessment was 1 of 41 patients in the arthroscopic group and none in the open excision group, and, after a minimum of 12 months after excision, recurrence was 3 of 28 in the arthroscopic group and 2 of 23 in the open group. CONCLUSIONS: This study compares the rates of ganglion recurrence between arthroscopic and open DG excision. Our results demonstrate that at 12 months follow-up, the rates of recurrence with arthroscopic DG excision are comparable with and not superior to those of open excision. Our results suggest that additional long-term comparative studies are needed to accurately differentiate the efficacy of open and arthroscopic techniques.