Active Learning of Contrast Sensitivity to Assess Visual Function in Macula-off Retinal Detachment.

PURPOSE: To characterize the contrast sensitivity function (CSF) in patients with successful repair of macula-off rhegmatogenous retinal detachment (RD) using an adaptive computerized contrast testing device. METHODS: CSF was prospectively measured in macula-off RD patients following successful repair and age-matched controls at W. K. Kellogg Eye Center and Massachusetts Eye and Ear, employing the active learning device Manifold Contrast Vision Meter (Adaptive Sensory Technology, San Diego, CA). Outcome measures included average area under the CSF curve (AULCSF), CS thresholds at 1-18 cycles per degree (cpd) and best correctd visual acuity (BCVA) in RD eyes fellow eyes and controls. A sub-analysis was performed in eyes with BCVA of 20/30 or better. RESULTS: Twenty-three macula-off RD eyes status post repair, fellow healthy eyes and 45 age-matched control eyes underwent CSF testing. The mean BCVA of the 23 RD eyes was 0.250 logMAR, significantly reduced compared to fellow eyes 0.032 (p<0.001) and controls 0.026 (p< 0.00001). There was a statistically significant reduction in AULCSF in RD eyes compared to the fellow eyes (p<0.0001) and to age-matched controls (Z-score -0.90, p<0.0001) and CSF reduction across all spatial frequencies. In the 15 RD eyes with BCVA of 20/30 or better, the mean CSF was significantly reduced compared to fellow eyes (p=0.0158) and controls (p=0.0453). CONCLUSIONS: CSF in macula-off RD eyes following repair was significantly reduced compared to fellow eyes and age-matched controls. CSF seems to be a promising visual function endpoint with potential applications in the clinical practice and future clinical trials.

Subjective Age in Older Korean Americans: The Impact of Functional Disability Mediated by Attitudes Toward Aging.

The present study aims to examine how subjective age of older Korean Americans would be affected by functional disability and attitudes toward aging. We hypothesized that (a) both functional disability and attitudes toward aging would have a direct effect on subjective age and (b) the effect of functional disability on subjective age would be mediated by attitudes toward aging. Our analyses of the survey data with 208 community-dwelling Korean Americans aged 60 and older (mean age = 69.6, SD = 7.51) showed that the indirect effect of functional disability on subjective age through attitudes toward aging [-.020 (.009)] was significant (bias-corrected 95% confidence interval [-.039, -.006]). The findings suggest that functional disability fosters negative attitudes toward aging, which in turn leads to the feelings of being older than actual age. Our study suggests ways to preserve and promote positive perceptions of age and aging.

Bifid Mandibular Canal: A Case Review and Retrospective Review of CBCTs.

PURPOSE: This case presentation and retrospective review of cone-beam computed tomograms is to evaluate prevalence, classification, and demographics of bifid mandibular canals (BMC) to inform practitioners on this variation and avoid untoward complications due to failure to diagnose. MATERIALS AND METHODS: Two thousand one hundred thirty scans were evaluated by 2 oral and maxillofacial radiologists. BMCs were noted and classified according to Naitoh. Demographic data were also collected and analyzed. RESULTS: Twenty-eight patients were noted to have bifid mandibular canal, with an average age of 39 years (± 19.5), with no strong sex predilection. Patients (1.31%) were noted to have bifid canals. A greater percentage of patients were shown to have bilateral bifid canals (42.9%) versus either unilateral side (25% left, 32.1% right), but is statistically insignificant. Prevalence was greatest in types 1 and 3 (35.9% and 51.3%, respectively, P = 0.000011). Types 2 and 4 were much less common. CONCLUSION: BMCs are an important anatomic variation that has implications on any mandibular surgery, including implant surgery. Just more than 1% of patients have this variation, but failure to recognize this in a patient can result in poor outcome, as illustrated in the case presented.

Novel single-nucleotide polymorphism markers predictive of pathologic response to preoperative chemoradiation therapy in rectal cancer patients.

PURPOSE: Studies aimed at predicting individual responsiveness to preoperative chemoradiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. METHODS AND MATERIALS: A 3-step strategy for the determination of CRT sensitivity is proposed based on (1) the screening of a human genome-wide single-nucleotide polymorphism (SNP) array in correlation with histopathologic tumor regression grade (TRG); (2) clinical association analysis of 113 patients treated with preoperative CRT; and (3) a cell-based functional assay for biological validation. RESULTS: Genome-wide screening identified 9 SNPs associated with preoperative CRT responses. Positive responses (TRG 1-3) were obtained more frequently in patients carrying the reference allele (C) of the SNP CORO2A rs1985859 than in those with the substitution allele (T) (P=.01). Downregulation of CORO2A was significantly associated with reduced early apoptosis by 27% (P=.048) and 39% (P=.023) in RKO and COLO320DM colorectal cancer cells, respectively, as determined by flow cytometry. Reduced radiosensitivity was confirmed by colony-forming assays in the 2 colorectal cancer cells (P=.034 and .015, respectively). The SNP FAM101A rs7955740 was not associated with radiosensitivity in the clinical association analysis. However, downregulation of FAM101A significantly reduced early apoptosis by 29% in RKO cells (P=.047), and it enhanced colony formation in RKO cells (P=.001) and COLO320DM cells (P=.002). CONCLUSION: CRT-sensitive SNP markers were identified using a novel 3-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may be of value for the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts.

Genome-wide identification of possible methylation markers chemosensitive to targeted regimens in colorectal cancers.

PURPOSE: Few efficient methylation markers of chemosensitivity have been discovered. The genome-wide analysis of methylation markers is needed to identify chemosensitive candidates to targeted therapy. METHODS: This study describes a two-step process to select chemosensitive candidates of methylation genes. A genome-wide screening of methylation genes was performed using a Beadarray and an in vitro chemosensitivity assay of 119 colorectal cancers (CRCs). Ten candidate genes identified during the initial screening were verified by biological utility assessment using cell viability assays of transfected CRC cells. RESULTS: Five methylation genes related to sensitivity to bevacizumab regimens (RASSF1, MMP25, KCNQ1, ESR1, and GALR2) or cetuximab regimens (SCL18A2, GPX7, NID2, IGFBP3, and ALX4) were chosen during the first step. A viability assay revealed that GALR2-overexpressing HCT116 cells were significantly more chemosensitive to bevacizumab regimens than control cells (P = 0.022 and 0.019 for bevacizumab with FOLFIRI and FOLFOX, respectively), concurrently verified on a caspase-3 activity assay. GPX7- or ALX4-overexpressed RKO cells were significantly less viable to cetuximab regimens compared to control cells (GPX7: P = 0.027 each for cetuximab with FOLFIRI and FOLFOX; ALX4: P = 0.049 and 0.003 for cetuximab with FOLFIRI and FOLFOX, respectively), but caspase-3 activity was not prominent in GPX7-overexpressed RKO cells. CONCLUSIONS: Two novel genes, GALR2 and ALX4, have been identified as chemosensitive methylation candidates to bevacizumab and cetuximab regimens, respectively. As our study did not include a clinical association study, the two candidates should be validated in large clinical cohorts, hopefully predicting responsive patients to targeted regimens.

Novel chemosensitive single-nucleotide polymorphism markers to targeted regimens in metastatic colorectal cancer.

PURPOSE: Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost. EXPERIMENTAL DESIGN: A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. RESULTS: Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P ≤ 0.001-0.024). CONCLUSIONS: Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts.

Genome-wide identification of chemosensitive single nucleotide polymorphism markers in colorectal cancers.

Improved methods for predicting chemoresponsiveness involving the identification of polymorphic markers is highly desirable, considering narrow therapeutic index and frequent resistance to anti-cancer regimens. The genome-wide screening of chemosensitive single nucleotide polymorphisms (SNPs) was undertaken in association with in vitro chemosensitivity assays in 104 colorectal cancer patients for the initial screening step. Allele frequency, linkage disequilibrium, potential function, and Hardy-Weinberg equilibrium of the candidate SNPs were then determined for the identifying step. Finally, clinical association analysis in the other 260 evaluable patients or cell viability assays of transfected RKO cells was used to verify candidate SNPs for the validation step. In total, 12 SNPs to six regimens were initially chosen during the screening and identifying steps. In patients receiving fluoropyrimidine-based adjuvant chemotherapy, the substitution alleles of GPC5 rs553717 (AA) correlated significantly with tumor recurrence and shorter disease-free survival (P = 0.019 and 0.023, respectively). Interestingly, RKO cells expressing mutant GPC5 showed enhanced cell death in response to 5-FU in cytotoxicity assays. Patients that were homozygous for the reference alleles SSTR4 rs2567608 (AA) and EPHA7 rs2278107 (TT) showed lower disease control rates in response to irinotecan and oxaliplatin regimens, respectively, than those with substitution alleles (P = 0.022 and 0.014, respectively). Thus, we identified chemosensitive SNP markers using a novel three step process of genome-wide analysis consisting of in vitro screening, identification, and validation. The candidate chemosensitive SNP markers identified in our study, including those identified in vitro, can now be further verified in a large cohort study.