Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers.
Cardiovasc Res. 2010 Feb 1;85(3):444-53
Authors: Jearawiriyapaisarn N, Moulton HM, Sazani P, Kole R, Willis MS
AIMS: The cardiomyopathy found in Duchenne muscular dystrophy (DMD) is responsible for death due to heart failure in approximately 30% of patients and additionally contributes to many DMD morbidities. Strategies to bypass DMD-causing mutations to allow an increase in body-wide dystrophin have proved promising, but increasing cardiac dystrophin continues to be challenging. The purpose of this study was to determine if therapeutic restoration of cardiac dystrophin improved the significant cardiac hypertrophy and diastolic dysfunction identified in X-linked muscular dystrophy (mdx) dystrophin-null mouse due to a truncation mutation over time after treatment. METHODS AND RESULTS: Mice lacking dystrophin due to a truncation mutation (mdx) were given an arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that delivered a splice-switching oligonucleotide-mediated exon skipping therapy to restore dystrophin in mdx mice before the development of detectable cardiomyopathy. PPMO successfully restored cardiac dystrophin expression, preserved cardiac sarcolemma integrity, and prevented the development of cardiac pathology that develops in mdx-null mice over time. By echocardiography and Doppler analysis of the mitral valve, we identified that PPMO treatment of mdx mice prevented the cardiac hypertrophy and diastolic dysfunction identified in sham-treated, age-matched mdx mice, characteristic of DMD patients early in the disease process, in as little as 5-6 weeks after the initiation of treatment. Surprisingly, despite the short-term replacement of cardiac dystrophin (<1% present after 12 weeks by immunodetection), PPMO therapy also provided a durable cardiac improvement in cardiac hypertrophy and diastolic dysfunction for up to 7 months after the initiation of treatment. CONCLUSION: These results demonstrate for the first time that PPMO-mediated exon skipping therapy early in the course of DMD may effectively prevent or slow down associated cardiac hypertrophy and diastolic dysfunction with significant long-term impact.
PMID: 19815563 [PubMed - indexed for MEDLINE]
More here:
Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers.
Acute myelogenous leukemia and myelodysplasia secondary to breast cancer treatment: case studies and literature review.
Am J Med Sci. 2010 Jan;339(1):36-40
Authors: Cole M, Strair R
BACKGROUND AND PURPOSE: Chemotherapy and radiation therapy for breast cancer are known to increase the risk of developing a myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML). Alkylating agents and topoisomerase II inhibitors, fundamental to the treatment of breast cancer, are the most likely contributors to this increase in risk. Radiation therapy adds to the risk, and there is speculation that granulocyte colony-stimulating factor (G-CSF) may also predispose to leukemia. The purpose of this systemic review is to bring to the attention of family physicians the unintended consequence of leukemia secondary to aggressively treated breast cancer. METHODS: The medical records of several patients from Robert Wood Johnson University Hospital, with previously treated breast cancer admitted for therapy for AML or myelodysplasia, were reviewed. In addition, the recent literature on this topic was reviewed. RESULTS: Cases of patients whose AML was likely secondary to their treatment for breast cancer were used to illustrate the role of chemotherapy, radiation therapy, and perhaps G-CSF in the development of leukemia. CONCLUSIONS: Chemotherapy and radiation therapy administered for breast cancer predispose patients to the development of MDS or AML. We hypothesize that the breast cancer (BRCA) gene mutations might add to the risk and that primary care physicians must be aware of the long-term risks of cytotoxic therapy, including the development of MDS or AML.
PMID: 19996729 [PubMed - indexed for MEDLINE]
…more
The role of prostacyclin in lung cancer.
Transl Res. 2010 Feb;155(2):57-61
Authors: Tennis MA, Vanscoyk M, Keith RL, Winn RA
Prostanoids are bioactive lipids that interact with 7-membrane-spanning G-protein-coupled receptors on target cells to impart their biologic effects.(1) They include prostaglandins, prostacyclin, and thromboxane. Prostanoids are widely distributed; mediate several diverse biologic effects like platelet aggregation and smooth-muscle contraction; and are known to be involved in allergies, acquired immunity, and cancer metastasis.(2) Prostanoids have also been associated with breast and endometrial cancer promotion, and with the inhibition of melanoma. The role of prostanoids in the development of lung disease has been poorly understood. In particular, prostacyclin possesses significant anti-inflammatory and antimetastatic properties and is the main product of cyclooxygenase-2 activity in the lung. In fact, the balance of the various members of the prostanoids family, specifically the prosoglandins PGE(2) and prostacyclin (PGI(2)), seems to play an increasingly important role in the development of lung cancer. Gaining a better understanding of prostanoids and their associated pathways is critical to the future development of molecular-based and pharmaceutical treatments of lung disease.
PMID: 20129485 [PubMed - in process]
…more
