Research Spotlight

Gomes, L. R., L. H. Cevidanes, M. R. Gomes, A. C. Ruellas, D. P. Ryan, B. Paniagua, L. M. Wolford and J. R. Goncalves (2017). “Counterclockwise maxillomandibular advancement surgery and disc repositioning: Can condylar remodeling in the long-term follow-up be predicted?” Int J Oral Maxillofac Surg: 2017 Jul [Epub ahead of print].

Full text of this article.

This study investigated predictive risk factors of condylar remodeling changes after counterclockwise maxillomandibular advancement (CCW-MMA) and disc repositioning surgery. Forty-one female patients (75 condyles) treated with CCW-MMA and disc repositioning had cone beam computed tomography (CBCT) scans taken pre-surgery, immediately after surgery, and at an average 16 months post-surgery. Pre- and post-surgical three-dimensional models were superimposed using automated voxel-based registration on the cranial base to evaluate condylar displacements after surgery. Regional registration was performed to assess condylar remodeling in the follow-up period. Three-dimensional cephalometrics, shape correspondence (SPHARM-PDM), and volume measurements were applied to quantify changes. Pearson product-moment correlations and multiple regression analysis were performed. Highly statistically significant correlation showed that older patients were more susceptible to overall condylar volume reduction following CCW-MMA and disc repositioning (P

Graham, J. P., P. Authie, A. Karolina Palucka and G. Zurawski (2017). “Targeting interferon-alpha to dendritic cells enhances a cd8+ t cell response to a human cd40-targeted cancer vaccine.” Vaccine: 2017 Jul [Epub ahead of print].

Full text of this article.

Targeting antigens to antigen presenting cells (APC) enhances the potency of recombinant protein CD8+ T cell vaccines. Recent comparisons of recombinant protein-based dendritic cell (DC) targeting vaccines revealed differences in cross-presentation and identified CD40 as a potent human DC receptor target for antigen cross-presentation. Contrary to in vitro-derived monocyte (mo)DC, we found that interferon-alpha (IFNalpha) stimulation of human blood-derived DC was necessary for an antigen-specific IFNgamma CD8+ T cell response to a CD40 targeted cancer vaccine. Importantly, targeting an adjuvant in the form of IFNalpha to DC increased their potency to elicit antigen-specific production of IFNgamma by CD8+ T cells. Thus, we introduce the concept of DC adjuvant targeting to enhance the potency of vaccination.

Packer, M. (2017). “Why has a run-in period been a design element in most landmark clinical trials? Analysis of the critical role of run-in periods in drug development.” J Card Fail: 2017 Jul [Epub ahead of print].

Full text of this article.

Prior exposure to one of the randomized treatments has been a routine design element of large-scale trials in patients at high cardiovascular risk. A run-in feature has allowed our trials to be more realistic; it has strengthened their ability to estimate the true treatment effect, and it has never undermined the validity of a trial’s findings. Those who suggest that run-in periods distort the results of large-scale trials should become more familiar with our history of drug development and our standards of clinical practice. Physicians use run-in periods every day in real life, and trialists have used run-in periods for decades to reliably establish the role of new cardiovascular drugs. Those who reflexively criticize the trials because of their inclusion of a run-in period need to carefully re-examine how medicine is practiced and how it advances.

Yoshida, K., S. Toden, W. Weng, K. Shigeyasu, J. Miyoshi, J. Turner, T. Nagasaka, Y. Ma, T. Takayama, T. Fujiwara and A. Goel (2017). “Snora21 – an oncogenic small nucleolar rna, with a prognostic biomarker potential in human colorectal cancer.” EBioMedicine: 2017 Jul [Epub ahead of print].

Full text of this article.

BACKGROUND: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) play a central role in oncogenesis. Herein, we systematically evaluated expression profiles of snoRNAs in colorectal cancer (CRC) and investigated their clinical and functional role in this malignancy. METHODS: We compared expression levels of snoRNAs between cancer and normal tissues using publicly available datasets and identified the most differentially expressed and commonly upregulated snoRNAs in CRC. These results were examined in 489 colorectal tissues to assess their clinical significance, followed by a series of in vitro and in vivo experiments to evaluate the functional role of candidate snoRNAs. RESULTS: Using multiple RNA profiling datasets, we identified consistent overexpression of SNORA21 in CRC. In the clinical validation cohorts, the expression level of SNORA21 was upregulated in colorectal adenomas and cancers. Furthermore, elevated SNORA21 emerged as an independent factor for predicting poor survival. Both in vitro and in vivo experiments revealed that CRISPR/Cas9-mediated inhibition of SNORA21 expression resulted in decreased cell proliferation and invasion through modulation of multiple cancer related pathways. CONCLUSIONS: We systematically identified SNORA21 as a key oncogenic snoRNA in CRC, which plays an important role in cancer progression, and might serve as an important prognostic biomarker in CRC.

Zurita, A. J., R. C. Gagnon, Y. Liu, H. T. Tran, R. A. Figlin, T. E. Hutson, A. M. D’Amelio, Jr., C. N. Sternberg, L. N. Pandite and J. V. Heymach (2017). “Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma.” Br J Cancer: 478-484.

Full text of this article.

BACKGROUND: In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters. METHODS: Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment). RESULTS: Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category. CONCLUSIONS: A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.