Research Spotlight

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.


Posted June 15th 2016

Predicting acute kidney injury prognosis.

Harold M. Szerlip M.D.

Harold M. Szerlip M.D.

Szerlip, H. M. and L. S. Chawla (2016). “Predicting acute kidney injury prognosis.” Curr Opin Nephrol Hypertens 25(3): 226-231.

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PURPOSE OF REVIEW: The incidence of acute kidney injury has been steadily increasing. The development of any degree of kidney injury is associated with worse outcomes. Therefore, the ability to risk stratify patients and to predict prognosis is essential to properly educate the patient and family, appropriately utilize healthcare resources, and provide therapeutic interventions that may improve outcomes. RECENT FINDINGS: Numerous biomarkers and clinical prediction models have been developed that improve our ability to predict which patients will progress to higher stages of chronic kidney disease, require dialysis, or survive. The integration of biomarkers in predictive models will likely provide the best information. Further investigation will be required to validate the utility of these tools. SUMMARY: Early risk stratification for acute kidney injury can aid clinical decision making. The use of various biomarkers and predictive clinical models will improve the ability to appropriately utilize resources and provide useful prognostic information.


Posted June 15th 2016

Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: A report from the Center for International Blood and Marrow Transplant Research.

Medhat Z. Askar M.D.

Medhat Z. Askar M.D.

Lazaryan, A., T. Wang, S. R. Spellman, H. L. Wang, J. Pidala, T. Nishihori, M. Askar, R. Olsson, M. Oudshoorn, H. Abdel-Azim, A. Yong, M. Gandhi, C. Dandoy, B. Savani, G. Hale, K. Page, M. Bitan, R. Reshef, W. Drobyski, S. G. Marsh, K. Schultz, C. R. Muller, M. A. Fernandez-Vina, M. R. Verneris, M. M. Horowitz, M. Arora, D. J. Weisdorf and S. J. Lee (2016). “Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: A report from the center for international blood and marrow transplant research.” Haematologica: May 2016 [Epub ahead of print].

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The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 vs. 429), -B (230 vs. 92), -C (365 vs. 349), and -DRB1 (153 vs. 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single-allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into 6 HLA-A (A01, A01A03, A01A24, A02, A03, A24), 6 HLA-B (B07, B08, B27, B44, B58, B62), 2 HLA-C (C1, C2), and 5 HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II-IV acute graft-versus-host disease (hazard ratio =1.78, p=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II-IV (hazard ratio=3.11, p=0.002) and III-IV (hazard ratio=3.15, p=0.01) acute graft-versus-host- disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II-IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available, and call for future studies to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation.


Posted May 15th 2016

Egfr fusions as novel therapeutic targets in lung cancer.

Kartik Konduri M.D.

Kartik Konduri, M.D.

Konduri, K., J. N. Gallant, Y. K. Chae, F. J. Giles, B. J. Gitlitz, K. Gowen, E. Ichihara, T. K. Owonikoko, V. Peddareddigari, S. S. Ramalingam, S. K. Reddy, B. Eaby-Sandy, T. Vavala, A. Whiteley, H. Chen, Y. Yan, J. H. Sheehan, J. Meiler, D. Morosini, J. S. Ross, P. J. Stephens, V. A. Miller, S. M. Ali and C. M. Lovly (2016). “Egfr fusions as novel therapeutic targets in lung cancer.” Cancer Discov Apr 21 [Epub ahead of print].

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Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKIs) with documented anti-tumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.