In silico repurposing the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing clear cell renal carcinoma

The pituitary tumor-transforming gene 1 (PTTG1), also known as Securin, is considered an oncogene. This study aimed to investigate the role of PTTG1 in clear cell renal cell carcinoma (ccRCC) using in silico bioinformatics approaches. A pan-cancer analysis using The Cancer Genome Atlas (TCGA) data indicated that among all cancer types copy number amplification of PTTG1 gene was most frequently found in ccRCC. However, amplification of PTTG1 gene copy number did not correlate with the increase of mRNA level in ccRCC, and did not predict the patients' overall survival. Instead, ccRCC was correlated with overexpression of PTTG1 mRNA, and its expression level was stage-dependent increased in cancer patients. An outlier analysis using the Oncomine database suggested that PTTG1 mRNA expression served as a good biomarker for ccRCC. Pathway analysis for upregulated genes enriched in PTTG1-high expressing ccRCC patients found that PTTG1 overexpression was associated with mitotic defects. Mining drug sensitivity data using the Cancer Therapeutics Response Portal (CTRP) discovered that PTTG1-high expressing ccRCC cell lines were susceptible to a Rac1 (Ras-related C3 botulinum toxin substrate 1) inhibitor NSC23766. Therefore, this study provides an in silico insight into the role of PTTG1 in ccRCC, and repurposes the Rac1 inhibitor NSC23766 for treating PTTG1-high expressing ccRCC.     

Pseudomonas aeruginosa sepsis presenting as oral ecthyma gangrenosum in identical twins with Bruton tyrosine kinase gene mutation: Two case reports and review of the literature

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease. We reported two 7-month-old identical male twins with Pseudomonas aeruginosa sepsis who initially manifested as oral ecthyma gangrenosum and were finally diagnosed to have XLA. In both cases, we confirmed the c.862C > T BTK missense mutation in exon 10 at the SH2 domain.     

Risk of Infection Associated With Ibrutinib in Patients With B-Cell Malignancies: A Systematic Review and Meta-analysis of Randomized Controlled Trials

IntroductionB-cell malignancies confer an increased risk of infection due to associated immune defects. Conflicting evidence exists on the risk of infection in patients receiving ibrutinib. We conducted a systematic review and meta-analysis to estimate relative risk of infection with ibrutinib in B-cell malignancies.MethodsA systematic search of Embase, Medline, Web of Science, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, European Union Clinical Trials Register, and ClinicalTrials.gov was performed through January 15, 2019, to identify randomized controlled trials comparing ibrutinib with other agents or placebo in B-cell malignancies. We pooled point estimates using the Der Simonian and Laird random-effects model. Statistical analyses were performed by Stata/SE 15.1.ResultsSeven studies randomizing 2167 patients were included in the final analysis. Treatment duration in studies ranged from 9.4 to 38.7 months. Ibrutinib was associated with a significantly increased risk of infection (any grade and grade 3-5) in patients with B-cell malignancies [pooled risk ratio (RR) = 1.34, 95% confidence interval [CI], 1.06-1.69, P = .015; and RR = 1.35, 95% CI, 1.05-1.74, P = .018, respectively]. In patients with chronic lymphocytic leukemia, a significantly increased risk of grade 3-5 infection was noted in the ibrutinib group [pooled RR = 1.24, 95% CI, 1.02-1.50, P = .028]. Incidences of pneumonia and upper respiratory tract infection were not significantly different between groups.ConclusionOur meta-analysis found that ibrutinib was associated with significantly higher risk of infections in patients with B-cell malignancies. Occurrence of major individual subtypes was not different between groups, possibly as a result of inconsistent reporting across studies.