Establishment of Induced Pancreatic Stem Cells by Yes-Associated Protein 1.

Recently, we and others generated induced tissue-specific stem/progenitor (iTS/iTP) cells. The advantages of iTS/iTP cells compared with induced pluripotent stem (iPS) cells are (1) easier generation, (2) efficient differentiation, and (3) no teratomas formation. In this study, we generated mouse induced pancreatic stem cells (iTS-P cells) by the plasmid vector expressing Yes-associated protein 1 (YAP). The iTS-P YAP9 cells expressed Foxa2 (endoderm marker) and Pdx1 (pancreatic marker) while the expressions of Oct3/4 and Nanog (marker of embryonic stem [ES] cells) in iTS-P YAP9 cells was significantly lower compared with those in ES cells. The iTS-P YAP9 cells efficiently differentiated into insulin-expressing cells compared with ES cells. The ability to generate autologous iTS cells may be applied to diverse applications of regenerative medicine.

How using light touch immersion research revealed important insights into the lack of progress in malaria elimination in Eastern Indonesia.

BACKGROUND: By 2022, the Government of Indonesia had successfully eliminated malaria in 389 out of 514 districts but continues to face a challenge in Eastern Indonesia where 95% of the total 2021 malaria cases were reported from Papua, West Papua and Nusa Tenggara Timur provinces. There is an increased recognition that malaria elimination will require a better understanding of the human behavioural factors hindering malaria prevention and treatment, informed by local context and local practice. METHODS: This research used a light-touch immersion research approach. Field researchers lived in communities over several days to gather data through informal conversations, group-based discussions using visual tools, participant observation and direct experience. The study was conducted in four high malaria endemic areas in Papua, West Papua, and Sumba Islands in Nusa Tenggara Timur. RESULTS: The research highlights how people's perception of malaria has changed since the introduction of effective treatment which, in turn, has contributed to a casual attitude towards early testing and adherence to malaria treatment. It also confirms that people rarely accept there is a link between mosquitoes and malaria based on their experience but nevertheless take precautions against the annoyance of mosquitoes. There is widespread recognition that babies and small children, elderly and incomers are more likely to be seriously affected by malaria and separately, more troubled by mosquitoes than indigenous adult populations. This is primarily explained by acclimatization and strong immune systems among the latter. CONCLUSIONS: Using immersion research enabled behaviour research within a naturalistic setting, which in turn enabled experiential-led analysis of findings and revealed previously unrecognized insights into attitudes towards malaria in Eastern Indonesia. The research provides explanations of people's lack of motivation to consistently use bed nets, seek early diagnosis or complete courses of treatment. The felt concern for the wellbeing of vulnerable populations highlighted during light touch immersion provides an entry point for future social behaviour change communication interventions. Rather than trying to explain transmission to people who deny this connection, the research concludes that it may be better to focus separately on the two problems of malaria and mosquitoes (especially for vulnerable groups) thereby resonating with local people's own experience and felt concerns.

MORPHOLOGIC CHARACTERISTICS AND PROGRESSION PATTERNS OF MACULAR NEOVASCULARIZATION-RELATED ATROPHY IN EYES WITH PATHOLOGIC MYOPIA.

PURPOSE: To investigate the development and progression patterns of macular neovascularization (MNV)-related atrophies in eyes with pathologic myopia. METHODS: Twenty-seven eyes of 26 patients with MNV followed from its onset to progression to macular atrophy were studied. A longitudinal series of autofluorescence and optical coherence tomography images were examined for the patterns of MNV-related atrophy. Changes in best-corrected visual acuity were determined for each pattern. RESULTS: The mean age was 67.2 ± 8.7 years. The mean axial length was 29.6 ± 1.5 mm. Three patterns of atrophy were identified: multiple-atrophic pattern, 63% of the eyes had small atrophies occurring at multiple sites around the MNV edge; single-atrophic pattern, 18.5% had atrophies occurring only on one side of the MNV edge; and exudation-related pattern, 18.5% had atrophy occurring within a previous serous exudation or hemorrhagic area and slightly away from the MNV edge. Eyes with atrophies in multiple-atrophic and exudation-related patterns progressed to large macular atrophies involving the central fovea and showed decrease in best-corrected visual acuity during the 3-year follow-up period. Eyes with single-atrophic pattern had a sparing of the fovea and had good recovery of the best-corrected visual acuity. CONCLUSION: There are three patterns of MNV-related atrophy in eyes with pathologic myopia with different courses of progression.

Papillary and Peripapillary Hemorrhages in Eyes With Pathologic Myopia.

Purpose: To determine the prevalence, characteristics, and causes of papillary and peripapillary hemorrhages (PPHs) in eyes with pathologic myopia (PM). Methods: PM patients were retrospectively studied between 2011 and 2018. Fundus images were used to diagnose and classify the PPHs. Fundus fluorescein angiographic (FFA) and optical coherence tomographic (OCT) images were used to determine the status of the retinal vessels and tissue at and around the PPH sites. Visual field data determined by Goldmann perimetry and Humphrey visual field analyzer were also analyzed. Results: A total of 2171 PM patients (3774 eyes) were examined. Eighty-eight patients (97 eyes) had PPHs (mean age 66.8 ± 11.9 years; mean axial length 30.79 ± 2.17 mm) for a prevalence of 4.05%. Thirty (30.9%) eyes recurred. Among the 90 eyes with a single-site PPH, the most common type and location were the conus type (49 eyes, 54.4%) and the temporal side (66 eyes, 73.3%), respectively. Regression analysis showed that patchy atrophy reduced the risk of recurrences than diffuse atrophy (P < 0.05), whereas a longer axial length and potential glaucoma increased the risk (both P < 0.05). FFA and OCT showed that PPHs developed in the area of straightened retinal arterioles (24 eyes), at or beside the peak of a ridge (10 eyes), in an area of compressed retinal tissue (two eyes). Conclusions: PPHs are present in 4.05% of PM eyes, and they are most often located in the temporal peripapillary atrophic region of the retina. Axial elongation, mild myopic maculopathy, and potential glaucoma are risk factors for recurrences.

Hospital-based study of risk factors associated with development of myopic macular neovascularization in highly myopic eyes.

INTRODUCTION: Myopic macular neovascularization (MNV) is the most common cause of a reduction of central vision in eyes with pathologic myopia, and it can progress to macular atrophy in the long-term. The aim of this study was to determine the risk factors associated with the development of MNVs. METHODS: There were 17,198 follow-up records from 5,409 eyes of 2,784 highly myopic patients that were reviewed. The general information and ophthalmic information in the records were studied. The significance of the correlations of factors associated with the development and predicting the development of myopic MNV were determined. RESULTS: Being a woman (odds ratio [OR]: 0.727, P<0.001), having a longer axial length (OR = 0.948, P<0.001), a poorer baseline best-correct visual acuity (BCVA, OR = 2.098, P<0.001), having severe myopic maculopathy (overall: P<0.001), prior myopic MNV in the fellow eye (OR = 4.105, P<0.001), presence of patchy atrophy (overall P<0.001), lacquer cracks (OR = 1.718, P<0.001), prior foveal retinal detachment (RD, OR = 3.269, P<0.001), prior macular hole (MH, OR = 0.641, P <0.001), prior macular retinoschisis (OR = 1.533, P<0.001), and prior macular edema (OR = 1.508, P<0.001) were significantly correlated with the development of myopic MNV. Eyes with MNV and patchy atrophy would require an intensive follow-up examination for myopic patients as the fellow eye would have a risk of >70% for the development of myopic MNV in 3-years and nearly 80% in 5-years. CONCLUSIONS: Clinicians need to pay special attention to eyes with severe grades of myopic maculopathy, prior myopic MNV in the fellow eye, presence of patchy atrophy, and prior foveal retinal detachment to determine the onset of myopic MNV.

Dilated choroidal veins and their role in recurrences of myopic macular neovascularisations.

AIM: To determine whether there is a correlation between the presence of macular dilated choroidal vein (DCV) and the recurrence of myopic macular neovascularisation (MNV) after antivascular endothelial growth factor (VEGF) treatment. METHODS: Medical records of 168 eyes of 163 patients with myopic MNV were reviewed for the presence of macular DCV and episodes of recurrences. A macular DCV was defined as a choroidal vein whose diameter was 2× larger than the adjacent veins coursing in the macular area of 5.5 mm diameter. RESULTS: Macular DCV existed in 47 (28%) of the eyes with myopic MNV. 70 eyes (41.7%) had recurrence during a mean follow-up period of 52.5±23.0 months. Recurrence was found in 28 of the 47 eyes (59.6%) with DCV, which was significantly more frequent than the 42 of the 121 eyes (34.7%) without DCV (p=0.003). Cox model analysis showed that macular DCV was an independent risk factor (HR: 2.0, 95% CI 1.1 to 3.5) for recurrence. The recurrence rate was significantly higher in eyes with DCV within the first 2 years after the onset than in eyes without DCV. CONCLUSIONS: Macular DCVs may be indicators of a more aggressive phenotype of eyes with myopic MNV. These eyes need careful monitoring after anti-VEGF therapies.

Validation of Soft Labels in Developing Deep Learning Algorithms for Detecting Lesions of Myopic Maculopathy From Optical Coherence Tomographic Images.

PURPOSE: It is common for physicians to be uncertain when examining some images. Models trained with human uncertainty could be a help for physicians in diagnosing pathologic myopia. DESIGN: This is a hospital-based study that included 9176 images from 1327 patients that were collected between October 2015 and March 2019. METHODS: All collected images were graded by 21 myopia specialists according to the presence of myopic neovascularization (MNV), myopic traction maculopathy (MTM), and dome-shaped macula (DSM). Hard labels were made by the rule of major wins, while soft labels were possibilities calculated by whole grading results from the different graders. The area under the curve (AUC) of the receiver operating characteristics curve, the area under precision-recall (AUPR) curve, F-score, and least square errors were used to evaluate the performance of the models. RESULTS: The AUC values of models trained by soft labels in MNV, MTM, and DSM models were 0.985, 0.946, and 0.978; and the AUPR values were 0.908, 0.876, and 0.653 respectively. However, 0.56% of MNV "negative" cases were answered as "positive" with high certainty by the hard label model, whereas no case was graded with extreme errors by the soft label model. The same results were found for the MTM (0.95% vs none) and DSM (0.43% vs 0.09%) models. CONCLUSIONS: The predicted possibilities from the models trained by soft labels were close to the results made by myopia specialists. These findings could inspire the novel use of deep learning models in the medical field.

ROLE OF DILATED SUBFOVEAL CHOROIDAL VEINS IN EYES WITH MYOPIC MACULAR NEOVASCULARIZATION.

PURPOSE: To investigate the dilated choroidal veins (DCVs) at or around myopic macular neovascularizations (MNVs) and to determine whether there is a hemodynamic relationship between them. METHODS: Fifty-eight eyes of 57 patients with myopic MNVs were examined. Dilated choroidal veins were defined as choroidal veins whose diameter was 2X larger than adjacent veins. Indocyanine green angiography and swept-source optical coherence tomography images were reviewed to detect DCVs that crossed the subfoveal area. The filling sequence of the DCVs and MNVs was determined. RESULTS: Patients' mean age was 71.4 ± 10.6 years. The mean axial length was 29.3 ± 1.8 mm. Dilated choroidal veins below or around the MNV were found in 17 eyes (29.3%). Emissaries of the short posterior ciliary arteries were seen at or around MNVs in 8 of the 17 eyes. In these eyes, the short posterior ciliary artery was filled first or almost simultaneously with the filling of the MNV, followed by a laminar filling of the DCVs. In one eye, afferent arterioles from the short posterior ciliary arteries and efferent venules connected to DCVs were seen. CONCLUSION: Dilated choroidal veins are present below or around MNVs in about 30% of eyes with myopic MNVs. Our findings suggest that an MNV might be a vascular unit consisting of short posterior ciliary arteries, afferent arterioles, efferent venules, and DCVs.

RIDGE-SHAPED MACULA IN YOUNG MYOPIC PATIENTS AND ITS DIFFERENTIATION FROM TYPICAL DOME-SHAPED MACULA IN ELDERLY MYOPIC PATIENTS.

PURPOSE: To assess and compare clinical features of a ridge-shaped macula (defined as macular elevation only in one meridian across the fovea) in individuals younger than 20 years with those of a dome-shaped macula (DSM) in patients aged 20+ years. METHODS: The retrospective observational case series study included 185 highly myopic eyes of 100 consecutive patients younger than 20 years, who were compared with highly myopic patients with DSMs, aged 20+ years and examined in previous studies. RESULTS: Seventeen (9.2%) eyes of the highly myopic young patients showed macular elevations all of which ran only in the horizontal direction across the vertical optical coherence tomographic section fulfilled the definition of a ridge and did not show any staphylomas or any macular Bruch membrane defects. By contrast, in the older patients with DSMs, the DSMs were significantly higher and had a narrower base than the ridges in the young patients, and showed macular Bruch membrane defects in their vicinity, with the axial length being significantly longer, the myopic maculopathy more severe, and the subfoveal choroid thinner. CONCLUSION: Macular elevations detected in children and adolescents are usually ridge-shaped maculas and do not have the characteristics of DSMs. In comparison with DSMs, ridge-shaped maculas do not show a spatial association with macular Bruch membrane defects or posterior staphylomas and have a wider basis and smoother elevation slope. As a hypothesis, ridge-shaped maculas may be due to a folding of Bruch membrane at the posterior pole, potentially caused by an asymmetrical enlargement of Bruch membrane in the equatorial region.

RIDGE-SHAPED MACULA PROGRESSING PARALLEL TO BRUCH MEMBRANE DEFECTS AND MACULAR SUPRACHOROIDAL CAVITATION.

PURPOSE: To report on a progressing ridge-shaped macula parallel to Bruch membrane defects and a macular suprachoroidal cavitation. METHOD: Single case report. RESULT: The right eye of a 54-year-old man with an axial length of 30.96 mm showed 2 extrafoveal Bruch membrane defects with a partial herniation of the retina into the choroidal space and an ophthalmoscopically yellowish area inferior to one of the Bruch membrane defects. Optical coherence tomography revealed a horizontal transfoveal ridge of the sclera, Bruch membrane, and macula and a deepening of the suprachoroidal space, corresponding to the ophthalmoscopically detectable yellowish area and fulfilling the criteria of a macular suprachoroidal cavitation. After a follow-up of 10 years, the height of the ridge increased parallel to a further deepening of the macular suprachoroidal cavitation and an increase in axial length by 0.67 mm. CONCLUSION: The findings support the notion of a progression of a ridge-shaped macula parallel to a further deepening of a macular suprachoroidal cavitation in an axially elongating eye.

Posterior staphylomas and scleral curvature in highly myopic children and adolescents investigated by ultra-widefield optical coherence tomography.

PURPOSE: To determine the early signs of posterior staphylomas in highly myopic eyes of younger subjects by swept-source ultra-widefield optical coherence tomography (WF-OCT). METHODS: This was an observational case series study. Highly myopic subjects younger than 20 years old who were examined consecutively by prototype WF-OCT were studied. High myopia was defined according to the Ministry of Health and Welfare, Japan classification. A posterior displacement of the sclera and two OCT features indicating the staphyloma edges were used as markers of a staphyloma. RESULTS: Fifty-five eyes of 30 patients with the mean age of 12.3 years, and the mean axial length of 27.9 mm were studied. Seven of the 55 eyes (12.7%) had a posterior displacement of the sclera and were diagnosed as having a staphyloma. Among the two OCT features of the staphyloma edges, a gradual thinning of the choroid toward the staphyloma edge and gradual re-thickening of choroid from the staphyloma edge toward the posterior pole were found in these 7 eyes. However, the other feature of an inward protrusion of the sclera at the staphyloma edge, was obvious in only 2 eyes. The subfoveal choroid and choroid nasal to the optic disc were significantly thinner in eyes with a staphyloma than those without it. CONCLUSIONS: The changes of the choroidal thickness toward the staphyloma edge with the posterior displacement of the sclera were considered an early sign which precedes an inward protrusion of sclera at the staphyloma edge.

Cilioretinal Arteries and Cilioretinal Veins in Eyes with Pathologic Myopia.

We investigated the clinical characteristics of cilioretinal arteries (CAs) and cilioretinal veins (CVs) in eyes with pathologic myopia. Ninety-five eyes with pathologic myopia and CAs were studied. The retrobulbar vessels from which the CAs originated were identified by indocyanine green angiography (ICGA). The results showed that 114 CAs were identified in the 95 eyes. ICGA showed that 60% of the CAs branched directly off the short posterior ciliary arteries (SPCAs) and 40% originated from the Zinn-Haller arterial circle (ZHAC). The SPCA-derived CAs tended to be located superiorly and served a large retinal area whereas the ZHAC-associated CAs tended to be located temporally and served mainly the macular area. In 15% of the 95 eyes, the CVs were observed to run parallel to the CAs. The CVs exited the eye at the same point where the CAs entered the eye. This study showed that CAs in eyes with pathologic myopia can be divided into those that are SPCA-derived and tend to emerge in the superior optic disc sector, and those that are ZHAC-associated and usually emerge temporally. An elongating peripapillary scleral flange in eyes with progressive axial myopia may lead to a change of chorioretinal vascular system.

OCT-Based Diagnostic Criteria for Different Stages of Myopic Maculopathy.

PURPOSE: To analyze the choroidal thickness (CT) of each type of myopic maculopathy, and to establish an OCT-based classification of myopic maculopathy. DESIGN: Retrospective, hospital-based, cross-sectional study. PARTICIPANTS: Highly myopic (HM) eyes that were examined by swept-source OCT. METHODS: The CT was measured at the subfovea and at 3 mm nasal, temporal, superior, and inferior to the fovea. Myopic maculopathy was classified as tessellation, diffuse atrophy, patchy atrophy, and macular atrophy (MA) based on the fundus photographs. Diffuse atrophy was subdivided into peripapillary diffuse choroidal atrophy (PDCA) or macular diffuse choroidal atrophy (MDCA). MAIN OUTCOME MEASURES: The CT of each type of myopic maculopathy and cut-off value for diagnosis of diffuse atrophy. RESULTS: We studied 1487 eyes of 884 patients (mean age: 58 years; mean axial length [AxL]: 29.9 mm). Subfoveal CT decreased with an increase in the severity of the myopic maculopathy. The mean subfoveal CT in HM eyes with normal fundus was 274.5 µm, with tessellation was 129.1 µm, with PDCA was 84.6 µm, with MDCA was 50.2 µm, with patchy atrophy was 48.6 µm, with choroidal neovascularization-related MA was 27.3 µm, and with patchy atrophy-related MA was 3.5 µm. Using receiver operating characteristic curves, the optimal CT to predict the presence of PDCA was 56.5 µm nasally, and the CT to predict the presence of MDCA was 62 µm subfoveally. The subfoveal CT was not significantly different in eyes with MDCA and patchy atrophy. A decrease of the subfoveal CT was associated with an older age (P < 0.001), longer AxL (P < 0.001), presence of myopic maculopathy (P < 0.001), and presence of CNV (P = 0.002). A decrease of best-corrected visual acuity was not significantly associated with the subfoveal CT. CONCLUSIONS: Progressive and continuous choroidal thinning plays a key role in the progression from no maculopathy to tessellation and to diffuse atrophy. The cut-off value of CT can be used for diagnosing PDCA and MDCA. For progression from MDCA to patchy atrophy, factors other than further choroidal thinning such as Bruch membrane defect may be involved. The subfoveal CT was not a predictor of visual acuity in HM eyes without CNV.

Color Photometric Stereo Using Multi-Band Camera Constrained by Median Filter and Occluding Boundary.

One of the main problems faced by the photometric stereo method is that several measurements are required, as this method needs illumination from light sources from different directions. A solution to this problem is the color photometric stereo method, which conducts one-shot measurements by simultaneously illuminating lights of different wavelengths. However, the classic color photometric stereo method only allows measurements of white objects, while a surface-normal estimation of a multicolored object using this method is theoretically impossible. Therefore, it is necessary to add some constraints to estimate the surface normal of a multicolored object using the framework of the color photometric stereo method. In this study, a median filter is employed as the constraint condition of albedo, and the surface normal of the occluding boundary is employed as the constraint condition of the surface normal. By employing a median filter as the constraint condition, the smooth distribution of the albedo and normal is calculated while the sharp features at the boundary of different albedos and normals are preserved. The surface normal at the occluding boundary is propagated into the inner part of the object region, and forms the abstract shape of the object. Such a surface normal gives a great clue to be used as an initial guess to the surface normal. To demonstrate the effectiveness of this study, a measurement device that can realize the multispectral photometric stereo method with seven colors is employed instead of the classic color photometric stereo method with three colors.

FIVE-YEAR OUTCOMES OF INTRAVITREAL RANIBIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN PATIENTS WITH PATHOLOGIC MYOPIA.

PURPOSE: To determine the 5-year outcome of intravitreal ranibizumab (IVR) for myopic choroidal neovascularization (CNV). METHOD: We retrospectively analyzed the medical records of 51 eyes of 51 consecutive patients with myopic CNV who had been treated with IVR with a minimum follow-up period of 5 years after the initial IVR injection. The factors that predicted the best-corrected visual acuity (BCVA) at 5 years after IVR were determined by multiple regression analysis. RESULTS: The mean age of the subjects was 63.6 years, and the mean axial length was 29.4 mm. The mean number of IVR was 1.6, and 34 eyes (66.7%) had only a single IVR. At the baseline and at the 1-year, 2-year, 4-year, and 5-year period, the mean BCVAs were 20/49, 20/37, 20/41, 20/45, and 20/42, respectively. Stepwise multiple regression analysis showed that the BCVA at 5-year period was significantly correlated with the baseline BCVA, the number of IVR injections, and the size of the CNV-related macular atrophy. CONCLUSION: Intravitreal ranibizumab provide a 5-year visual benefit in eyes with myopic CNV compared with the natural course. A lack of enlargement of the CNV-related macular atrophy, a better baseline BCVA, and a minimum number of IVR injections were associated with better visual outcomes.

Involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells.

Free fatty acid receptor 1 (FFA1) and FFA4 mediate a variety of biological responses through binding of medium- and long-chain free fatty acids. The aim of this study was to investigate an involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells. The long-term fluorouracil (5-FU) and cisplatin (CDDP) treated cells were generated from DLD1 cells (DLD-5FU and DLD-CDDP cells, respectively). FFAR1 expressions were lower in DLD-5FU and DLD-CDDP cells than in DLD1 cells. In contrast, DLD-5FU and DLD-CDDP cells showed the high FFAR4 expressions, compared with DLD1 cells. The cell motile activities of DLD-5FU and DLD-CDDP cells were reduced by GW9508 which is an agonist of FFA1 and FFA4. Moreover, GW1100, an antagonist of FFA1, inhibited the cell motile activities of DLD-5FU and DLD-CDDP cells. To evaluate whether FFA1 and FFA4 regulate the enhancement of cell motility, invasion and colony formation, highly migratory (hmDLD1) cells were established from DLD1 cells. FFAR1 expression was significantly higher in hmDLD1 cells than in DLD1 cells, but no change of FFAR4 expression was observed. The elevated cell motile and invasive activities and colony formation of hmDLD1 cells were suppressed by FFA1 inhibition. These results suggest that FFA1 and FFA4 are involved in the regulation of cellular functions during tumor progression in colon cancer DLD1 cells.

Progression of Myopic Maculopathy during 18-Year Follow-up.

PURPOSE: To examine the progression pattern of myopic maculopathy. DESIGN: Retrospective, observational case series. PARTICIPANTS: Highly myopic patients who had been followed up for 10 years or more. METHODS: Using fundus photographs, myopic features were differentiated according to Meta-analysis of Pathologic Myopia (META-PM) Study Group recommendations. MAIN OUTCOME MEASURES: Progression pattern of maculopathy. RESULTS: The study included 810 eyes of 432 patients (mean age, 42.3±16.8 years; mean axial length, 28.8±1.9 mm; mean follow-up, 18.7±7.1 years). The progression rate of myopic maculopathy was 47.0 per 1000 eye-years. Within the pathologic myopia (PM) group (n = 521 eyes), progression of myopic maculopathy was associated with female gender (odds ratio [OR], 2.21; P = 0.001), older age (OR, 1.03; P = 0.002), longer axial length (OR, 1.20; P = 0.007), greater axial elongation (OR, 1.45; P = 0.005), and development of parapapillary atrophy (PPA; OR, 3.14; P < 0.001). Diffuse atrophy, found in 217 eyes without choroidal neovascularization (CNV) or lacquer cracks (LCs) at baseline, progressed in 111 (51%) eyes, leading to macular diffuse atrophy (n = 64; 64/111 or 58%), patchy atrophy (n = 59; 53%), myopic CNV (n = 18; 16%), LCs (n = 9; 5%), and patchy-related macular atrophy (n = 3; 3%). Patchy atrophy, detected in 63 eyes without CNV or LCs at baseline, showed progression in 60 eyes (95%), leading to enlargement of original patchy atrophy (n = 59; 59/60 or 98%), new patchy atrophy (n = 29; 48%), CNV-related macular atrophy (n = 13; 22%), and patchy-related macular atrophy (n = 5; 8%). Of 66 eyes with LCs, 43 eyes (65%) showed progression with development of new patchy atrophy (n = 38; 38/43 or 88%) and new LCs (n = 7; 16%). Reduction in best-corrected visual acuity (BCVA) was associated mainly (all P < 0.001) with the development of CNV or CNV-related macular atrophy and enlargement of macular atrophy. CONCLUSIONS: The most frequent progression patterns were an extension of peripapillary diffuse atrophy to macular diffuse atrophy in diffuse atrophy, enlargement of the original atrophic lesion in patchy atrophy, and development of patchy atrophy in LCs. Main risk factors for progression were older age, longer axial length, and development of PPA.

Lysophosphatidic acid signaling via LPA1 and LPA3 regulates cellular functions during tumor progression in pancreatic cancer cells.

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors exhibits a variety of biological effects, such as cell proliferation, motility and differentiation. The aim of this study was to evaluate the roles of LPA1 and LPA3 in cellular functions during tumor progression in pancreatic cancer cells. LPA1 and LPA3 knockdown cells were generated from PANC-1 cells. The cell motile and invasive activities of PANC-1 cells were inhibited by LPA1 and LPA3 knockdown. In gelatin zymography, LPA1 and LPA3 knockdown cells indicated the low activation of matrix metalloproteinase-2 (MMP-2) in the presence of LPA. Next, to assess whether LPA1 and LPA3 regulate cellular functions induced by anticancer drug, PANC-1 cells were treated with cisplatin (CDDP) for approximately 6 months. The cell motile and invasive activities of long-term CDDP treated cells were markedly higher than those of PANC-1 cells, correlating with the expression levels of LPAR1 and LPAR3 genes. In soft agar assay, the long-term CDDP treated cells formed markedly large sized colonies. In addition, the cell motile and invasive activities enhanced by CDDP were significantly suppressed by LPA1 and LPA3 knockdown as well as colony formation. These results suggest that LPA signaling via LPA1 and LPA3 play an important role in the regulation of cellular functions during tumor progression in PANC-1 cells.

Different effects of G-protein-coupled receptor 120 (GPR120) and GPR40 on cell motile activity of highly migratory osteosarcoma cells.

G-protein-coupled receptor 120 (GPR120) and GPR40 are members of free fatty acid (FFA) receptors and mediate a variety of biological responses through binding of medium- and long-chain FFAs. Recently, it has been reported that GPR120 and GPR40 regulated cellular functions of cancer cells. In the present study, to assess whether GPR120 and GPR40 are involved in the enhancement of cell motile activity of osteosarcoma cells, we established highly migratory (MG63-R7) cells from osteosarcoma MG-63 cells. The expression level of GPR120 gene was significantly higher in MG63-R7 cells than in MG-63 cells, while no change of GPR40 expression was observed. In cell motility assay, the cell motile activity of MG63-R7 cells was approximately 200 times higher than that of MG-63 cells. The cell motile activity of MG63-R7 cells was stimulated by GW9508, which is an agonist of GPR120 and GPR40. Moreover, a GPR40 antagonist GW1100 elevated the cell motile activity of MG63-R7 cells in the presence of GW9508. To confirm the effects of GPR120 and GPR40 on the cell motile activity of MG63-R7 cells, GPR120 knockdown cells were generated from MG63-R7 cells. The cell motile activity of MG63-R7 cells was markedly suppressed by GPR120 knockdown. These results indicated that GPR120 enhanced and GPR40 inhibited the cell motile activity of highly migratory osteosarcoma cells.