WATUNet: a deep neural network for segmentation of volumetric sweep imaging ultrasound.

Limited access to breast cancer diagnosis globally leads to delayed treatment. Ultrasound, an effective yet underutilized method, requires specialized training for sonographers, which hinders its widespread use. Volume sweep imaging (VSI) is an innovative approach that enables untrained operators to capture high-quality ultrasound images. Combined with deep learning, like convolutional neural networks, it can potentially transform breast cancer diagnosis, enhancing accuracy, saving time and costs, and improving patient outcomes. The widely used UNet architecture, known for medical image segmentation, has limitations, such as vanishing gradients and a lack of multi-scale feature extraction and selective region attention. In this study, we present a novel segmentation model known as Wavelet_Attention_UNet (WATUNet). In this model, we incorporate wavelet gates and attention gates between the encoder and decoder instead of a simple connection to overcome the limitations mentioned, thereby improving model performance. Two datasets are utilized for the analysis: the public 'Breast Ultrasound Images' dataset of 780 images and a private VSI dataset of 3818 images, captured at the University of Rochester by the authors. Both datasets contained segmented lesions categorized into three types: no mass, benign mass, and malignant mass. Our segmentation results show superior performance compared to other deep networks. The proposed algorithm attained a Dice coefficient of 0.94 and an F1 score of 0.94 on the VSI dataset and scored 0.93 and 0.94 on the public dataset, respectively. Moreover, our model significantly outperformed other models in McNemar's test with false discovery rate correction on a 381-image VSI set. The experimental findings demonstrate that the proposed WATUNet model achieves precise segmentation of breast lesions in both standard-of-care and VSI images, surpassing state-of-the-art models. Hence, the model holds considerable promise for assisting in lesion identification, an essential step in the clinical diagnosis of breast lesions.

Smartphone-based versus traditional face-to-face collaborative care for community-dwelling older adults living with dementia in China: protocol for an implementation science-based sequential multiple assignment randomised trial.

INTRODUCTION: The high costs of institutional care and the burdensome demands of home care are challenging for families of adults with dementia. The collaborative care model (CCM) provides a potential solution to these challenges. Leveraging advancements in mobile technologies, smartphone-based management could offer a feasible means of providing collaborative care in a community setting. Therefore, this study aims to establish a CCM for home-cared older adults with dementia to determine the best strategy to deliver collaborative care, including both the channel and frequency of delivery. METHODS AND ANALYSIS: This study will be conducted in the communities of Chengdu city, Sichuan province, China. It is designed under the framework of implementation science. In the first stage, intervention strategies for community-dwelling older adults with dementia and their caregivers will be developed using Delphi methods and focus group interviews. The second stage will involve designing a sequential multiple assignment randomised trial to compare the effectiveness of face-to-face intervention versus a WeChat mini program-based intervention. This comparison will involve 358 pairs of older adults with dementia and their caregivers, with the frequency of intervention also assessed. Follow-up evaluations will be implemented at the 6th, 12th and 18th months post-intervention initiation. Primary outcomes encompass the proportion of patients demonstrating an improvement in quality of life and the proportion of caregivers exhibiting a reduction in caregiver burden. Analysis will be based on the intention-to-treat principle, and the generalised estimating equation approach will be used. Incremental cost-effectiveness ratios will be used to evaluate the cost-effectiveness of different delivery methods and frequencies. ETHICS AND DISSEMINATION: This study has received approval from the Ethics Committee of West China Fourth Hospital/School of Public Health, Sichuan University (Gwll2022004). Informed consent will be obtained for all participants. The findings of the study will be disseminated through peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ChiCTR2200057945.

Systematic evaluation of the associations between mental disorders and dementia: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Increasing evidence support the correlation between mental disorders and the likelihood of developing dementia. We aim to conduct an umbrella review to assess the risk of dementia in patients with eight mental disorders. METHODS: We searched PubMed, Embase, Web of science, CNKI, VIP, and Wanfang databases from inception to October 29, 2021. For each included meta-analysis, the effect size with a 95% confidence interval was estimated using either a random effect model or a fixed effect model, and between-study heterogeneity was expressed by I2 and Cochran's Q test. The ROBIS tool was used to assess the risk of bias. RESULTS: A total of ten systematic reviews were included. Among these studies, we identified seven risk factors, including anxiety disorder, bipolar disorder, depression, late-life depression, post-traumatic stress disorder, schizophrenia, and sleep disorder. Light to moderate alcohol drinking was identified as a protective factor. The evaluation results of the ROBIS tool showed that nine systematic reviews had high risk of bias and one had low risk of bias. The strength of evidence supporting the associations between late-life depression and all-cause dementia, Alzheimer's disease, and vascular dementia was high; the strength of evidence supporting the association between depression and all-cause dementia was moderate. LIMITATIONS: Most associations had low strength of evidence and high risk of bias. CONCLUSIONS: This umbrella review shows that high and moderate evidence supports the associations between some mental disorders and dementia. More cohort studies are needed to support the associations between mental disorders and dementia.

No sonographer, no radiologist: Assessing accuracy of artificial intelligence on breast ultrasound volume sweep imaging scans.

Breast ultrasound provides a first-line evaluation for breast masses, but the majority of the world lacks access to any form of diagnostic imaging. In this pilot study, we assessed the combination of artificial intelligence (Samsung S-Detect for Breast) with volume sweep imaging (VSI) ultrasound scans to evaluate the possibility of inexpensive, fully automated breast ultrasound acquisition and preliminary interpretation without an experienced sonographer or radiologist. This study was conducted using examinations from a curated data set from a previously published clinical study of breast VSI. Examinations in this data set were obtained by medical students without prior ultrasound experience who performed VSI using a portable Butterfly iQ ultrasound probe. Standard of care ultrasound exams were performed concurrently by an experienced sonographer using a high-end ultrasound machine. Expert-selected VSI images and standard of care images were input into S-Detect which output mass features and classification as "possibly benign" and "possibly malignant." Subsequent comparison of the S-Detect VSI report was made between 1) the standard of care ultrasound report by an expert radiologist, 2) the standard of care ultrasound S-Detect report, 3) the VSI report by an expert radiologist, and 4) the pathological diagnosis. There were 115 masses analyzed by S-Detect from the curated data set. There was substantial agreement of the S-Detect interpretation of VSI among cancers, cysts, fibroadenomas, and lipomas to the expert standard of care ultrasound report (Cohen's κ = 0.73 (0.57-0.9 95% CI), p<0.0001), the standard of care ultrasound S-Detect interpretation (Cohen's κ = 0.79 (0.65-0.94 95% CI), p<0.0001), the expert VSI ultrasound report (Cohen's κ = 0.73 (0.57-0.9 95% CI), p<0.0001), and the pathological diagnosis (Cohen's κ = 0.80 (0.64-0.95 95% CI), p<0.0001). All pathologically proven cancers (n = 20) were designated as "possibly malignant" by S-Detect with a sensitivity of 100% and specificity of 86%. Integration of artificial intelligence and VSI could allow both acquisition and interpretation of ultrasound images without a sonographer and radiologist. This approach holds potential for increasing access to ultrasound imaging and therefore improving outcomes related to breast cancer in low- and middle- income countries.

Lung ultrasound volume sweep imaging for respiratory illness: a new horizon in expanding imaging access.

BACKGROUND: Respiratory illness is a leading cause of morbidity in adults and the number one cause of mortality in children, yet billions of people lack access to medical imaging to assist in its diagnosis. Although ultrasound is highly sensitive and specific for respiratory illness such as pneumonia, its deployment is limited by a lack of sonographers. As a solution, we tested a standardised lung ultrasound volume sweep imaging (VSI) protocol based solely on external body landmarks performed by individuals without prior ultrasound experience after brief training. Each step in the VSI protocol is saved as a video clip for later interpretation by a specialist. METHODS: Dyspneic hospitalised patients were scanned by ultrasound naive operators after 2 hours of training using the lung ultrasound VSI protocol. Separate blinded readers interpreted both lung ultrasound VSI examinations and standard of care chest radiographs to ascertain the diagnostic value of lung VSI considering chest X-ray as the reference standard. Comparison to clinical diagnosis as documented in the medical record and CT (when available) were also performed. Readers offered a final interpretation of normal, abnormal, or indeterminate/borderline for each VSI examination, chest X-ray, and CT. RESULTS: Operators scanned 102 subjects (0-89 years old) for analysis. Lung VSI showed a sensitivity of 93% and a specificity of 91% for an abnormal chest X-ray and a sensitivity of 100% and a specificity of 93% for a clinical diagnosis of pneumonia. When any cases with an indeterminate rating on chest X-ray or ultrasound were excluded (n=38), VSI lung ultrasound showed 92% agreement with chest X-ray (Cohen's κ 0.83 (0.68 to 0.97, p<0.0001)). Among cases with CT (n=21), when any ultrasound with an indeterminate rating was excluded (n=3), there was 100% agreement with VSI. CONCLUSION: Lung VSI performed by previously inexperienced ultrasound operators after brief training showed excellent agreement with chest X-ray and high sensitivity and specificity for a clinical diagnosis of pneumonia. Blinded readers were able to identify other respiratory diseases including pulmonary oedema and pleural effusion. Deployment of lung VSI could benefit the health of the global community.

Establishing cut-off scores for the self-rating AD8 based on education level.

This study aimed to explore the threshold of self-rating AD8 in mild cognitive impairment (MCI) and dementia screening among community-dwelling older adults with and without education. 523 participants in Chengdu, China, were recruited: 346 with normal cognitive function, 160 with MCI and 17 with dementia. At the cut-off score of 2, the area under the receiver operator characteristic curves (AUC) of self-rating AD8 for MCI and dementia screening was 0.607 and 0.931 regardless of educational level, respectively. Grouping by educational level, the cut-off in MCI screening was 1 for literate (AUC=0.662) and 2 for illiterate individuals (AUC=0.588). For dementia screening, the cut-off was 2 for illiterate (AUC=0.912) and 4 for literate individuals (AUC=0.963). We concluded that the self-rating AD8 was ideal for dementia screening in community-dwelling older adults, with a cut-off score of 2 for illiterate and 4 for literate people, while its effectiveness for MCI screening required further evaluation.

Heterogeneity in the dynamic change of cognitive function among older Chinese people: A growth mixture model.

OBJECTIVES: Our aim is to distinguish different trajectories of cognitive change in Chinese geriatric population and identify risk factors for cognitive decline in each subpopulation. METHODS: We obtained data from five waves (2002, 2005, 2008, 2011, 2014) of the Chinese Longitudinal Health Longevity Survey, using the Chinese Mini-Mental State Examination (C-MMSE) as a proxy for cognitive function. We applied growth mixture modeling (GMM) to identify heterogeneous subpopulations and potential risk factors. RESULTS: Our sample included 3859 older adults, 1387 (48.7%) male and 1974 (51.2%) female with age range of 62 to 108 (average of 74.5) at initial survey. Using GMM and best fit statistics, we identified two distinct subgroups in respect to their longitudinal cognitive function: (a) cognitively stable (87.8%) group with 0.49 C-MMSE points decline per 3 years, and (b) cognitively declining (12.2%) group with 6.03 C-MMSE points decline per 3 years. Of note, cognitive activities were protective, and hearing and visual impairments were risk factors in both groups. Diabetes, hypertension, stroke and cardiovascular disease were associated with cognitive decline in the cognitively declining group. Physical activities, and intake of fresh vegetables, fruits, and fish products were protective in the cognitively stable group. CONCLUSIONS: Using GMM, we identified heterogeneity in trajectories of cognitive change in older Chinese people. Moreover, we found risk factors specific to each subgroup, which should be considered in future studies.

The temporal trend and distribution characteristics in mortality of Alzheimer's disease and other forms of dementia in China: Based on the National Mortality Surveillance System (NMS) from 2009 to 2015.

BACKGROUND: China is experiencing rapid age, which will lead to increasing burden of age-related diseases, such as Alzheimer disease and other forms of dementia. OBJECTIVES: The aim of this study was to 1) Explore the temporal trend of mortality of Alzheimer disease (AD) and other forms of dementia in China and 2) Analyze its geographic variations and urban-rural differences and calculate the years of life lost (YLLs) from AD and other forms of dementia. DATA AND METHODS: Data were extracted from the National Mortality Surveillance System (NMS). Age-standardized mortalities were calculated with the Western Grade 26 Standard Life List, and the YLLs were calculated using the DALY template provided by the WHO / World Bank global burden of disease (GBD) Working Group. The trends in crude and age-standardized mortality of AD and other forms of dementia were examined using Cochran-Armitage trend test. RESULTS: In China, the crude mortality from AD and other forms of dementia increased from 2009 to 2015, but the age-standardized mortality decreased. The YLLs of AD and other forms of dementia increased during the study period. The age-standardized mortality in the east was higher than those in the west and middle regions, and the age-standardized mortality in rural areas was higher than that in urban areas. CONCLUSION: In China, the age-standardized mortality of AD and other forms of dementia decreased from 2009 to 2015. However, the disease burden from AD and other forms of dementia is becoming heavier due to increasing elderly population. Moreover, there were geographic variations and urban-rural differences in mortality of AD and other forms of dementia in China.

High-mobility group box-1 translocation and release after hypoxic ischemic brain injury in neonatal rats.

Inflammation contributes to neonatal brain injury. Pro-inflammatory cytokines represent key inflammatory meditators in neonatal hypoxic-ischemic (HI) brain injury. The high mobility group box-1 (HMGB1) protein is a nuclear protein with pro-inflammatory cytokine properties when it is translocated from the nucleus and released extracellularly after stroke in adult rodents. We have previously shown that HMGB1 is translocated from the nucleus to cytosolic compartment after ischemic brain injury in fetal sheep. In the current study, we utilized the Rice-Vannucci model to investigate the time course of HMGB1 translocation and release after HI injury in neonatal rats. HMGB1 was located in cellular nuclei of brains from sham control rats. Nuclear to cytoplasmic translocation of HMGB1 was detected in the ipsilateral-HI hemisphere as early as zero h after HI, and released extracellularly as early as 6 h after HI. Immunohistochemical double staining detected HMGB1 translocation mainly in neurons along with release from apoptotic cells after HI. Serum HMGB1 increased at 3 h and decreased by 24 h after HI. In addition, rat brains exposed to hypoxic injury alone also exhibited time dependent HMGB1 translocation at 3, 12 and 48 h after hypoxia. Consequently, HMGB1 responds similarly after HI injury in the brains of neonatal and adult subjects. We conclude that HMGB1 is sensitive early indicator of neonatal HI and hypoxic brain injury.

Childhood adversities and mid-late depressive symptoms over the life course: Evidence from the China health and retirement longitudinal study.

BACKGROUND: The cumulative effect of childhood adversities on depressive symptoms in later life is well documented. However, there is a dearth of accurate information about this effect among Chinese population. The aim of this study is to examine the cumulative effect of childhood adversities on mid-late depressive symptoms in the Chinese population. METHODS: Data were drawn from the China Health and Retirement Longitudinal Study (CHARLS). We included 17,425 respondents aged 45 and over, and retrospectively collected information of childhood adversities. The depressive symptoms were assessed using a 10-item Center for Epidemiologic Studies Depression Scale (CES-D). A structural equation model was employed for analysis. RESULTS: Parental mental health problems had a direct effect on mid-late depressive symptoms (ß = 0.180, P < 0.001). Lack of friends showed direct effect on mid-late depressive symptoms (ß = 0.118, P < 0.001) and indirect effect through low SES and poor health status in mid-late life (ß = 0.054, P < 0.001). Poor health status, child neglect and abuse, and low SES in childhood had an indirect effect on mid-late depressive symptoms (ß = 0.128, ß = 0.040, ß = 0.098, P < 0.001). LIMITATIONS: Limitations of this study include recall bias on life course data collection, absence of adolescent data, limited construction of latent variables. CONCLUSIONS: These findings are crucial for preventing childhood adversities and subsequently reducing the prevalence of depression. Moreover, the indirect effects of childhood adversities suggest that early intervention and resource mobilization can circumvent some of the long-term mental health consequences.

Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice.

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1ß (IL-1ß) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1ß expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.

Photoreceptor glucose metabolism determines normal retinal vascular growth.

The neural cells and factors determining normal vascular growth are not well defined even though vision-threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet-derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon-induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia-associated retinal abnormalities and suppress phase I ROP in premature infants.

PPARα is essential for retinal lipid metabolism and neuronal survival.

BACKGROUND: Peroxisome proliferator activated receptor-alpha (PPARα) is a ubiquitously expressed nuclear receptor. The role of endogenous PPARα in retinal neuronal homeostasis is unknown. Retinal photoreceptors are the highest energy-consuming cells in the body, requiring abundant energy substrates. PPARα is a known regulator of lipid metabolism, and we hypothesized that it may regulate lipid use for oxidative phosphorylation in energetically demanding retinal neurons. RESULTS: We found that endogenous PPARα is essential for the maintenance and survival of retinal neurons, with Pparα -/- mice developing retinal degeneration first detected at 8 weeks of age. Using extracellular flux analysis, we identified that PPARα mediates retinal utilization of lipids as an energy substrate, and that ablation of PPARα ultimately results in retinal bioenergetic deficiency and neurodegeneration. This may be due to PPARα regulation of lipid transporters, which facilitate the internalization of fatty acids into cell membranes and mitochondria for oxidation and ATP production. CONCLUSION: We identify an endogenous role for PPARα in retinal neuronal survival and lipid metabolism, and furthermore underscore the importance of fatty acid oxidation in photoreceptor survival. We also suggest PPARα as a putative therapeutic target for age-related macular degeneration, which may be due in part to decreased mitochondrial efficiency and subsequent energetic deficits.

Adiponectin Mediates Dietary Omega-3 Long-Chain Polyunsaturated Fatty Acid Protection Against Choroidal Neovascularization in Mice.

Purpose: Neovascular age-related macular degeneration (AMD) is a major cause of legal blindness in the elderly. Diets with omega3-long-chain-polyunsaturated-fatty-acid (ω3-LCPUFA) correlate with a decreased risk of AMD. Dietary ω3-LCPUFA versus ω6-LCPUFA inhibits mouse ocular neovascularization, but the underlying mechanism needs further exploration. The aim of this study was to investigate if adiponectin (APN) mediated ω3-LCPUFA suppression of neovessels in AMD. Methods: The mouse laser-induced choroidal neovascularization (CNV) model was used to mimic some of the inflammatory aspect of AMD. CNV was compared between wild-type (WT) and Apn-/- mice fed either otherwise matched diets with 2% ω3 or 2% ω6-LCPUFAs. Vldlr-/- mice were used to mimic some of the metabolic aspects of AMD. Choroid assay ex vivo and human retinal microvascular endothelial cell (HRMEC) proliferation assay in vitro was used to investigate the APN pathway in angiogenesis. Western blot for p-AMPKα/AMPKα and qPCR for Apn, Mmps, and IL-10 were used to define mechanism. Results: ω3-LCPUFA intake suppressed laser-induced CNV in WT mice; suppression was abolished with APN deficiency. ω3-LCPUFA, mediated by APN, decreased mouse Mmps expression. APN deficiency decreased AMPKα phosphorylation in vivo and exacerbated choroid-sprouting ex vivo. APN pathway activation inhibited HRMEC proliferation and decreased Mmps. In Vldlr-/- mice, ω3-LCPUFA increased retinal AdipoR1 and inhibited NV. ω3-LCPUFA decreased IL-10 but did not affect Mmps in Vldlr-/- retinas. Conclusions: APN in part mediated ω3-LCPUFA inhibition of neovascularization in two mouse models of AMD. Modulating the APN pathway in conjunction with a ω3-LCPUFA-enriched-diet may augment the beneficial effects of ω3-LCPUFA in AMD patients.

Ileal Ureter Replacement Combined With Boari Flap-Psoas Hitch to Treat Full-Length Ureteral Defects: Technique and Initial Experience.

OBJECTIVE: To evaluate the feasibility of ileal ureter replacement combined with Boari flap-psoas hitch procedure for the management of full-length ureteral defects (>20 cm). METHODS: Three patients diagnosed with full-length ureteral defect were treated with our technique performed by a single surgeon between January 2015 to January 2016. All the patients had borderline renal function preoperatively. In each case, the ureteral reconstruction was performed by combining ileal ureter replacement with Boari flap-psoas hitch. Data on indications for surgery, intraoperative and postoperative outcomes, and changes in renal function were collected. RESULTS: Surgery was performed successfully with an operation duration between 210 and 250 minutes. The mean estimated blood loss was 230 mL. The mean length of hospital stay was 11 days, and no major complications (grade ≥3) occurred. Postoperative follow-up showed radiological resolution of hydronephrosis and improved renal function in all 3 patients. CONCLUSION: Ileal ureter replacement combined with Boari flap-psoas hitch is a feasible option for bridging full-length ureteral defects. This technique minimizes the length of ileal graft required as well as limitations concerning patient selection. Larger series with longer follow-up to confirm the value of the technique are warranted.

RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis.

Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood. Here we showed that retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor and transcription factor, is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in a mouse model of oxygen-induced proliferative retinopathy. We found that genetic deficiency of RORα substantially induced Sema3e expression in retinopathy. Both RORα and SEMA3E were expressed in retinal ganglion cells. RORα directly bound to a specific ROR response element on the promoter of Sema3e and negatively regulated Sema3e promoter-driven luciferase expression. Suppression of Sema3e using adeno-associated virus 2 carrying short hairpin RNA targeting Sema3e promoted disoriented pathological neovascularization and partially abolished the inhibitory vascular effects of RORα deficiency in retinopathy. Our findings suggest that RORα is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in pathological retinal angiogenesis.-Sun, Y., Liu, C.-H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., Kamenecka, T. M., Solt, L. A., Chen, J. RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis.

Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos.

Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases, such as age-related macular degeneration and macular telangiectasia. Ocular neovascularization is strongly associated with inflammation, but the source of inflammatory signals and the mechanisms by which these signals regulate the disruption of avascular privilege in photoreceptors are unknown. In this study, we found that c-Fos, a master inflammatory regulator, was increased in photoreceptors in a model of pathological blood vessels invading photoreceptors: the very low-density lipoprotein receptor-deficient (Vldlr-/- ) mouse. Increased c-Fos induced inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), leading to activation of signal transducer and activator of transcription 3 (STAT3) and increased TNFα-induced protein 3 (TNFAIP3) in Vldlr-/- photoreceptors. IL-6 activated the STAT3/vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)-activated STAT3/VEGFA indirectly. Inhibition of c-Fos using photoreceptor-specific AAV (adeno-associated virus)-hRK (human rhodopsin kinase)-sh_c-fos or a chemical inhibitor substantially reduced the pathological neovascularization and rescued visual function in Vldlr-/- mice. These findings suggested that the photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal-induced STAT3/VEGFA pathway.

Sema3f Protects Against Subretinal Neovascularization In Vivo.

Pathological neovascularization of the outer retina is the hallmark of neovascular age-related macular degeneration (nAMD). Building on our previous observations that semaphorin 3F (Sema3f) is expressed in the outer retina and demonstrates anti-angiogenic potential, we have investigated whether Sema3f can be used to protect against subretinal neovascularization in two mouse models. Both in the very low-density lipid-receptor knockout (Vldlr-/-) model of spontaneous subretinal neovascularization as well as in the mouse model of laser-induced choroidal neovascularization (CNV), we found protective effects of Sema3f against the formation of pathologic neovascularization. In the Vldlr-/- model, AAV-induced overexpression of Sema3f reduced the size of pathologic neovascularization by 56%. In the laser-induced CNV model, intravitreally injected Sema3f reduced pathologic neovascularization by 30%. Combined, these results provide the first evidence from two distinct in vivo models for a use of Sema3f in protecting the outer retina against subretinal neovascularization.

FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice.

Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.