Circulating vascular endothelial growth factor (VEGF) ligands and receptors are central regulators of vasculogenesis, angiogenesis, and lymphangiogenesis. In response to VEGF ligand binding, VEGF receptor tyrosine kinases initiate the chain of events that transduce extracellular signals into endothelial cell responses such as survival, proliferation, and migration. These events are controlled by intricate cellular processes that include the regulation of gene expression at multiple levels, interactions of numerous proteins, and intracellular trafficking of receptor–ligand complexes. Endocytic uptake and transport of macromolecular complexes through the endosome–lysosome system helps fine-tune endothelial cell responses to VEGF signals. Clathrin-dependent endocytosis remains the best understood means of macromolecular entry into cells, although the importance of non-clathrin-dependent pathways is increasingly recognized. Many of these endocytic events rely on adaptor proteins that coordinate internalization of activated cell-surface receptors. In the endothelium of both blood and lymphatic vessels, epsins 1 and 2 are functionally redundant adaptors involved in receptor endocytosis and intracellular sorting. These proteins are capable of binding both lipids and proteins and are important for promoting curvature of the plasma membrane as well as binding ubiquitinated cargo. Here, we discuss the role of epsin proteins and other endocytic adaptors in governing VEGF signaling in angiogenesis and lymphangiogenesis and discuss their therapeutic potential as molecular targets.

Naturally occurring inherited retinal diseases (IRDs) in cats and dogs provide a rich source of potential models for human IRDs. In many cases, the phenotypes between the species with mutations of the homologous genes are very similar. Both cats and dogs have a high-acuity retinal region, the area centralis, an equivalent to the human macula, with tightly packed photoreceptors and higher cone density. This and the similarity in globe size to that of humans means these large animal models provide information not obtainable from rodent models. The established cat and dog models include those for Leber congenital amaurosis, retinitis pigmentosa (including recessive, dominant, and X-linked forms), achromatopsia, Best disease, congenital stationary night blindness and other synaptic dysfunctions, RDH5-associated retinopathy, and Stargardt disease. Several of these models have proven to be important in the development of translational therapies such as gene-augmentation therapies. Advances have been made in editing the canine genome, which necessitated overcoming challenges presented by the specifics of canine reproduction. Feline genome editing presents fewer challenges. We can anticipate the generation of specific cat and dog IRD models by genome editing in the future.

Rodent models of breast cancer have played critical roles in our understanding of breast cancer development and progression as well as preclinical testing of cancer prevention and therapeutics. In this article, we first review the values and challenges of conventional genetically engineered mouse (GEM) models and newer iterations of these models, especially those with inducible or conditional regulation of oncogenes and tumor suppressors. Then, we discuss nongermline (somatic) GEM models of breast cancer with temporospatial control, made possible by intraductal injection of viral vectors to deliver oncogenes or to manipulate the genome of mammary epithelial cells. Next, we introduce the latest development in precision editing of endogenous genes using in vivo CRISPR-Cas9 technology. We conclude with the recent development in generating somatic rat models for modeling estrogen receptor–positive breast cancer, something that has been difficult to accomplish in mice.

Human retinal organoids recapitulate the cellular diversity, arrangement, gene expression, and functional aspects of the human retina. Protocols to generate human retinal organoids from pluripotent stem cells are typically labor intensive, include many manual handling steps, and the organoids need to be maintained for several months until they mature. To generate large numbers of human retinal organoids for therapy development and screening purposes, scaling up retinal organoid production, maintenance, and analysis is of utmost importance. In this review, we discuss strategies to increase the number of high-quality retinal organoids while reducing manual handling steps. We further review different approaches to analyze thousands of retinal organoids with currently available technologies and point to challenges that still await to be overcome both in culture and analysis of retinal organoids.

Our ability to interrogate the tumor immune microenvironment (TIME) at an ever-increasing granularity has uncovered critical determinants of disease progression. Not only do we now have a better understanding of the immune response in breast cancer, but it is becoming possible to leverage key mechanisms to effectively combat this disease. Almost every component of the immune system plays a role in enabling or inhibiting breast tumor growth. Building on early seminal work showing the involvement of T cells and macrophages in controlling breast cancer progression and metastasis, single-cell genomics and spatial proteomics approaches have recently expanded our view of the TIME. In this article, we provide a detailed description of the immune response against breast cancer and examine its heterogeneity in disease subtypes. We discuss preclinical models that enable dissecting the mechanisms responsible for tumor clearance or immune evasion and draw parallels and distinctions between human disease and murine counterparts. Last, as the cancer immunology field is moving toward the analysis of the TIME at the cellular and spatial levels, we highlight key studies that revealed previously unappreciated complexity in breast cancer using these technologies. Taken together, this article summarizes what is known in breast cancer immunology through the lens of translational research and identifies future directions to improve clinical outcomes.

Retinitis pigmentosa GTPase regulator (RPGR) gene variants are the predominant cause of X-linked retinitis pigmentosa (XLRP) and a common cause of cone-rod dystrophy (CORD). XLRP presents as early as the first decade of life, with impaired night vision and constriction of peripheral visual field and rapid progression, eventually leading to blindness. In this review, we present RPGR gene structure and function, molecular genetics, animal models, RPGR-associated phenotypes and highlight emerging potential treatments such as gene-replacement therapy.

Given the challenges with achieving effective and durable treatment for epithelial ovarian cancer, primary prevention is highly desirable. Fortunately, decades of research have provided evidence for several strategies that can be deployed to optimize risk reduction. These include surgery, chemoprevention, and lifestyle factor modifications. These broad categories vary in terms of the magnitude of risk reduction possible, the possible short-term and long-term side effects, the degree of difficulty, and acceptability. Thus, the concept of a risk-based model to personalize preventive interventions is advocated to guide discussion between care providers and women at risk. For women with inherited major gene mutations that greatly increase risk of ovarian cancer, surgical approaches have favorable risk to benefit ratios. Chemoprevention and lifestyle factor modifications portend a lower degree of risk reduction but confer lower risk of undesirable side effects. Since complete prevention is not currently possible, better methods for early detection remain a high priority.

Humans age at different rates and families with exceptional longevity provide an opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of extended life span, compression of morbidity with resultant extension of health span, and longevity-associated biomarker profiles. These biomarkers, including low-circulating insulin-like growth factor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels, are associated with functional genotypes that are enriched in centenarians, suggesting that they may be causative for longevity. While not all genetic discoveries from centenarians have been validated, in part due to exceptional life span being a rare phenotype in the general population, the APOE2 and FOXO3a genotypes have been confirmed in a number of populations with exceptional longevity. However, life span is now recognized as a complex trait and genetic research methods to study longevity are rapidly extending beyond classical Mendelian genetics to polygenic inheritance methodologies. Moreover, newer approaches are suggesting that pathways that have been recognized for decades to control life span in animals may also regulate life span in humans. These discoveries led to strategic development of therapeutics that may delay aging and prolong health span.

The goal of precision oncology is to translate the molecular features of cancer into predictive and prognostic tests that can be used to individualize treatment leading to improved outcomes and decreased toxicity. Success for this strategy in breast cancer is exemplified by efficacy of trastuzumab in tumors overexpressing ERBB2 and endocrine therapy for tumors that are estrogen receptor positive. However, other effective treatments, including chemotherapy, immune checkpoint inhibitors, and CDK4/6 inhibitors are not associated with strong predictive biomarkers. Proteomics promises another tier of information that, when added to genomic and transcriptomic features (proteogenomics), may create new opportunities to improve both treatment precision and therapeutic hypotheses. Here, we review both mass spectrometry-based and antibody-dependent proteomics as complementary approaches. We highlight how these methods have contributed toward a more complete understanding of breast cancer and describe the potential to guide diagnosis and treatment more accurately.

The embryology of the female reproductive organs is reviewed focusing on aspects relevant to the histogenesis of reproductive neoplasms. The evidence reviewed suggests that (1) there is no embryological link between the ovarian surface epithelium and the coelomic epithelium; (2) the ovarian surface epithelium is not composed of pluripotent cells that readily differentiate into various components of the reproductive tract before or after birth; (3) there is no embryological link between the ovarian surface epithelium and the Müllerian ducts, from which internal female reproductive organs other than the ovaries, including the endocervix, endometrium, and fallopian tubes, are derived; and (4) there is an embryological link between the Müllerian ducts and the renal collecting system, perhaps accounting for clear cell differentiation in some gynecological malignancies. Implications for our understanding of the origin of the tumors historically classified as ovarian epithelial neoplasms are discussed.