Presbyopia - A Review of Current Treatment Options and Emerging Therapies.

Presbyopia is a common age-related vision disorder characterized by a progressive inability to focus on near objects. If uncorrected or under-corrected, presbyopia can significantly impact patients' quality of life. Presbyopia represents an area of considerable unmet need due to its rising prevalence worldwide as the population ages, the high proportion of under-treated individuals in some parts of the world, and the limitations of currently available corrective methods. Progressive or bifocal spectacles are associated with peripheral blur, a restricted visual field and impaired depth perception, which have been linked to an increased risk of falls in the elderly. Contact lens options can be difficult to maintain due to the development of age-related dry eye symptoms and reduced manual dexterity. Other corrective methods involve surgical interventions that modify the optics of the cornea, replace the crystalline lens, or attempt to restore active accommodation. While patients undergoing surgery report satisfactory outcomes post-operatively, many of them eventually require reading glasses. Non-invasive therapies with novel mechanisms of action are currently being investigated; these include miotic agents and UNR844, a lipoic acid choline ester. In this narrative review, available evidence on presbyopia prevalence, quality of life impact and risk factors are described, with a focus on observational studies in non-clinical settings. The diagnosis pathway and patient journey in presbyopia are outlined, and various treatment options are analyzed. The data reviewed herein reveals significant gaps in the provision of vision correction for this common condition, with a paucity of effective, non-invasive treatment options broadly accessible to presbyopic individuals.

Surgical management of carcinoid tumors metastatic to the spine: Report of three cases.

BACKGROUND: Carcinoid tumors are rare, slow-growing neuroendocrine tumors that most frequently arise from the gastrointestinal tract or the lungs. Common sites of carcinoid metastases include lymph nodes, liver, lungs, and bone, with rare metastasis to the spine. We report three patients who presented with spinal cord compression secondary to carcinoid metastases to the spine. METHODS: Three patients presented with symptoms characteristic of spinal cord compression, including neck pain, radiculopathy, thoracic pain, weakness and numbness. All three patients underwent radiographic work-up and surgical treatment. RESULTS: One patient continued to have decreased strength in her right upper extremity, but was able to participate in physical therapy; another patient's numbness eventually resolved after completion of physical therapy; and the third patient's pain dramatically improved after surgery. One patient died more than two years post-surgery due to widespread metastasis; the other two remain alive more than two years post-surgery. CONCLUSIONS: Carcinoid tumor metastases rarely cause spinal cord compression, but should be considered when patients present with neurological symptoms consistent with cord compression. Work-up should include magnetic resonance imaging (MRI), computed tomography (CT) of the spine, and perhaps CT-guided biopsy. Surgery is indicated for symptomatic spinal cord compression in patients with carcinoid tumors.

Fine ambient air particulate matter exposure induces molecular alterations associated with vascular disease progression within plaques of atherosclerotic susceptible mice.

Epidemiology studies have reported associations between increased mortality and morbidity with exposure to particulate air pollution, particularly within individuals with preexisting cardiovascular disease (CVD). Clinical and toxicological studies have provided evidence that exposure to ambient air particulate matter (PM) impacts CVD by increasing plaque size. It is unclear whether PM-induced increased plaque size is associated with molecular disease progression. This study examines molecular profiles within plaques recovered from ApoE(-/-) mice exposed to concentrated ambient air particles (CAPs) to determine whether pulmonary deposition of PM contributes to molecular alterations leading to vascular disease progression. Laser capture microdissection was used to recover atherosclerotic plaques from ApoE(-/-) male mice exposed daily for 5 mo to filtered air or CAPs. Alterations in mRNA expression was assessed in microdissected plaques of CAPs-exposed and air controls using the Affymetrix microarray platform. Bioinformatic analysis indicated alterations in 611 genes: 395 genes downregulated and 216 genes upregulated. Gene ontology revealed CAPs-induced changes to inflammation, proliferation, cell cycle, hematological system, and cardiovascular pathways. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) verified microarray data also revealing gene expression alterations undetected by the microarray analysis, i.e., decreased expression of alpha-actin for smooth muscle cells, and increased expression of the macrophage marker Cd68 and of beta-actin. Comparison of CAPs-induced gene expression profiles demonstrated consistency with previously published gene expression profiles in the ApoE(-/-) mouse model and humans associated with plaque progression. These results indicate that exposure to fine PM induces molecular alterations associated with vascular disease progression and provides insight into potential biological pathways responsible for this effect.

Effects of mutant human Ki-ras(G12C) gene dosage on murine lung tumorigenesis and signaling to its downstream effectors.

Studies in cell culture have suggested that the level of RAS expression can influence the transformation of cells and the signaling pathways stimulated by mutant RAS expression. However, the levels of RAS expression in vivo appear to be subject to feedback regulation, limiting the total amount of RAS protein that can be expressed. We utilized a bitransgenic mouse lung tumor model that expressed the human Ki-ras(G12C) allele in a tetracycline-inducible, lung-specific manner. Treatment for 12 months with 500 microg/ml of doxycycline (DOX) allowed for maximal expression of the human Ki-ras(G12C) allele in the lung, and resulted in the development of focal hyperplasia and adenomas. We determined if different levels of mutant RAS expression would influence the phenotype of the lung lesions. Treatment with 25, 100 and 500 microg/ml of DOX resulted in dose-dependent increases in transgene expression and tumor multiplicity. Microscopic analysis of the lungs of mice treated with the 25 microg/ml dose of DOX revealed infrequent foci of hyperplasia, whereas mice treated with the 100 and 500 microg/ml doses exhibited numerous hyperplastic foci and also adenomas. Immunohistochemical and RNA analysis of the downstream effector pathways demonstrated that different levels of mutant RAS transgene expression resulted in differences in the expression and/or phosphorylation of specific signaling molecules. Our results suggest that the molecular alterations driving tumorigenesis may differ at different levels of mutant Ki-ras(G12C) expression, and this should be taken into consideration when inducible transgene systems are utilized to promote tumorigenesis in mouse models.

Genetic and epigenetic alterations in lung tumors from bitransgenic Ki-rasG12C expressing mice.

Mutations in Ki-ras occur in approximately 30-50% of patients with adenocarcinoma (AC) of the lung. We previously reported the development of a bitransgenic mouse model that expressed the human Ki-ras(G12C) allele in a lung-specific, tetracycline-inducible manner and gave rise to benign lung tumors. In the current study, these benign tumors, which represent relatively early lesions in neoplastic progression, were analyzed for molecular alterations secondary to mutant Ki-ras expression to determine the gene(s) that contribute to adenoma (AD) development. Tumors were removed following doxycycline (DOX) treatment for 9 and 12 mo and examined for alterations in cell-cycle regulatory genes. Quantification of mRNA expression for cyclin D1, retinoblastoma, p16(Ink4a), p19(Arf), and survivin was carried out by real-time PCR. All of the tumors examined exhibited a mean reduction of approximately fivefold for the retinoblastoma gene (P < 0.02). Increased expression of both p19(Arf) and survivin were detected in a majority of the tumors examined (P < 0.01 and 0.001, respectively), but no change in cyclin D1 RNA expression was observed. A subset of the lung tumors (8/28) displayed reduced levels of p16(Ink4a) expression (P = 0.02). Immunohistochemical analysis confirmed the upregulation of p19(Arf) and survivin in all 10 of the lung tumors examined. However, increased staining for cyclin D1 was observed in the tumor tissue. In addition, increased levels of activated p53 were found in lung tumor tissues stained with an anti-phospho-p53 antibody, while an absence of staining was observed with an anti-phospho-pRb antibody in both normal control and tumor tissue. Analysis of the methylation status of p16(Ink4a) by methylation-specific PCR (MSP) demonstrated that seven of eight tumors exhibiting decreased expression of p16(Ink4a) had at least partial methylation of the promoter region. Single stranded conformational polymorphism (SSCP) analysis demonstrated that neither exons 1 or 2 of p16(Ink4a) nor exons 5-8 of p53 exhibited mutations. These data thus identify alterations in specific genes and pathways that combine with the mutation in Ki-ras to promote the formation of benign lung tumors and suggest potential targets for the development of novel chemotherapeutic and chemopreventive agents during the early stages of lung tumor progression.

Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model.

To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-ras(G12C) allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-ras(G12C) caused multiple, small lung tumors over a 12-month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well-differentiated adenomas. This is in contrast to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-ras(G12C) was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38 and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of doxycycline for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-ras(G12C) expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.

Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects.

Perillyl alcohol (POH) is currently being tested in clinical trials as an anticancer agent, though its mechanism of action has not been definitively established. We treated two human lung cancer cell lines, H322 and H838, with POH to determine its antitumor properties. A sulforhodamine B (SRB) cell proliferation assay was used to determine the effects of POH after 1 and 5 days of treatment with 0.25, 0.5, 0.75, 1.0, and 1.5 mM POH. After 1 day of treatment, little difference could be seen between the lowest and highest concentrations of POH. However, after 5 days, both cell lines showed a dose-dependent decrease in cell proliferation that ranged from 15% to 83%. A clonogenic assay confirmed these results-while there was no significant effect of POH after 1 day of exposure, a dose-dependent decrease in colony formation, ranging from 15% to 100%, was seen after 5 days of treatment. Time-lapse video microscopy revealed that apoptotic cells were evident within 24-48 h of treatment with 1.5 mM POH. The appearance of apoptotic cells was preceded by increased caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP) as POH activated caspase-3 activity 3-6-fold. Nuclear staining with 4',6-diamidino-2-phenylindole (DAPI) confirmed the classical characteristics of apoptosis in POH-treated cells. DNA microarray expression analysis was performed following 8 and 24 (H322) or 8 and 48 (H838) h of treatment with 1.5 mM POH. While a large number of genes were up- or downregulated in the two cell lines at various times after POH treatment, the levels of expression of only eight genes were up- or down-related in both cell lines at both of the time points examined. The significance of these genes as potential mediators of POH action is still uncertain, but the limited number of commonly up- or downregulated genes detected by microarray expression analysis suggests that POH may mediate its effects via posttranscriptional mechanisms. Our results suggest that POH may have potential use as an anticancer drug that stimulates or sensitizes lung tumor cells to apoptosis, and this effect may depend on genetic lesions present in tumor cells.