Research Spotlight

Chan, J., X. Wang, J. A. Turner, N. E. Baldwin and J. Gu (2019). “Breaking the paradigm: Dr Insight empowers signature-free, enhanced drug repurposing.” Bioinformatics 35(16): 2818-2826.

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MOTIVATION: Transcriptome-based computational drug repurposing has attracted considerable interest by bringing about faster and more cost-effective drug discovery. Nevertheless, key limitations of the current drug connectivity-mapping paradigm have been long overlooked, including the lack of effective means to determine optimal query gene signatures. RESULTS: The novel approach Dr Insight implements a frame-breaking statistical model for the ‘hand-shake’ between disease and drug data. The genome-wide screening of concordantly expressed genes (CEGs) eliminates the need for subjective selection of query signatures, added to eliciting better proxy for potential disease-specific drug targets. Extensive comparisons on simulated and real cancer datasets have validated the superior performance of Dr Insight over several popular drug-repurposing methods to detect known cancer drugs and drug-target interactions. A proof-of-concept trial using the TCGA breast cancer dataset demonstrates the application of Dr Insight for a comprehensive analysis, from redirection of drug therapies, to a systematic construction of disease-specific drug-target networks. AVAILABILITY AND IMPLEMENTATION: Dr Insight R package is available at https://cran.r-project.org/web/packages/DrInsight/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Brown, M. N., D. C. Walters, M. A. Schmidt, J. Hill, A. McConnell, E. E. W. Jansen, G. S. Salomons, E. Arning, T. Bottiglieri, K. M. Gibson and J. B. Roullet (2019). “Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of gamma-aminobutyric acid metabolism.” J Inherit Metab Dis 42(5): 1030-1039.

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Murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of gamma-aminobutyric acid (GABA) and gamma-hydroxybutyrate (GHB) and low glutamine in the brain. To understand the pathogenic contribution of central glutamine deficiency, we exposed aldh5a1(-/-) (SSADHD) mice and their genetic controls (aldh5a1(+/+) ) to either a 4% (w/w) glutamine-containing diet or a glutamine-free diet from conception until postnatal day 30. Endpoints included brain, liver and blood amino acids, brain GHB, ataxia scores, and open field testing. Glutamine supplementation did not improve aldh5a1(-/-) brain glutamine deficiency nor brain GABA and GHB. It decreased brain glutamate but did not change the ratio of excitatory (glutamate) to inhibitory (GABA) neurotransmitters. In contrast, glutamine supplementation significantly increased brain arginine (30% for aldh5a1(+/+) and 18% for aldh5a1(-/-) mice), and leucine (12% and 18%). Glutamine deficiency was confirmed in the liver. The test diet increased hepatic glutamate in both genotypes, decreased glutamine in aldh5a1(+/+) but not in aldh5a1(-/-) , but had no effect on GABA. Dried bloodspot analyses showed significantly elevated GABA in mutants (approximately 800% above controls) and decreased glutamate (approximately 25%), but no glutamine difference with controls. Glutamine supplementation did not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity were observed in aldh5a1(-/-) mice but remained unchanged by the diet intervention. The study suggests that glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Future studies are needed to fully understand the pathogenic role of brain glutamine deficiency in SSADHD.

Bissonnette, R., P. Fernandez-Penas, L. Puig, A. M. Mendelsohn, S. J. Rozzo and A. Menter (2019). “Incidence of cardiovascular events among tildrakizumab-treated patients with moderate-to-severe plaque psoriasis: pooled data from three large randomised clinical trials.” J Eur Acad Dermatol Venereol Aug 12. [Epub ahead of print].

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Psoriasis is an independent risk factor for incidence of major adverse cardiovascular (CV) events (MACE), a composite endpoint including myocardial infarction, stroke and death. While many biologics, including tumour necrosis factor inhibitors, interleukin (IL)‐17 inhibitors, and IL‐12/23 inhibitors are approved for the treatment of psoriasis, evidence is limited on the impact of biologics on CV outcomes in patients with psoriasis. In a phase 2b (P05495, NCT01225731) and 2 phase 3 (reSURFACE 1, NCT01722331; and reSURFACE 2, NCT01729754) trials conducted in patients with moderate‐to‐severe chronic plaque psoriasis, tildrakizumab—a high‐affinity, humanised, immunoglobulin G1κ, anti–IL‐23p19 antibody—was well tolerated, with low frequencies of serious adverse events and discontinuations due to adverse events. Here, we evaluated incidence of CV events using pooled safety data obtained from the full trial periods and year 1 of the phase 3 extension studies. (Excerpt from text of authors’ commentary on the article, Papp K, Thaci D, Reich K et al. Tildrakizumab (MK‐3222), an anti‐interleukin‐23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo‐controlled trial. Br J Dermatol 2015; 173: 930– 939, and related studies.)

Barros, A. A. G., C. C. Vassalo, L. P. Costa, J. Gomez-Hoyos, V. O. Paganini and M. A. P. Andrade (2019). “Reliability of the Arthroscopic Classifications of Hip Chondral Lesions.” Rev Bras Ortop (Sao Paulo) 54(4): 440-446.

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Objective: To evaluate the inter- and intraobserver reliability of the Outerbridge, Beck, and Haddad classifications for acetabular joint cartilage lesions through the arthroscopic procedure. Methods: A total of 60 hip arthroscopy videos were evaluated twice by 4 surgeons at 2 different times to assess the inter- and intraobserver reproducibility of the classifications, and the data was analyzed by means of the weighted Cohen Kappa index. Results: The mean weighted Kappa values in the interobserver assessment of the Outerbridge, Beck, and Haddad classifications were, respectively, 0.72, 0.78, and 0.68. The three classifications were considered as presenting good interobserver agreement. Regarding the intraobserver assessment of the Outerbridge, Beck, and Haddad classifications, the weighted Kappa values were, respectively, 0.9, 0.9, and 0.93. The three classifications were considered as presenting excellent intraobserver agreement. Conclusion: In the present series, the Outerbridge, Beck, and Haddad classifications presented good interobserver reproducibility and excellent intraobserver reproducibility when evaluating acetabular chondral lesions by the arthroscopic approach.

Badhwar, V., M. Alkhouli, M. J. Mack, V. H. Thourani and G. Ailawadi (2019). “Reply: Surgical and transcatheter therapy for secondary mitral regurgitation.” J Thorac Cardiovasc Surg 158(3): e93-e95.

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Recent clinical trials have added valuable information, as well as controversy, for the surgical and transcatheter management of secondary mitral regurgitation (MR). One thing is clear, secondary MR is not a binary disease state. It is not present or absent. It is a pathoanatomic continuum. Based on the evidence, a recent grading system has been proposed to suggest targeted surgical and transcatheter therapy of secondary MR based on pathoanatomy and comorbid risk. The experience of Nappi and colleagues with a subvalvular adjunct to restrictive annuloplasty informed a recent letter to the Editor. They make a few important points. First, they re-emphasize the importance of revascularization in ventricular remodeling and suggest potential improvement of secondary MR when viable myocardium is noted. Second, they attest that for patients with nonviable myocardium, a restrictive annuloplasty combined with a subvalvular sling repair should be considered. Finally, by the title of their letter they suggest that a proposed grading system for mitral valve (MV) intervention forfeits the opportunity for MV repair as an important therapy [. . .] Nappi and colleagues are to be congratulated for their steadfast outcome reporting of adjunctive subvalvular papillary muscle repair and their institutional results are admirable, yet their recent identification of failures of this technique indicate that it may not actually be for everyone. They report failures of MV annuloplasty and subvalvular repair with MV tenting area ≥ 3.1 cm2 and left ventricle end-diastolic diameter ≥ 64 mm. In fact, their findings that patients with significant left ventricle remodeling and MV tenting have a higher incidence of recurrent MR aligns precisely with the recently proposed grading system. The cumulative evidence and surgical outcomes with MV repair and replacement in secondary MR do not amount to forfeiture of this complex disease state to transcatheter therapy. To the contrary, the proposed grading system suggests that MV repair still has a role in at least Grade I secondary MR in patients the heart team believes may benefit from surgical therapy. Perhaps MV annuloplasty and subvalvular repair may have a role in Grade II secondary MR, provided the patient does not have the predictors identified by Nappi and colleagues. (Excerpts from text of authors’ reply to letters concerning their article, Badhwar V., Alkhouli M., Mack M.J., Thourani V.H., and Ailawadi G.: A pathoanatomic approach to secondary functional mitral regurgitation: evaluating the evidence. J Thorac Cardiovasc Surg 2019; 158: pp. 76-81.)