TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis

Comparison of outcomes of trabeculectomy with mitomycin C vs. ologen implant in primary glaucoma

Purpose: To compare the safety and efficacy of trabeculectomy with Ologen implant vs. trabeculectomy with Mitomycin C (MMC). Materials and Methods: In a prospective, randomized, pilot study, 39 eyes of 33 subjects with medically uncontrolled primary glaucoma, aged 18 years or above underwent trabeculectomy either with MMC (20 eyes) or with Ologen implant (19 eyes). The primary outcome measure was cumulative success probability, defined as complete if the intraocular pressure (IOP) was > 5 and ≤ 21 mm Hg without anti-glaucoma medications or additional surgery and qualified if an IOP was > 5 and ≤ 21 mm Hg with or without anti-glaucoma medications. Results: Mean (± standard deviation) follow-up in Ologen group was 19.1 ± 8.1 months, and in MMC group was 18.0 ± 8.4 months. Mean IOP reduction at 6 months was significantly lower (P = 0.01) in the MMC group (11.9 ± 2.9 mm Hg) as compared to Ologen group (14.6 ± 2.7 mm Hg). However, at 12 months (P = 0.81) and 24 months (P = 0.32), the mean IOP was similar between the 2 groups. Complete success probability at the end of 6 months in Ologen group was 100% (95% confidence interval: 59.1 - 99.0) was similar (P = 0.53) to that in MMC group (93.8%, 95% CI: 63.2 - 99.1). The incidences of early post-operative complications were similar in the 2 groups, except hyphema, which was significantly more in Ologen group (P = 0.02). Conclusion: In this pilot study, the success of trabeculectomy and complications were similar in both Ologen and MMC groups at the end of 6 months

Effect of optic disc size and disease severity on the diagnostic capability of glaucoma imaging technologies in an Indian population

PURPOSE: To evaluate the influence of optic disc size and disease severity on the diagnostic validity of optical coherence tomography (Stratus OCT), scanning laser polarimetry [GDx variable corneal compensator (VCC)], and confocal scanning laser ophthalmoscopy [Heidelberg retina tomograph II (HRT II)] in Indian eyes with glaucoma. METHODS: Ninety-five normal and 125 glaucoma patients underwent imaging with Stratus OCT, GDx VCC, and HRT II. One eye of each person was randomly selected for analysis. Using disc area determined on HRT II, discs were classified as small (3 mm). The parameter with the best sensitivity for each device, at a fixed specificity, was compared for different disc sizes. Logistic marginal regression was used to study the effect of disc size and disease severity (mean deviation on standard automated perimetry) on the diagnostic performance of these imaging devices. RESULTS: At a fixed specificity of 84.2%, the sensitivity of HRT II was significantly different for varying disc sizes (P=0.0004). The sensitivities for dissimilar disc sizes were not significantly different for the GDx VCC (P=0.928) or Stratus OCT (P=0.381). Logistic marginal regression also showed that sensitivity of HRT II increased with increasing disc size, whereas sensitivity of OCT and GDx were independent of the disc size. The sensitivity of all 3 technologies increased with increasing disease severity (decreasing mean deviation). CONCLUSIONS: Optic disc size affects the diagnostic capability of HRT II but not that of GDx VCC or Stratus OCT. The sensitivity of all 3 imaging technologies increased with increasing disease severity

Agreement of glaucoma specialists and experienced optometrists in gonioscopy and optic disc evaluation

Purpose: To compare the diagnostic performance of glaucoma specialists and experienced optometrists in gonioscopy and optic disc assessment. Methods: This study was done to validate the diagnostic performance of two experienced optometrists for using their skills of detecting glaucoma using gonioscopy and optic disc assessment in a major epidemiological study, the L V Prasad Eye Institute Glaucoma Epidemiology and Molecular Genetics Study (LVPEI-GLEAMS). Gonioscopic findings for 150 eyes were categorized as 0, 1 and 2 for open angle, primary angle closure suspect (PACS) and primary angle closure (PAC) respectively. Optic disc findings for 200 eyes were categorized as 0, 1 and 2 for normal, suspects and glaucomatous respectively. Weighted kappa (κ) and diagnostic accuracy parameters were calculated. Two optometrists (#1 and #2) participated in the study. Results: Agreement between glaucoma specialists and optometrist for interpretation of gonioscopy to discriminate PACS and PAC from open angles and for interpretation of optic disc to discriminate glaucomatous and suspicious discs from normal, the kappa (κ) was 0.92 and 0.84 and 0.90 and 0.89 for optometrists #1 and #2 respectively. Sensitivities and specificities were above 90% for gonioscopy. Optic disc evaluation had specificities greater than 95% to discriminate normal from glaucomatous discs while the sensitivities were 83% and 93% for optometrists #1 and #2 respectively. Conclusion: Agreement between optometrists and glaucoma specialists, in diagnostic performance of gonioscopy and optic assessment was excellent with high sensitivity and specificity. Hence, we conclude that the experienced optometrists can detect glaucoma accurately in the LVPEI-GLEAMS

Scanning the macula for detecting glaucoma

Background: With the advent of spectral domain optical coherence tomography (SDOCT), there has been a renewed interest in macular region for detection of glaucoma. However, most macular SDOCT parameters currently are thickness parameters which evaluate thinning of the macular layers but do not quantify the extent of area over which the thinning has occurred. We therefore calculated a new macular parameter, "ganglion cell complex surface abnormality ratio (GCC SAR)" that represented the surface area over which the macular thickness was decreased. Purpose: To evaluate the ability of SAR in detecting perimetric and preperimetric glaucoma. Design: Retrospective image analysis. Materials and Methods: 68 eyes with perimetric glaucoma, 62 eyes with preperimetric glaucoma and 165 control eyes underwent GCC imaging with SDOCT. SAR was calculated as the ratio of the abnormal to total area on the GCC significance map. Statistical Analysis: Diagnostic ability of SAR in glaucoma was compared against that of the standard parameters generated by the SDOCT software using area under receiver operating characteristic curves (AUC) and sensitivities at fixed specificities. Results: AUC of SAR (0.91) was statistically significantly better than that of GCC average thickness (0.86, P = 0.001) and GCC global loss volume (GLV; 0.88, P = 0.01) in differentiating perimetric glaucoma from control eyes. In differentiating preperimetric glaucoma from control eyes, AUC of SAR (0.72) was comparable to that of GCC average thickness (0.70, P > 0.05) and GLV (0.72, P > 0.05). Sensitivities at specificities of 80% and 95% of SAR were comparable (P > 0.05 for all comparisons) to that of GCC average thickness and GLV in diagnosing perimetric and preperimetric glaucoma. Conclusion: GCC SAR had a better ability to diagnose perimetric glaucoma compared to the SDOCT software provided global GCC parameters. However, in diagnosing preperimetric glaucoma, the ability of SAR was similar to that of software provided global GCC parameters

Circular functional analysis of OCT data for precise identification of structural phenotypes in the eye.

Progressive optic neuropathies such as glaucoma are major causes of blindness globally. Multiple sources of subjectivity and analytical challenges are often encountered by clinicians in the process of early diagnosis and clinical management of these diseases. In glaucoma, the structural damage is often characterized by neuroretinal rim (NRR) thinning of the optic nerve head, and other clinical parameters. Baseline structural heterogeneity in the eyes can play a key role in the progression of optic neuropathies, and present challenges to clinical decision-making. We generated a dataset of Optical Coherence Tomography (OCT) based high-resolution circular measurements on NRR phenotypes, along with other clinical covariates, of 3973 healthy eyes as part of an established clinical cohort of Asian Indian participants. We introduced CIFU, a new computational pipeline for CIrcular FUnctional data modeling and analysis. We demonstrated CIFU by unsupervised circular functional clustering of the OCT NRR data, followed by meta-clustering to characterize the clusters using clinical covariates, and presented a circular visualization of the results. Upon stratification by age, we identified a healthy NRR phenotype cluster in the age group 40-49 years with predictive potential for glaucoma. Our dataset also addresses the disparity of representation of this particular population in normative OCT databases