Research Spotlight

Posted June 15th 2016

Donor hearts: Time to look at them in a different light?

Gonzalo V. Gonzalez-Stawinski M.D.

Gonzalo V. Gonzalez-Stawinski M.D.

Gonzalez-Stawinski, G. V. (2016). “Donor hearts: Time to look at them in a different light?” J Card Fail 22(5): 383-384.

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In this edition of The Journal of Cardiac Heart Failure, 2 papers aim to inform readers of donor groups that could be considered at the time of cardiac donation in the hope of expanding the stagnant donor pool.


Posted June 15th 2016

Addition of a Medial Locking Plate to an In Situ Lateral Locking Plate Results in Healing of Distal Femoral Nonunions.

Bryan D. Hanus M.D.

Bryan D. Hanus M.D.

Holzman, M. A., B. D. Hanus, J. W. Munz, D. P. O’Connor and M. R. Brinker (2016). “Addition of a medial locking plate to an in situ lateral locking plate results in healing of distal femoral nonunions.” Clin Orthop Relat Res 474(6): 1498-1505.

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BACKGROUND: Nonunion of the distal femur after lateral plating is associated with axial malalignment, chronic pain, loss of ambulatory function, and decreased knee ROM. The addition of a medial locking plate with autogenous bone grafting can provide greater stability to allow bone healing and may be used to achieve union in these challenging cases. QUESTIONS/PURPOSES: We wished to determine (1) the proportion of patients who achieve radiographic signs of osseous union for distal femoral nonunions with an in situ lateral plate after treatment with addition of a medial locking plate and autogenous bone grafting, and (2) the frequency and types of complications associated with this treatment. METHODS: Between 2007 and 2013, we treated 22 patients for 23 distal femoral nonunions, defined as an unhealed fracture with no radiographic signs of osseous union at a mean of 16 months (SD, 13 months) after injury. During that time, we used a treatment algorithm consisting of treatment in one or two stages. The single-stage procedure performed in 16 aseptic nonunions with a stable lateral plate involved addition of a medial locking plate and autogenous bone graft. A two-stage treatment performed in seven nonunions with lateral plate failure involved placement of a new lateral locking plate followed by addition of a medial locking plate with autogenous bone graft at least 2 months after the first procedure. Of the 22 patients treated, 20 had a median followup of 18 months (SD, 6-94 months). We defined osseous union by bridging bone on three of four cortices with absence of a radiolucent line or more than 25% cross-sectional area of bridging bone via CT. RESULTS: Twenty of the 21 nonunions attained radiographic signs of osseous union by 12 months. Six of the 20 patients experienced complications: one patient had a persistent nonunion; four patients underwent removal of symptomatic hardware; and one patient experienced skin breakdown at the bone graft harvest site. CONCLUSIONS: A very high proportion of patients achieve union when using medial locking plates to treat distal femoral nonunions after lateral plating of the original injury. Addition of bone graft, staged reconstruction, and revision of the initial lateral plate is indicated when the nonunion is associated with fatigue failure of the initial lateral plate.


Posted June 15th 2016

miRNA-503 Promotes Tumor Progression and Is Associated with Early Recurrence and Poor Prognosis in Human Colorectal Cancer.

Shusuke Toden Ph.D.

Shusuke Toden Ph.D.

Noguchi, T., Y. Toiyama, T. Kitajima, H. Imaoka, J. Hiro, S. Saigusa, K. Tanaka, Y. Inoue, Y. Mohri, S. Toden and M. Kusunoki (2016). “Mirna-503 promotes tumor progression and is associated with early recurrence and poor prognosis in human colorectal cancer.” Oncology 90(4): 221-231.

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OBJECTIVES: MicroRNA (miR)-503 is downregulated in several cancers and plays a tumor-suppressive role in carcinogenesis. However, the miR-503 expression pattern, its clinical significance and its molecular mechanism in colorectal cancer (CRC) have not been investigated. METHODS: We analyzed miR-503 expression in normal mucosa (n = 20), adenoma (n = 27) and CRC (n = 20). We quantified miR-503 expression in an independent cohort (n = 191) and investigated the clinical significance of miR-503 in CRC. CRC cell lines were transfected with anti-miR-503 to assess its function and target gene. RESULTS: miR-503 expression increased according to the adenoma-carcinoma sequence. High miR-503 expression was significantly associated with large tumor size, serosal invasion, lymphatic and venous invasion as well as lymph node metastasis. CRC patients with high miR-503 expression had significantly earlier relapse and poorer prognosis than those with low expression. miR-503 was an independent recurrence marker in stage I/II CRC. In vitro, attenuated miR-503 expression resulted in inhibition of proliferation, invasion and migration and acquisition of anoikis of CRC cells. The putative target gene (calcium-sensing receptor) was significantly upregulated after miR-503 attenuation. CONCLUSIONS: miR-503 acts as an ‘onco-miR’ in CRC. High miR-503 expression is associated with early recurrence and poor prognosis in CRC.


Posted June 15th 2016

Best Practices in Caring for Patients Infected With Clostridium difficile.

Susan H. Smith D.N.P.

Susan H. Smith D.N.P.

Smith, S. and J. Taylor (2016). “Best practices in caring for patients infected with clostridium difficile.” Crit Care Nurse 36(3): 71-72.

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The number of C difficile infections (CDIs) has doubled from 2000 to 2009, and C difficile now rivals methicillin-resistant Staphylococcus aureus as the most frequent cause of health care–associated infection in the United States.1 It is the most common cause of health care– associated diarrhea and accounts for 15% to 25% of antibiotic-associated diarrhea.2,3 Costs are estimated to be more than $1.3 billion per year.2 For many reasons, CDI has captured the interest of both insurers and the public. Beginning in 2017, the Centers for Medicare and Medicaid Services will include CDI in the reimbursement metrics for its valuebased purchasing program.1


Posted June 15th 2016

Preclinical justification of pbi-shrna ews/fli1 lipoplex (lpx) treatment for ewing’s sarcoma.

Maurizio Ghisoli M.D.

Maurizio Ghisoli M.D.

Rao, D. D., C. Jay, Z. Wang, X. Luo, P. Kumar, H. Eysenbach, M. Ghisoli, N. Senzer and J. Nemunaitis (2016). “Preclinical justification of pbi-shrna ews/fli1 lipoplex (lpx) treatment for ewing’s sarcoma.” Mol Ther: May 2016 [Epub ahead of print].

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The EWS/FLI1 fusion gene is well-characterized as a driver of Ewing’s sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous pre-clinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing’s sarcoma. Clinical grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85-92% was demonstrated in vitro in type 1 human Ewing’s sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing’s sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low and high dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing.