Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

BACKGROUND: While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease.

RESULTS: We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations.

Phacoemulsification combined with posterior capsulorhexis and anterior vitrectomy in the management of malignant glaucoma in phakic eyes

Purpose: To describe sequential phacoemulsification-intraocular lens (IOL) implantation-posterior capsulorhexis-anterior vitrectomy in the management of phakic malignant glaucoma. Methods: Twenty consecutive patients (25 eyes) with phakic malignant glaucoma were enrolled at the Zhongshan Ophthalmic Center, Sun Yat-sen University. All patients underwent phacoemulsification, IOL implantation and posterior capsulorhexis together with anterior vitrectomy via a clear corneal paracentesis. Visual acuity, intraocular pressure (IOP), anterior chamber depth (ACD), surgical complications and medications required after the surgery were recorded. Results: After surgery, the mean LogMAR visual acuity and ACD increased significantly (visual acuity from -1.56 ± 1.17 to -0.54 ± 0.81, p < 0.001; ACD from 0.367 ± 0.397 mm to 2.390 ± 0.575 mm, p < 0.001), and mean IOP decreased significantly (from 39.6 ± 10.6 mm Hg to 14.5 ± 4.1 mmHg, p < 0.001). No serious perioperative complications occurred, and only five eyes required topical glaucoma medications after surgery. Conclusion: Combined phacoemulsification-IOL implantation-posterior capsulorhexis-anterior vitrectomy surgery is a safe and effective method for treating patients with phakic malignant glaucoma. © 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.

Effect of technique on intraocular pressure after combined cataract and glaucoma surgery: An evidence-based review.

TOPIC:

To analyze the literature pertaining to the techniques used in combined cataract and glaucoma surgery, including the technique of cataract extraction, the timing of the surgery (staged procedure versus combined procedure), the anatomic location of the operation, and the use of antifibrosis agents.

CLINICAL RELEVANCE:

Cataract and glaucoma are both common conditions and are often present in the same patient. There is no agreement concerning the optimal surgical management of these disorders when they coexist.

METHODS/LITERATURE REVIEWED:

Electronic searches of English language articles published since 1964 were conducted in Pub MED and CENTRAL, the Cochrane Collaboration's database. These were augmented by a hand search of six ophthalmology journals and the reference lists of a sample of studies included in the literature review. Evidence grades (A, strong; B, moderate; C, weak; I, insufficient) were assigned to the evidence that involved a direct comparison of alternative techniques.

RESULTS:

The preponderance of evidence from the literature suggests a small (2-4 mmHg) benefit from the use of mitomycin-C (MMC), but not 5-fluorouracil (5-FU), in combined cataract and glaucoma surgery (evidence grade B). Two-site surgery provides slightly lower (1-3 mmHg) intraocular pressure (IOP) than one-site surgery (evidence grade C), and IOP is lowered more (1-3 mmHg) by phacoemulsification than by nuclear expression in combined procedures (evidence grade C). There is insufficient evidence to conclude either that staged or combined procedures give better results or that alternative glaucoma procedures are superior to trabeculectomy in combined procedures.

CONCLUSIONS:

In the literature on surgical techniques and adjuvants used in the management of coexisting cataract and glaucoma, the strongest evidence of efficacy exists for using MMC, separating the incisions for cataract and glaucoma surgery, and removing the nucleus by phacoemulsification.