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Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells., (© 2024. The Author(s).)

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of multiple myeloma patients to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically-actionable vulnerabilities in aneuploid cells.

Culture-acquired variants in human pluripotent stem cells (hPSCs) hinder their applications in research and clinic. However, the mechanisms that underpin selection of variants remain unclear. Here, through analysis of comprehensive karyotyping datasets from over 23,000 hPSC cultures of more than 1,500 lines, we explored how culture conditions shape variant selection. Strikingly, we identified an association of chromosome 1q gains with feeder-free cultures and noted a rise in its prevalence in recent years, coinciding with increased usage of feeder-free regimens. Competition experiments of multiple isogenic lines with and without a chromosome 1q gain confirmed that 1q variants have an advantage in feeder-free (E8/vitronectin), but not feeder-based, culture. Mechanistically, we show that overexpression of MDM4, located on chromosome 1q, drives variants' advantage in E8/vitronectin by alleviating genome damage-induced apoptosis, which is lower in feeder-based conditions. Our study explains condition-dependent patterns of hPSC aberrations and offers insights into the mechanisms of variant selection., Competing Interests: Declaration of interests T.E.L. is a co-inventor and receives a share of royalties on various hPSC media- and culture-related patents currently owned and licensed by the Wisconsin Alumni Research Foundation (WARF). I.B. is a member of the scientific advisory board of WiCell. U.B.-D. received consulting fees from Accent Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The co-occurrence of chromosome 10 loss and chromosome 7 gain in gliomas is the most frequent loss-gain co-aneuploidy pair in human cancers. This phenomenon has been investigated since the late 1980s without resolution. Expanding beyond previous gene-centric studies, we investigated the co-occurrence in a genome-wide manner taking an evolutionary perspective. Mining of large-scale tumor aneuploidy data confirmed the previous finding of a small-scale longitudinal study that the most likely order is chromosome 10 loss followed by chromosome 7 gain. Extensive analysis of genomic and transcriptomic data from both patients and cell lines revealed that this co-occurrence can be explained by functional rescue interactions that are highly enriched on chromosome 7, which could potentially compensate for any detrimental consequences arising from the loss of chromosome 10. Transcriptomic data from various normal, non-cancerous human brain tissues were analyzed to assess which tissues may be most predisposed to tolerate compensation of chromosome 10 loss by chromosome 7 gain. The analysis indicated that the pre-existing transcriptomic states in the cortex and frontal cortex, where gliomas arise, are more favorable than other brain regions for compensation by rescuer genes that are active on chromosome 7. Collectively, these findings suggest that the phenomenon of chromosome 10 loss and chromosome 7 gain in gliomas is orchestrated by a complex interaction of many genes residing within these two chromosomes and provide a plausible reason why this co-occurrence happens preferentially in cancers originating in certain regions of the brain.

Background: Lymphadenectomy is debated in patients with ovarian cancer. The aim of our study was to evaluate the impact of lymphadenectomy in patients with high-grade serous ovarian cancer receiving neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS)., Methods: A retrospective, unicentric study including all patients undergoing NACT and IDS was carried out from 2005 to 2018. Patients with and without lymphadenectomy were compared in terms of recurrence free survival (RFS), overall survival (OS), and complication rates., Results: We included 203 patients. Of these, 133 had a lymphadenectomy (65.5%) and 77 had involved nodes (57.9%). Patients without a lymphadenectomy were older, had a more extensive disease and less complete CRS. No differences were noted between the lymphadenectomy and no lymphadenectomy group concerning 2-year RFS (47.4% and 48.6%, p = 0.87, respectively) and 5-year OS (63.2% versus 58.6%, p = 0.41, respectively). Post-operative complications tended to be more frequent in the lymphadenectomy group (18.57% versus 31.58%, p = 0.09). In patients with a lymphadenectomy, survival was significantly altered if the nodes were involved (positive nodes: 2-year RFS 42.5% and 5-year OS 49.4%, negative nodes: 2-year RFS 60.7% and 5-year OS 82.2%, p = 0.03 and p < 0.001, respectively)., Conclusion: Lymphadenectomy during IDS does not improve survival and increases post-operative complications., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Aniridia is a panocular inherited rare eye disease linked to heterozygous mutations on the PAX6 gene, which fail to properly produce sufficient protein essential for normal eye development and function. Most of the patients suffer from aniridia-related keratopathy, a progressive opacification of the cornea. There is no effective treatment for this blinding disease. Here we screen for small compounds and identified Ritanserin, a serotonin 2A receptor antagonist, that can rescue PAX6 haploinsufficiency of mutant limbal cells, defective cell migration and PAX6-target gene expression. We further demonstrated that Ritanserin activates PAX6 production through the selective inactivation of the MEK/ERK signaling pathway. Our data strongly suggest that repurposing this therapeutic molecule could be effective in preventing or treating existing blindness by restoring corneal transparency., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The benefit of a systematic lymphadenectomy is still debated in patients undergoing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in ovarian cancer (OC). The objective of this study was to evaluate the predictive value of the pre-NACT and post-NACT CT in predicting definitive histological lymph node involvement. The prognostic value of a positive node on the CT was also assessed., Materiel and Methods: A retrospective, unicentric cohort study was performed including all patients with ovarian cancer who underwent NACT and IDS with a lymphadenectomy between 2005 and 2018. CT were analyzed blinded to pathology, and nodes with small axis ≥ 10 mm on CT were considered positive. Sensitivity (Se), specificity (Sp), and negative (NPV) and positive predictive values (PPV) and their CI95% were calculated. The 2-year recurrence free survival (RFS) and 5-year overall survival (OS) was compared., Results: 158 patients were included, among which 92 (58%) had histologically positive lymph nodes. CT had a Se, Sp, NPV and PPV of 35%, 82%, 47% and 73% before NACT and 20%, 97%, 47% and 91% after NACT, respectively. Patients with nodes considered positive had a non-significant lower 2-year RFS and 5-year OS on the pre-NACT and post-NACT CT. Patients at 'high risk' (nodes stayed positive on the CT or became positive after NACT) also had a non-significant lower 2-year RFS and 5-year OS., Conclusion: Presence of enlarged lymph nodes on CT is a weak indicator of lymph node involvement in patients with advanced ovarian cancer undergoing NACT. However, it could be used to assess prognosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment 1 . However, it is unclear whether aneuploidy generates any clinically relevant vulnerabilities in cancer cells. Here we mapped the aneuploidy landscapes of about 1,000 human cancer cell lines, and analysed genetic and chemical perturbation screens 2-9 to identify cellular vulnerabilities associated with aneuploidy. We found that aneuploid cancer cells show increased sensitivity to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis 10 . Unexpectedly, we also found that aneuploid cancer cells were less sensitive than diploid cells to short-term exposure to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly sensitive to inhibition of SAC over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing when the SAC was inhibited, resulting in the accumulation of mitotic defects, and in unstable and less-fit karyotypes. Therefore, although aneuploid cancer cells could overcome inhibition of SAC more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to depletion of KIF18A, and KIF18A overexpression restored their response to SAC inhibition. Our results identify a therapeutically relevant, synthetic lethal interaction between aneuploidy and the SAC.

Intravitreal anti-vascular epithelial growth factor (anti-VEGF) injections have revolutionised the treatment of macular diseases, but can be stressful for the patient. We surveyed 904 patients receiving injections at 5 centres in France regarding their feelings toward anti-VEGF injections. The mean age was 77.4 years, and the injections were performed mostly for age related macular degeneration (72%). Half of the patients had previously received>10 injections, 35.6% had received 3-10 injections, and 14.2% had received<3 injections. The mean (SD) stress score was 4.2 [on a scale from 1-10 (0=least stressful, 10=extremely stressful)]. Most patients (70%) reported low to moderate stress (score ≤5). The number of previous injections did not influence stress scores. Paradoxically, 61.2% of patients reported finding injections to be less stressful over time. Most patients found injections to be less traumatic than expected (64%) or just as they had anticipated (25%). Most patients (88%) were not bothered by the presence of other patients in the waiting room. Most patients (78.8%) preferred to be injected quickly before they had time to feel stressed about the procedure. Injections were generally well accepted; most patients would prefer to maintain their current schedule of injections and their current vision (55.7%), or would be willing to have more frequent injections for better vision (39.5%). Our results suggest that stress appears to be more related to the patient's psychological make-up than to the treatment experience or the number of injections received., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: To describe the phenotype and genotype of a 10-year-old boy affected with enhanced S-cone syndrome associated with neovascularization., Methods: Fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, full-field electroretinogram and NR2E3 molecular testing were performed., Results: Best-corrected visual acuity was measured as 20/32, right eye and 20/20, left eye. Fluorescein and indocyanine green angiographies showed unilateral macular retinochoroidal anastomosis on his right eye, and spectral domain optical coherence tomography showed typical signs of subretinal exudation and foveolar pseudoschisis consistent with the diagnosis of enhanced S-cone syndrome. Genetic analysis revealed biparental transmission of mutations in the enhanced S-cone syndrome-causing gene, NR2E3, namely, c.194&#95;202del (p.Asn65&#95;Cys67del), and c.932 G>A (p.Arg311Gln), supporting an autosomal recessive inheritance. The patient received three intravitreal injections of anti-VEGF agents., Conclusion: Evidence of retinochoroidal anastomosis in an individual affected with enhanced S-cone syndrome supports the view that neovascularization can occur early in the course of the disease, and raises the question to know whether it might be responsible for previously described enhanced S-cone syndrome-associated hemorrhage-induced fibrosis.

Purpose: To describe the management of active choroidal neovascularization (CNV) during pregnancy with the use of a dexamethasone intravitreal implant (DXI) (Ozurdex)., Methods: Case series of active CNV treated with DXI with at least 12-month follow-up retrospectively analyzed at 2 high-volume referral centers in France. Medical records and multimodal macular imaging were evaluated., Results: Three eyes of 3 patients (age 30.0 ± 3.6 years) were included. One case of idiopathic CNV and two cases of CNV secondary to multifocal choroiditis were analyzed. Mean follow-up was 20.6 ± 4.0 months (range, 16-23 months). The DXI was given at second trimester of established pregnancy in all cases. Mean central retinal thickness decreased from 359 ± 53 μm to 301 ± 17 μm 1 month after DXI and remained stable up to 12 months of follow-up. Visual improvement in all cases was observed (mean 10 letters; range, 5-30 letters) 1 month after DXI and remained stable/increased up to 12-month follow-up (mean 22 letters; range, 10-30 letters). All patients had an uneventful prenatal course and delivered a healthy full-term infant., Conclusion: In the authors' experience, a single DXI revealed safe and effective in CNV treatment during pregnancy.

Purpose: The purpose of this study was to build and evaluate a high-performance algorithm to detect and characterize the presence of a meniscus tear on magnetic resonance imaging examination (MRI) of the knee., Material and Methods: An algorithm was trained on a dataset of 1123 MR images of the knee. We separated the main task into three sub-tasks: first to detect the position of both horns, second to detect the presence of a tear, and last to determine the orientation of the tear. An algorithm based on fast-region convolutional neural network (CNN) and faster-region CNN, was developed to classify the tasks. The algorithm was thus used on a test dataset composed of 700 images for external validation. The performance metric was based on area under the curve (AUC) analysis for each task and a final weighted AUC encompassing the three tasks was calculated., Results: The use of our algorithm yielded an AUC of 0.92 for the detection of the position of the two meniscal horns, of 0.94 for the presence of a meniscal tear and of 083 for determining the orientation of the tear, resulting in a final weighted AUC of 0.90., Conclusion: We demonstrate that our algorithm based on fast-region CNN is able to detect meniscal tears and is a first step towards developing more end-to-end artificial intelligence-powered diagnostic tools., (Copyright © 2019. Published by Elsevier Masson SAS.)

Purpose and Context: Intravitreal administration of anti-VEGF agents, available in France since 2007, allows stabilization and improvement in visual acuity in wet age-related macular degeneration (AMD). In the past few years, the management of this disease has evolved in terms of both diagnostic methods and treatment schedules, which have been adapted to the pathophysiology of AMD. The goal of this survey, performed in a representative sample of French ophthalmologists, was to describe the evolution of medical practices one year after a similar survey (Massé et al., J Fr Ophtalmol 2016; 39: 40-7)., Method: The survey was performed from December, 2014 to March, 2015 in 191 ophthalmologists (53 general ophthalmologists and 98 retina specialists) with an on-line questionnaire. This questionnaire was designed by a committee of ophthalmologists to describe practices concerning screening, diagnosis, treatment and follow-up of wet AMD., Results: An initial intravitreal injection of an anti-VEGF agent was usually performed within 10 days after the diagnosis of wet AMD by 98% of ophthalmologists and within 5 days by 63%. The treatment protocols favored by retina specialists were pro re nata (PRN) for 58%, Observe and Plan for 25% and Treat and Extend for 17%. Bilateral intravitreal injections were performed on the same day by 46% of retina specialists, mostly for the convenience of the patient and because of the low infectious risk. The initial protocol was maintained by one third of retina specialists throughout the course of treatment, while two thirds of them reported that they reassessed the protocol on average after 5 months., Conclusion: This survey on the practices of the ophthalmologists in wet AMD highlights an improvement in the time course of patient management and an evolution of treatment schedules toward individualized protocols., (Copyright © 2017. Published by Elsevier Masson SAS.)

Purpose: To analyze retrospectively the efficacy of intravitreal ranibizumab injections for the management of choroidal neovascularization in patients with angioid streaks over a long term., Methods: In this "nonrandomized," double-center, retrospective, interventional case series, a consecutive series of patients affected with choroidal neovascularization associated with angioid streaks were treated with intravitreal ranibizumab injections (0.5 mg/0.05 mL). Best-corrected visual acuity, fundus photography, optical coherence tomography, and fluorescein angiography were examined before and after treatment. The primary endpoint was the percentage of eyes with stable or improved visual acuity at the end of follow-up (loss of less than 3 Early Treatment Diabetic Retinopathy Study lines). Secondary endpoints were the percentage of eyes with stable or decreased macular thickness on optical coherence tomography (less than a 10% increase in macular thickness) and the percentage of eyes with persistent leakage on fluorescein angiography at the last observation carried forward., Results: Thirty-five eyes of 27 patients were treated with repeated intravitreal ranibizumab injections (mean of 9.9 ± 7.2 injections, range 2-26) for a mean of 48.6 ± 17.1 months (range 8-66). At the end of follow-up, best-corrected visual acuity was stabilized or improved in 22 of 35 eyes (62.9%). Macular thickness had stabilized or decreased in 16 of 35 eyes (45.7%). At the last follow-up examination, on fluorescein angiography, no further leakage was observed in 27 of 35 eyes (77.1%)., Conclusion: In this large series of patients with choroidal neovascularization associated with angioid streaks followed for 4 years, ranibizumab injections allowed stabilization of best-corrected visual acuity in most eyes. Ranibizumab appear as an effective therapeutic option in CNV associated with angioid streaks over long time.

Background and Objectives: Wet AMD is characterized by the formation of choroidal neovascularization, mediated by vascular endothelial growth factor (VEGF) and responsible for a decrease in visual acuity and metamorphopsia of sudden onset. Intravitreal anti-VEGF can stabilize or even improve visual acuity. Although there is a consensus among ophthalmologists about the induction phase injection of anti-VEGF, there appear to be differences in practice regarding therapeutic treatment modalities. The goal of this work was to explore this hypothesis and to better understand real life practices., Method: The Ipsos institute conducted a qualitative survey of 16 retinal specialists and 9 general ophthalmologists in September and October 2013, using a questionnaire developed by a scientific committee of experts. Fifteen telephone interviews and 4 face-to-face meetings with a retina specialist and an ophthalmologist were conducted. This qualitative study allowed the development of a quantitative survey of 200 retina specialists and general ophthalmologists, conducted between November 2013 and January 2014, to describe practices in diagnosis, treatment and follow-up of wet AMD., Results: A distribution of roles between the ophthalmologist making the initial diagnosis and the retinal specialists responsible for treatment and follow-up was noted. Treatment was initiated within 10 days of diagnosis as recommended by the HAS in only one third of patients. After the induction phase of treatment, i.e. three monthly injections of anti-VEGF, treatment and monitoring practices were heterogeneous with 74% of physicians using a PRN treatment protocol, 22% a bimonthly protocol (with monthly monitoring in 19.4% of cases) and 4% a "treat and extend" protocol. There was little change in the protocol chosen in the case of recurrence., Conclusion: Three quarters of ophthalmologists report using a PRN protocol, and over 90% report seeing their patients monthly, either for injection or for a check-up. This apparent uniformity is in reality more complex: for the large majority, they prefer to closely follow the patient so as to treat the slightest recurrence, but with great variability in practices with regard to individualization of treatment., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Purpose: To suggest a clinical distinction between idiopathic polypoidal choroidal vasculopathy (PCV) and secondary polyps associated with neovascular age-related macular degeneration (NV-AMD)., Methods: The study was a retrospective case series of 52 eyes of 52 consecutive patients (31 females and 21 males) diagnosed with PCV. Initial diagnosis was based on scanning laser ophthalmoscope-indocyanine green angiography (SLO-ICGA) in association with fluorescein angiography (FA) and optical coherence tomography (OCT). All the data and images were analyzed in a masked fashion by four experienced examiners in two different sessions: the first, to classify patients into the two hypothesized groups (idiopathic polyps or NV-AMD-related polyps); the second, following a predetermined scheme, to describe objective features. The results obtained in each session underwent a cross multivariate analysis to identify statistically significant differences (P ≤ 0.05) between the two groups., Results: The two groups were clinically different on the basis of FA (leakage origin [P = 0.001] and presence of drusen [P = 0.001]), ICGA (evidence of choroidal neovascularization [CNV; P = 0.001] and/or branching vascular network [BVN; P = 0.001]), OCT imaging (type of pigmented epithelium detachment [P = 0.001], presence of BVN [P = 0.001], and subfoveal choroidal thickness [P = 0.001]). Further significant differences were observed according to the location of lesion (uni- or multifocal) (P = 0.001), type of CNV (P = 0.001), and best-corrected visual acuity (P = 0.001)., Conclusions: Our study demonstrated clinical and statistically significant differences between idiopathic PCV and NV-AMD-related polyps that could be considered as distinct entities. Although they share some similarities, mainly the sub-RPE location, the ability to identify a specific clinical pattern suggests a more specific therapeutic approach for these two entities.

Purpose: To describe unusual retinal findings of a patient affected by hemochromatosis., Methods: Case report of a 49-year-old patient who presented a progressive loss of vision. Fundus photography, fluorescein angiography, full-field electroretinogram, autofluorescence imaging, and spectral domain optical coherence tomography were performed. The patient was known to be homozygous for the C282Y mutation in the HFE gene., Results: Visual acuity was measured at 20/20 on his right eye and 20/25 on his left eye. Retinal imaging showed alterations of the retinal pigment epithelium clearly visible on fundus autofluorescence and fluorescein angiography. The spectral domain optical coherence tomography showed retinal pigmentary epithelial atrophy associated with irregularities and focal interruption of the ellipsoid zone. A thin retina was also observed in the foveolar region associated to a thickened choroid. Full-field electroretinogram showed a decrease of rods and cones responses., Conclusion: Here, the authors describe the retinal findings of a patient affected by hemochromatosis, characterized by unusual retinal pigment epithelium changes associated to altered visual function. The authors hypothesize that the retinopathy could be linked to hemochromatosis because of the pathophysiology of iron homeostasis and the toxicity of iron overload for the photoreceptors.

This study aims to elucidate the mechanisms by which tumor necrosis factor alpha (TNFα) provides protection from hypoxic damage to neonatal rat cardiomyocyte cultures. We show that when intracellular Ca(2+) ([Ca(2+)]i) levels are elevated by extracellular Ca(2+) ([Ca(2+)]o) or by hypoxia, then TNFα decreased [Ca(2+)]i in individual cardiomyocytes. However, TNFα did not reduce [Ca(2+)]i after its increase by thapsigargin, (a SERCA2a inhibitor), indicating that TNFα attenuates Ca(2+) overload through Ca(2+) uptake by SERCA2a. TNFα did not reduce [Ca(2+)]i, following its elevation when [Ca(2+)]o levels were elevated in TNFα receptor knock-out mice. H-89, a protein kinase A (PKA) inhibitor, attenuated the protective effect of TNFα when the cardiomyoctyes were subjected to hypoxia, as determined by lactate dehydrogenase (LDH) and creatine kinase (CK) released and from the cardiomyocytes. Moreover, when the levels of [Ca(2+)]i were increased by hypoxia, H-89, but not KN93, (a calmodulin kinase II inhibitor), prevented the reduction in [Ca(2+)]i by TNFα. TNFα increased the phosphorylation of PKA in normoxic and hypoxic cardiomyoctes, indicating that the cardioprotective effect of TNFα against hypoxic damage was via PKA activation. Hypoxia decreased phosphorylated phospholamban levels; however, TNFα attenuated this decrease following hypoxia. It is suggested that TNFα activates phospholamban phosphorylation in hypoxic heart cultures via PKA to stimulate SERCA2a activity to limit Ca(2+) overload.

Purpose: We observed hyperreflective dome-shaped or pyramidal structures (HPS) on spectral domain optical coherence tomography (SD-OCT) in patients affected with geographic atrophy (GA). Our purpose was to describe the multimodal imaging features of HPS identified in areas of GA in patients with age-related macular degeneration., Methods: This is a retrospective case series of patients with GA harboring HPS in atrophic areas. Multimodal imaging examination including infrared reflectance, fundus autofluorescence, and SD-OCT, was performed for each patient. Infrared and fundus autofluorescence appearance and mean SD-OCT height of HPS in GA were analyzed., Results: A total of 36 eyes of 25 patients (20 women; mean age, 82.3 ± 5.9 years, range, 73-92 years) with GA were included. A total of 96 HPS in GA were analyzed by SD-OCT. In all HPS (96/96, 100%), the peripheral part was hyperreflective. In 66 of 96 HPS (69%), the center was heterogeneously hyperreflective, whereas in 30 of 96 HPS (31%), the center was hyporeflective. On infrared reflectance images, HPS in GA appeared as hyporeflective lesions surrounded by hyperreflective halos, within an area of background hyperreflectivity because of GA in all eyes. On fundus autofluorescence, 39 of 96 HPS (41%) were heterogeneously hyperautofluorescent, whereas 57 of 96 HPS (59%) were hypoautofluorescent. Mean height of HPS was 91 ± 50.9 μm in the foveal scan (range, 42-291 μm)., Conclusion: We describe a multimodal imaging of distinctive lesions that presented as hyperreflective pyramidal structures on SD-OCT. We suggest the name "ghost drusen" because these HPS appear in GA areas, and because of their pyramidal or dome-shaped aspect on SD-OCT.

Purpose: The purpose of the CAP (Creteil AMD PHRC-funded) Study was to analyze risk factors of exudative age-related macular degeneration (AMD) in a large French case-control population., Patients and Methods: One thousand and twenty-four patients with exudative AMD and 275 controls were recruited. Information about lifestyle, medical history, and dietary intake were collected. Associations of risk factors were estimated using logistic regression., Results: After multivariate adjustment, CFH Y402H and ARMS2 A69S polymorphisms were associated with very high risk for exudative AMD (OR = 6.21 and OR = 11.7, respectively, p < 0.0001). Risk for exudative AMD was increased in current smokers (OR = 3.79, p = 0.0003) and former smokers having quitted since less than 20 years ago (OR = 2.30, p = 0.002), but not in former smokers having quitted since 20 years or more ago (OR = 0.81, p = 0.43). Heavy smokers (at least 25 pack-years) were particularly at risk (OR = 3.61, p < 0.0001). Use of cooking oils rich in omega 3 fatty acids was significantly associated with a reduced risk of exudative AMD (OR = 0.55, 95 % CI: 0.36-0.84, p = 0.006), as well as a high consumption of fruits (OR = 0.60, 95 % CI: 0.37-0.98, p = 0.04), but not the consumption of fish, vegetables or oils rich in omega 6. High waist circumference was associated with increased risk for exudative AMD (OR = 2.53, p < 0.0001), but not hypercholesterolemia, hypertension, or body mass index., Conclusions: The CAP Study confirms major genetic risk factors for exudative AMD. It further documents the high risk in heavy smokers and the long persistence of risk after smoking cessation, and the associations with waist circumference and fruit consumption. Furthermore, we observed an inverse correlation between AMD and cooking oils harboring a beneficial omega-3 fatty acid profile.

Purpose: To investigate the multimodal morphological features in the different stages of Best vitelliform macular dystrophy (VMD) in subjects harboring mutations in the BEST1 gene, and their changes during the progression of the disease., Methods: In this retrospective observational study performed between January 2007 and December 2012, 21 patients (42 eyes) with Best VMD from eight families with the BEST1 mutation were included. Best-corrected visual acuity (BCVA), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SDOCT) were evaluated at study entry and at last visit., Results: The mean age of patients was 26.3±17.4 years. Seven new missense mutations in BEST1 were identified. Mean follow-up was 41.1±18.5 months. Mean BCVA was 0.34±0.34 LogMAR at study entry and 0.32±0.33 LogMAR at last follow-up visit (p = 0.2). The overall lesion area on FAF increased from 6.62±4.9 mm² to 7.34±6.1 mm² (p = 0.05). At study entry, on SD-OCT, photoreceptor inner segment ellipsoid portion (ellipsoid zone, EZ) was normal in 15 eyes, disrupted in 14 eyes, and absent in 13 eyes. In two eyes, EZ changed from normal to disrupted during follow-up. Three eyes of three patients showing pseudohypopyon lesions at study entry progressed to vitelliruptive lesions at the last follow-up visit. Three eyes of three patients showing vitelliruptive lesion at study entry reverted to pseudohypopyon lesion with overall enlargement of the lesion size., Conclusions: Multimodal analysis allowed documenting a continuous material accumulation and reabsorption in Best VMD progression. Blue FAF and SD-OCT could represent noninvasive imaging techniques to monitor Best VMD.

Background: Our purpose was to describe the different morphological features in adult onset foveomacular vitelliform dystrophy (AOFVD), using en face enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT)., Methods: Thirty eyes of 22 consecutive patients presenting with diagnosis of AOFVD were enrolled. Diagnosis of AOFVD was concluded based on fundus examination, autofluorescence imaging, fluorescein angiography and SD-OCT. En face OCT imaging was obtained with the Spectralis EDI SD-OCT; 97 inverted sections (nine averaged B-scans per image) were acquired., Results: On en face OCT, vitelliform lesions appeared as regular concentric rings of different reflectivity. From the periphery to center of the ring, we observed: (1) the hypereflective ring representing the inner segment/ outer segment (IS/OS) junction, which was continuous in 23 out of 30 eyes, and (2) a well-detectable hyporeflective ring between the IS/OS junction and vitelliform material in 20 out of 30 eyes; the innermost composant of the lesion was hypereflective, and it corresponded to vitelliform material. In eight out of 30 eyes, a hyporeflective "croissant"-shaped lesion with inferior concavity in the upper part of the hyperreflective material was present. Hypereflective retinal pigment epithelium (RPE) elevations or bumps were detected in 25 out of 30 eyes. These areas of focal RPE thickening or bumps appeared to be intensely hypereflective on infrared reflectance imaging., Conclusion: En face imaging of the retina helps visualizing the distribution of vitelliform material in AOFVD. The sedimentation of vitelliform lesions is characterized by a upper "croissant"-shaped hypoflectivity. The bumps/thickening of RPE appeared as hypereflective lesions on IR imaging.

Purpose: To describe the choroidal findings in a patient with Bietti's crystalline dystrophy., Methods: A 43-year-old woman with Bietti's crystalline dystrophy underwent a complete ophthalmologic examination including enhanced depth imaging spectral domain optical coherence tomography and en face optical coherence tomography., Results: We observed a severe thinning of the choroid, 123 μm in the right eye and 110 μm in the left eye. Crystal deposits were found not only in the retina but also in the choroid. En face optical coherence tomography clearly showed the intraretinal crystals as small hyperreflective dots in the different retinal layers and in the choroid., Conclusion: Our study gives new information on the aspect and the location of crystal deposits in the choroid and the abnormalities of the outer retina associated with the disease.

Purpose: To analyze the outer retinal and retinal pigment epithelium (RPE) features of reticular pattern dystrophy of the retina using spectral-domain optical coherence tomography (SDOCT)., Design: Retrospective observational case series., Methods: Consecutive patients with reticular pattern dystrophy of the retina underwent a complete ophthalmologic examination, including assessment of best-corrected visual acuity (BCVA), fundus biomicroscopy, fluorescein angiography (FA), and SDOCT., Results: Twenty-two eyes of 13 patients (6 men, 7 women, mean age 68.6 ± 14.5 years) were included. In the foveal area, the RPE layer appeared normal in 45.5% of eyes, while small RPE elevations and RPE bumps were detected in 31.8% and 22.7% of eyes, respectively. The SDOCT scans showed disruption of inner segment/outer segment (IS/OS) junction in 54.6% of eyes, a slight elevation in 59.1% of eyes, and an absence in 45.5% of eyes. The outer limiting membrane (OLM) appeared disrupted in 50.0% of eyes, absent in 22.7% of eyes, and elevated in 63.6% of eyes. Hyper-reflective subretinal material accumulation or hyporeflective subretinal lesions in the retrofoveolar region were detected in 70% and in 20% of eyes, respectively. SDOCT showed hyporeflective retinal pseudocysts in 13.6% of eyes., Conclusion: In this study on reticular pattern dystrophy of the retina, SDOCT provided a description of the material deposits and the alterations of the RPE and the different retinal layers. We observe that the lesions present specific features distinct from other macular dystrophies, but closer to those reported in fundus flavimaculatus than those reported in adult-onset foveomacular vitelliform dystrophy. Further analyses are needed, particularly to analyze the progression of the lesions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10(-8)). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10(-5), OR = 2.8; joint P = 5.2 × 10(-9), OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10(-5), OR = 2.2; joint P = 6.5 × 10(-7), OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.

Background: To evaluate the anatomical and functional outcomes of intravitreal dexamethasone implant in patients with macular edema (ME) secondary to retinitis pigmentosa (RP)., Methods: Three patients (four eyes), aged 24 to 46 years, presented with refractory ME secondary to RP. Intravitreal dexamethasone implant (Ozurdex) was administered to treat ME. The anatomical (central macular thickness [CMT]) and functional (best-corrected visual acuity [BCVA]) outcomes as well as adverse events were recorded., Results: All patients completed 6 months follow-up. After intravitreal Ozurdex all patients showed regression of ME. At baseline, mean CMT was 443 ± 185 μm (range 213-619 μm); ME improved to 234 ± 68 μm (range 142-307 μm) at 1 month, to 332 ± 177 μm (range 139-513 μm) at 3 months, and to 305 ± 124 μm (range 144-447 μm) at 6 months. Recurrent ME was recorded in 2 patients (both patients at 3 months from intravitreal dexamethasone implant). Retreatment with intravitreal Ozurdex was performed in two patients. Mean BCVA improved form 20/160 (range 20/50-20/200) (baseline) to 20/100 (range 20/40-20/125) at 1 month, to ∼20/125 (range 20/100-20/200) at 3 months, and to ∼ 20/125 (range 20/100-20/160) at 6 months. No serious ocular and systemic adverse events were observed during the study period., Conclusions: Intravitreal dexamethasone implant provides anatomic and functional improvements and may represent a valuable treatment option for patients with ME secondary to RP.