Engrailed-1 Promotes Pancreatic Cancer Metastasis.

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, it is reported that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating roles in the activation of MAPK pathways and the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. The findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

Performance measures of 8,169,869 examinations in the National Breast Cancer Screening Program in Taiwan, 2004-2020.

BACKGROUND: The benefits of mammographic screening have been shown to include a decrease in mortality due to breast cancer. Taiwan's Breast Cancer Screening Program is a national screening program that has offered biennial mammographic breast cancer screening for women aged 50-69 years since 2004 and for those aged 45-69 years since 2009, with the implementation of mobile units in 2010. The purpose of this study was to compare the performance results of the program with changes in the previous (2004-2009) and latter (2010-2020) periods. METHODS: A cohort of 3,665,078 women who underwent biennial breast cancer mammography screenings from 2004 to 2020 was conducted, and data were obtained from the Health Promotion Administration, Ministry of Health and Welfare of Taiwan. We compared the participation of screened women and survival rates from breast cancer in the earlier and latter periods across national breast cancer screening programs. RESULTS: Among 3,665,078 women who underwent 8,169,869 examinations in the study population, the screened population increased from 3.9% in 2004 to 40% in 2019. The mean cancer detection rate was 4.76 and 4.08 cancers per 1000 screening mammograms in the earlier (2004-2009) and latter (2010-2020) periods, respectively. The 10-year survival rate increased from 89.68% in the early period to 97.33% in the latter period. The mean recall rate was 9.90% (95% CI: 9.83-9.97%) in the early period and decreased to 8.15% (95%CI, 8.13-8.17%) in the latter period. CONCLUSIONS: The evolution of breast cancer screening in Taiwan has yielded favorable outcomes by increasing the screening population, increasing the 10-year survival rate, and reducing the recall rate through the participation of young women, the implementation of a mobile unit service and quality assurance program, thereby providing historical evidence to policy makers to plan future needs.

Immortalization and transformation of primary cells mediated by engineered ecDNAs.

Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general approach to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs, also known as "double minutes") in a spatiotemporally controlled manner in cancer cell lines and in primary cells derived from genetically engineered mice. With this strategy, ecDNA formation can be coupled with expression of fluorescent reporters or other selectable markers to enable the identification and tracking of ecDNA-containing cells. We demonstrate the feasibility of this approach by engineering MDM2-containing ecDNAs in near-diploid human cells, showing that GFP expression can be used to track ecDNA dynamics under physiological conditions or in the presence of specific selective pressures. We also apply this approach to generate mice harboring inducible Myc - and Mdm2 -containing ecDNAs analogous to those spontaneously occurring in human cancers. We show that the engineered ecDNAs rapidly accumulate in primary cells derived from these animals, promoting proliferation, immortalization, and transformation.

Automatic Calcification Morphology and Distribution Classification for Breast Mammograms With Multi-Task Graph Convolutional Neural Network.

The morphology and distribution of microcalcifications are the most important descriptors for radiologists to diagnose breast cancer based on mammograms. However, it is very challenging and time-consuming for radiologists to characterize these descriptors manually, and there also lacks of effective and automatic solutions for this problem. We observed that the distribution and morphology descriptors are determined by the radiologists based on the spatial and visual relationships among calcifications. Thus, we hypothesize that this information can be effectively modelled by learning a relationship-aware representation using graph convolutional networks (GCNs). In this study, we propose a multi-task deep GCN method for automatic characterization of both the morphology and distribution of microcalcifications in mammograms. Our proposed method transforms morphology and distribution characterization into node and graph classification problem and learns the representations concurrently. We trained and validated the proposed method in an in-house dataset and public DDSM dataset with 195 and 583 cases,respectively. The proposed method reaches good and stable results with distribution AUC at 0.812 ± 0.043 and 0.873 ± 0.019, morphology AUC at 0.663 ± 0.016 and 0.700 ± 0.044 for both in-house and public datasets. In both datasets, our proposed method demonstrates statistically significant improvements compared to the baseline models. The performance improvements brought by our proposed multi-task mechanism can be attributed to the association between the distribution and morphology of calcifications in mammograms, which is interpretable using graphical visualizations and consistent with the definitions of descriptors in the standard BI-RADS guideline. In short, we explore, for the first time, the application of GCNs in microcalcification characterization that suggests the potential of using graph learning for more robust understanding of medical images.

Association Between Myopia and Primary Open-Angle Glaucoma by Race and Ethnicity in Older Adults in the California Medicare Population.

Importance: Racial and ethnic differences in the association between myopia and primary open-angle glaucoma (POAG) are not well understood. Objective: To investigate the association between myopia and POAG in the 2019 California Medicare population and to investigate whether there was evidence of effect measure modification of this association by race and ethnicity. Design, Setting, and Participants: This cross-sectional study used administrative claims data from 2019 California Medicare beneficiaries 65 years or older with California residence and active coverage with Medicare parts A and B. Analysis took place between October 2021 and October 2023. Exposures: The primary exposure was myopia, which was defined by International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes. Main Outcomes and Measures: The outcome of interest was POAG, which was defined by ICD-10-CM code. Results: Of 2 717 346 California Medicare beneficiaries in 2019, 1 440 769 (53.0%) were aged 65 to 74 years, 1 544 479 (56.8%) identified as female, 60 211 (2.2%) had myopia, and 171 988 (6.3%) had POAG. Overall, 346 723 individuals (12.8%) identified as Asian, 117 856 (4.3%) as Black, 430 597 (15.8%) as Hispanic, 1 705 807 (62.8%) as White, and 115 363 (4.2%) as other race and ethnicity. In adjusted logistic regression analyses, beneficiaries with myopia had higher odds of POAG compared with beneficiaries without myopia (odds ratio [OR], 2.41; 95% CI, 2.35-2.47). In multivariable models stratified by race and ethnicity, the association between myopia and POAG was stronger in Asian (OR, 2.74; 95% CI, 2.57-2.92), Black (OR, 2.60; 95% CI, 2.31-2.94), and Hispanic (OR, 3.28; 95% CI, 3.08-3.48) beneficiaries compared with non-Hispanic White beneficiaries (OR, 2.14; 95% CI, 2.08-2.21). Conclusions and Relevance: In the 2019 California Medicare population, myopia was associated with greater adjusted odds of POAG. This association was stronger among Asian, Black, and Hispanic beneficiaries compared with non-Hispanic White beneficiaries. These findings suggest possible disparities in glaucoma risk by race and ethnicity in individuals with myopia and may indicate greater need for glaucoma screening in individuals with myopia from racial and ethnic minority backgrounds.

End-to-End Calcification Distribution Pattern Recognition for Mammograms: An Interpretable Approach with GNN.

Purpose: We aimed to develop a novel interpretable artificial intelligence (AI) model algorithm focusing on automatic detection and classification of various patterns of calcification distribution in mammographic images using a unique graph convolution approach. Materials and methods: Images from 292 patients, which showed calcifications according to the mammographic reports and diagnosed breast cancers, were collected. The calcification distributions were classified as diffuse, segmental, regional, grouped, or linear. Excluded were mammograms with (1) breast cancer with multiple lexicons such as mass, asymmetry, or architectural distortion without calcifications; (2) hidden calcifications that were difficult to mark; or (3) incomplete medical records. Results: A graph-convolutional-network-based model was developed. A total of 581 mammographic images from 292 cases of breast cancer were divided based on the calcification distribution pattern: diffuse (n = 67), regional (n = 115), group (n = 337), linear (n = 8), or segmental (n = 54). The classification performances were measured using metrics including precision, recall, F1 score, accuracy, and multi-class area under the receiver operating characteristic curve. The proposed model achieved a precision of 0.522 ± 0.028, sensitivity of 0.643 ± 0.017, specificity of 0.847 ± 0.009, F1 score of 0.559 ± 0.018, accuracy of 64.325 ± 1.694%, and area under the curve of 0.745 ± 0.030; thus, the method was found to be superior compared to all baseline models. The predicted linear and diffuse classifications were highly similar to the ground truth, and the predicted grouped and regional classifications were also superior compared to baseline models. The prediction results are interpretable using visualization methods to highlight the important calcification nodes in graphs. Conclusions: The proposed deep neural network framework is an AI solution that automatically detects and classifies calcification distribution patterns on mammographic images highly suspected of showing breast cancers. Further study of the AI model in an actual clinical setting and additional data collection will improve its performance.

Machine Learning Algorithm for Distinguishing Ductal Carcinoma In Situ from Invasive Breast Cancer.

PURPOSE: Given that early identification of breast cancer type allows for less-invasive therapies, we aimed to develop a machine learning model to discriminate between ductal carcinoma in situ (DCIS) and minimally invasive breast cancer (MIBC). METHODS: In this retrospective study, the health records of 420 women who underwent biopsies between 2010 and 2020 to confirm breast cancer were collected. A trained XGBoost algorithm was used to classify cancers as either DCIS or MIBC using clinical characteristics, mammographic findings, ultrasonographic findings, and histopathological features. Its performance was measured against other methods using area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, precision, and F1 score. RESULTS: The model was trained using 357 women and tested using 63 women with an overall 420 patients (mean [standard deviation] age, 57.1 [12.0] years). The model performed well when feature importance was determined, reaching an accuracy of 0.84 (95% confidence interval [CI], 0.76-0.91), an AUC of 0.93 (95% CI, 0.87-0.95), a specificity of 0.75 (95% CI, 0.67-0.83), and a sensitivity of 0.91 (95% CI, 0.76-0.94). CONCLUSION: The XGBoost model, combining clinical, mammographic, ultrasonographic, and histopathologic findings, can be used to discriminate DCIS from MIBC with an accuracy equivalent to that of experienced radiologists, thereby giving patients the widest range of therapeutic options.

Availability of Trauma-Specific Services in US Substance Use Disorder and Other Mental Health Treatment Facilities: 2015-2019.

This study assessed trends in provision of trauma-specific services, defined as dedicated programming for persons with a history of trauma, in US Substance Use Disorder (SUD) and other Mental Health (MH) facilities. Facility level data from the National Survey of Substance Abuse Treatment Services and the National Mental Health Services Survey (2015-2019) were used to examine trends in provision of trauma specific-services. Trauma specific service provision trended up significantly between 2015 and 2019. In 2019, they were more commonly offered at MH facilities (49.9%) than SUD facilities (42.7%). Licensing by state SUD authorities were associated with provision of trauma-specific services at both MH (Adjusted Odds Ratio (AOR) = 1.23, 95% Confidence interval (CI) = 1.18-1.47, p < .001) and SUD (AOR = 1.19, 95% CI = 1.04-1.37, p = .012) facilities. The proportions of facilities that offer trauma-specific services were correlated within states (Pearson's r = .44, p = .001). State policies to implement trauma screening at public facilities were associated with higher odds of offering trauma-specific services in MH (AOR = 1.31, 95% CI = 1.04-1.64, p = .021) and SUD (AOR 1.51, 95% CI = 1.19-1.12, p = .001) facilities; whereas, state implementation of trauma-specific CBT at public facilities was associated with higher odds of this outcome only in MH facilities (AOR = 1.23, 95% CI = 1.01-1.51, p = .043). Although trauma-specific services trended up significantly, fewer than half of treatment facilities offer such services nationally. Certain facility characteristics, such SUD authority certification, are associated with trauma-specific services. Variability among states in these services is linked to state policy. Increased efforts by states may be an effective point of intervention to further disseminate trauma-specific services.

Correlation between hand grip strength and regional muscle mass in older Asian adults: an observational study.

BACKGROUND: Previous research has demonstrated a correlation between hand grip strength (HGS) and muscle strength. This study aims to determine the relationship between HGS and muscle mass in older Asian adults. METHODS: We retrospectively reviewed the dual-energy X-ray absorptiometry (DXA) records of 907 older adults (239 (26.4%) men and 668 (73.6%) women) at one medical institution in Taipei, Taiwan, from January 2019, to December 2020. Average age was 74.80 ± 9.43 and 72.93 ± 9.09 for the males and females respectively. The inclusion criteria were: 1) aged 60 and older, 2) underwent a full-body DXA scan, and 3) performed hand grip measurements. Patients with duplicate results, incomplete records, stroke history, and other neurological diseases were excluded. Regional skeletal muscle mass was measured using DXA. HGS was measured using a Jamar handheld dynamometer. RESULTS: Total lean muscle mass (kg) averaged 43.63 ± 5.81 and 33.16 ± 4.32 for the males and females respectively. Average HGS (kg) was 28.81 ± 9.87 and 19.19 ± 6.17 for the males and females respectively. In both sexes, HGS and regional muscle mass consistently declined after 60 years of age. The rates of decline per decade in upper and lower extremity muscle mass and HGS were 7.06, 4.95, and 12.30%, respectively, for the males, and 3.36, 4.44, and 12.48%, respectively, for the females. In men, HGS significantly correlated with upper (r = 0.576, p < 0.001) and lower extremity muscle mass (r = 0.532, p < 0.001). In women, the correlations between HGS and upper extremity muscle mass (r = 0.262, p < 0.001) and lower extremity muscle mass (r = 0.364, p < 0.001) were less strong, though also statistically significant. CONCLUSION: Muscle mass and HGS decline with advancing age in both sexes, though the correlation is stronger in men. HGS measurements are an accurate proxy for muscle mass in older Asian adults, particularly in males.

Today's radiologists meet tomorrow's AI: the promises, pitfalls, and unbridled potential.

Advances in information technology have improved radiologists' abilities to perform an increasing variety of targeted diagnostic exams. However, due to a growing demand for imaging from an aging population, the number of exams could soon exceed the number of radiologists available to read them. However, artificial intelligence has recently resounding success in several case studies involving the interpretation of radiologic exams. As such, the integration of AI with standard diagnostic imaging practices to revolutionize medical care has been proposed, with the ultimate goal being the replacement of human radiologists with AI 'radiologists'. However, the complexity of medical tasks is often underestimated, and many proponents are oblivious to the limitations of AI algorithms. In this paper, we review the hype surrounding AI in medical imaging and the changing opinions over the years, ultimately describing AI's shortcomings. Nonetheless, we believe that AI has the potential to assist radiologists. Therefore, we discuss ways AI can increase a radiologist's efficiency by integrating it into the standard workflow.

Bismuth breast-shield use in chest computed tomography for efficient dose reduction and sufficient image quality.

BACKGROUND: Radiosensitivity in the breasts increases the risk of carcinogenesis from exposure to the ionizing radiation of computed tomography (CT) administered in the course of medical attention. Bismuth shielding techniques have been used to reduce radiation, but image noise increased, degrading image quality. PURPOSE: The aim of this study was to investigate how the use of iterative reconstruction (IR) combined with bismuth shielding influences image quality. MATERIALS AND METHODS: Women aged at least 20 years with body mass indexes <28 were recruited and randomly assigned to 1 of 3 CT scanning protocols without shielding, with a bismuth breast shield before the scout view, or with a bismuth breast shield after the scout view. All obtained images were reconstructed using an IR algorithm. To evaluate radiation dose, 2 Gafchromic films were placed over the clothes, 1 near each nipple. RESULTS: Average dose reduction was significant (27.99%, P < .05) when bismuth shielding was applied after the scout view. Using the contrast-to-noise ratio, the image quality was found to be superior when the IR algorithm was applied. Using quantitative evaluations by 2 radiologists applying a 4-point Likert scale, significant differences in image quality were not found among the 3 protocols. CONCLUSION: Bismuth breast shields, particularly when used after acquiring scout images, are effective at reducing radiation dose without undermining the diagnostic value of the images when the IR technique is applied.

Federated learning: a collaborative effort to achieve better medical imaging models for individual sites that have small labelled datasets.

Despite the overall success of using artificial intelligence (AI) to assist radiologists in performing computer-aided patient diagnosis, it remains challenging to build good models with small datasets at individual sites. Because many medical images do not come with proper labelling for training, this requires radiologists to perform strenuous labelling work and to prepare the dataset for training. Placing such demands on radiologists is unsustainable, given the ever-increasing number of medical images taken each year. We propose an alternative solution using a relatively new learning framework. This framework, called federated learning, allows individual sites to train a global model in a collaborative effort. Federated learning involves aggregating training results from multiple sites to create a global model without directly sharing datasets. This ensures that patient privacy is maintained across sites. Furthermore, the added supervision obtained from the results of partnering sites improves the global model's overall detection abilities. This alleviates the issue of insufficient supervision when training AI models with small datasets. Lastly, we also address the major challenges of adopting federated learning.

Quantifying lumbar vertebral perfusion by a Tofts model on DCE-MRI using segmental versus aortic arterial input function.

The purpose of this study was to investigate the influence of arterial input function (AIF) selection on the quantification of vertebral perfusion using axial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In this study, axial DCE-MRI was performed on 2 vertebrae in each of eight healthy volunteers (mean age, 36.9 years; 5 men) using a 1.5-T scanner. The pharmacokinetic parameters Ktrans, ve, and vp, derived using a Tofts model on axial DCE-MRI of the lumbar vertebrae, were evaluated using various AIFs: the population-based aortic AIF (AIF_PA), a patient-specific aortic AIF (AIF_A) and a patient-specific segmental arterial AIF (AIF_SA). Additionally, peaks and delay times were changed to simulate the effects of various AIFs on the calculation of perfusion parameters. Nonparametric analyses including the Wilcoxon signed rank test and the Kruskal-Wallis test with a Dunn-Bonferroni post hoc analysis were performed. In simulation, Ktrans and ve increased as the peak in the AIF decreased, but vp increased when delay time in the AIF increased. In humans, the estimated Ktrans and ve were significantly smaller using AIF_A compared to AIF_SA no matter the computation style (pixel-wise or region-of-interest based). Both these perfusion parameters were significantly greater using AIF_SA compared to AIF_A.

Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. METHODS: By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or ß-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. RESULTS: Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced ß-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. CONCLUSIONS: This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.

Image Quality and Performance Benchmarks in Vehicle and Hospital Mammography.

BACKGROUND: Whether the quality and clinical performance of mammograms obtained in vehicles and those obtained in fixed facilities are equal remains unknown. We compared the characteristics of examinees screened in hospital and vehicle settings. PATIENTS AND METHODS: Data from women who had undergone mammography at Shuang Ho Hospital from January 1, 2013, to December 31, 2016, were obtained from the Women's Breast Screening Database and used for analysis. The records revealed that 43,807 and 11,955 women had undergone mammography in vehicle and hospital settings, respectively. The performance benchmarks, including recall rate, cancer detection rate, and positive predictive value, in the 2 settings were compared. In addition, the image quality was compared by reviewing 110 records from each setting. RESULTS: The hospital mammograms had greater subtotal mean scores (189.2 ± 5.9) compared with the vehicle mammograms (185.5 ± 7.7; P < .0001) in the mediolateral oblique view. Mobile mammography contributed to a lower odds ratio of classification in the Breast Imaging Reporting and Data System categories of 0, 4, and 5. In general, all performance benchmarks, including the cancer detection rate and positive predictive value of mobile and hospital mammography, were satisfactory. However, the recall rate with the hospital mammography service was slightly greater than the acceptable benchmark. CONCLUSION: Mobile mammography services should be continued with improvements in image quality. The reduction in the number of patients with a category of 0 in the classification system in both mammography service settings and the enhancement of data linking to previous mammograms warrants additional attention.

eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA.

Bioactivation of Napabucasin Triggers Reactive Oxygen Species-Mediated Cancer Cell Death.

PURPOSE: Napabucasin (2-acetylfuro-1,4-naphthoquinone or BBI-608) is a small molecule currently being clinically evaluated in various cancer types. It has mostly been recognized for its ability to inhibit STAT3 signaling. However, based on its chemical structure, we hypothesized that napabucasin is a substrate for intracellular oxidoreductases and therefore may exert its anticancer effect through redox cycling, resulting in reactive oxygen species (ROS) production and cell death. EXPERIMENTAL DESIGN: Binding of napabucasin to NAD(P)H:quinone oxidoreductase-1 (NQO1), and other oxidoreductases, was measured. Pancreatic cancer cell lines were treated with napabucasin, and cell survival, ROS generation, DNA damage, transcriptomic changes, and alterations in STAT3 activation were assayed in vitro and in vivo. Genetic knockout or pharmacologic inhibition with dicoumarol was used to evaluate the dependency on NQO1. RESULTS: Napabucasin was found to bind with high affinity to NQO1 and to a lesser degree to cytochrome P450 oxidoreductase (POR). Treatment resulted in marked induction of ROS and DNA damage with an NQO1- and ROS-dependent decrease in STAT3 phosphorylation. Differential cytotoxic effects were observed, where NQO1-expressing cells generating cytotoxic levels of ROS at low napabucasin concentrations were more sensitive. Cells with low or no baseline NQO1 expression also produced ROS in response to napabucasin, albeit to a lesser extent, through the one-electron reductase POR. CONCLUSIONS: Napabucasin is bioactivated by NQO1, and to a lesser degree by POR, resulting in futile redox cycling and ROS generation. The increased ROS levels result in DNA damage and multiple intracellular changes, one of which is a reduction in STAT3 phosphorylation.

Effect of chronic topical latanoprost on the sclera and lamina cribrosa of form-deprived myopic Guinea pigs.

The purpose of this study was to investigate the effects of latanoprost, an ocular hypotensive prostaglandin analog, on scleral collagen fibers and laminar pores in myopic guinea pigs. Young guinea pigs underwent monocular form deprivation (FD; white plastic diffusers) from 14-days of age for 10-weeks. After the first week, FD eyes also received daily topical A) latanoprost (Lat, 0.005%, n = 5) or B) artificial tears (AT; n = 5). At the end of the treatment period, animals were sacrificed, eyes enucleated and optic nerve heads (ONH) excised to include a 4 mm diameter ring of surrounding sclera for scanning electron microscopy (SEM), and an additional 6 mm ring of sclera surrounding the ONH was excised for transmission electron microscopy (TEM). For SEM, ONH samples were first immersed in 0.2M NaOH for 30 h to isolate the collagenous structures. All samples were stained with osmium tetroxide, dried through an ethanol series and finally subjected to critical point drying before imaging. Image J was used to analyze the dimensions of laminar pores (SEM images) and scleral collagen fibers (TEM images). As previously reported in a related study, latanoprost was effective in inhibiting myopia progression in FD eyes of the guinea pigs. The scleral fibers of FD myopic eyes treated with AT were smaller and more variable in cross-sectional areas compared to untreated (fellow) eyes (mean areas: 0.0059 ±â€¯0.0013 vs. 0.0085 ±â€¯0.002 µm2; p < 0.001), consistent with scleral changes reported for human myopia. In contrast, the scleral fibers of the Lat-treated FD eyes were similar to those of fellow eyes (0.0083 ±â€¯0.002 vs. 0.0078 ±â€¯0.0014 µm2). However, laminar pore size appeared unaffected by either the FD or drug treatments, with no significant difference found between FD eyes and their fellows, for either treatment group. That daily topical latanoprost appeared to protect against myopia-related changes in scleral collagen, rather than exaggerating them, as might be predicted from its known action on the uveoscleral extracellular matrix, lends further support its use for myopia control. In this guinea pig myopia model, the lamina cribrosa appeared unaffected.

Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.

Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.This article is highlighted in the In This Issue feature, p. 1143.