Photocoagulation of blood vessels offers unambiguous advantages to current radiofrequency approaches considering the high specificity of blood absorption at available laser wavelengths (e.g., 532 nm and 1.064 µm). Successful treatment of pediatric vascular lesions, such as port-wine stains requiring microvascular hemostasis, has been documented. Although laser treatments have been successful in smaller diameter blood vessels, photocoagulation of larger sized vessels is less effective. The hypothesis for this study is that a primary limitation in laser coagulation of large diameter blood vessels (500–1000 µm) originates from shear stress gradients associated with higher flow velocities along with temperature-dependent viscosity changes. Laser (1.07 µm) coagulation of blood vessels was tested in the chicken chorio-allantoic membrane (CAM). A finite element model is developed that includes hypothetical limitations in laser coagulation during irradiation. A protocol to specify laser dosimetry is derived from OCT imaging and angiography observations as well as finite element model results. Laser dosimetry is applied in the CAM model to test the experimental hypothesis that blood shear stress and flow velocity are important parameters for laser coagulation and hemostasis of large diameter blood vessels (500–1000 µm). Our experimental results suggest that shear stress and flow velocity are fundamental in the coagulation of large diameter blood vessels (500–1000 µm). Laser dosimetry is proposed and demonstrated for successful coagulation and hemostasis of large diameter CAM blood vessels.

This commentary focuses on the DESTINY-Breast12 study, published in Nature Medicine on 13 September 2024, which evaluates the efficacy of Trastuzumab deruxtecan (T-DXd) in treating HER2-positive advanced breast cancer, including those with brain metastases. We emphasize the broadened clinical potential of T-DXd in treating brain metastases from tumors originally classified as HER2-null or HER2-low, extending beyond its current use for breast cancer. This expanded application of T-DXd could provide new hope to patients dealing with challenging brain metastases, addressing an urgent need for effective treatment options.

This review examines circadian dysregulation and the role of Müller glial cells (MGCs) in retinal degeneration associated with Alzheimer’s disease (AD). Evidence supporting the interdependence of circadian rhythm (CR) disruption and AD progression is presented. Also reviweed are reports substantiating the role of MGCs in maintaining CR. Studies documenting MGC dysfunction in AD retinas suggest that gliosis, altered diurnal patterns in water homeostasis, blood-retina barrier breakdown, and impaired ocular glymphatic clearance are relevant to disease progression. Similarities between AD and various retinopathies are explored with respect to MGC physiology and CR dysfunction. We propose that MGC circadian dysregulation is diagnostically and therapeutically relevant to AD retinopathy.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated remarkable efficacy in HER2+ and HER2-low metastatic breast cancer (mBC). Yet, 40–50% of patients fail to respond, and mechanisms underlying resistance, particularly those involving the immune microenvironment, remain poorly understood. To address this gap, we conducted spatial proteomic profiling of metastatic lesions from 25 HER2+ mBC patients treated with T-DXd, using the Bruker GeoMX Digital Spatial Profiler (DSP) platform. Regions of interest (ROIs) were segmented by CD45 expression to distinguish immune-rich versus immune-poor compartments, and spatial marker expression was compared between responders (R) and non-responders (NR). Spearman correlation analysis was used to assess spatial coordination among HER2, fibronectin, and immune markers. Non-responders exhibited greater HER2 heterogeneity, lower CD45+ immune infiltration, and consistent upregulation of fibronectin and granzyme B. In both bone and brain metastases, NR tissues showed strong correlations between fibronectin and T cell markers, indicating spatial immune exclusion. In contrast, NR lymph node metastases displayed negative correlations between fibronectin and immune markers and uncoordinated B–T cell clustering, suggesting an alternative resistance mechanism rooted in immune disorganization rather than exclusion. Collectively, these results implicate HER2 heterogeneity, fibrotic immune exclusion, and immune suppression as key drivers of T-DXd resistance across metastatic sites. By integrating spatial proteomics with clinical outcomes, this study provides novel insights into the spatial immune landscape of ADC resistance and identifies actionable biomarkers for patient stratification and combination therapy design, laying a critical foundation for developing biomarker-guided therapies and personalized treatment strategies to overcome ADC resistance in metastatic breast cancer. Translational Significance T-DXd represents a major advance in antibody-drug conjugate (ADC) therapies to address HER2 heterogeneity in tumors through bystander killing. However, treatment options following resistance to T-DXd remain limited, leaving a critical unmet need. As new ADCs continue to emerge, resistance will likely remain a persistent challenge across tumor types. This work extends beyond T-DXd resistance—it provides a framework to address resistance mechanisms common to other ADCs. By investigating immune-mediated mechanisms of ADC resistance, this research identifies therapeutic targets that can be leveraged to develop new treatment strategies. By integrating spatial biology with clinical data, this study offers unprecedented insights into immune-tumor interactions within the resistant tumor microenvironment. This approach deepens mechanistic understanding and enables personalized treatment strategies guided by spatially resolved biomarkers. This novel combination of spatial mechanistic research with clinical data represents advancement toward overcoming ADC resistance and improving outcomes for patients with few therapeutic options.

Background: Amyloid beta (Aβ) deposits are well‐documented in the retinas of Alzheimer's disease (AD) patients, with retinal Aβ levels closely correlating with brain Aβ deposition. Impaired glymphatic clearance is a key mechanism implicated in Aβ accumulation in the AD brain; however the potential role of glymphatic clearance deficits in driving retinal Aβ accumulation remains poorly understood. Furthermore, alterations in Müller glial cell (MGC) biology, known to play a critical role in retinal homeostasis and neuroinflammatory responses, may exacerbate Aβ pathology. This study investigates whether optic nerve glymphatic clearance impairments and Müller glia cell (MGC) biology alterations collectively contribute to retinal Aβ accumulation. Methods: Comparing 3‐month‐old female 5xFAD vs. wild‐type (WT) mice, we compared MGC phenotypic differences and optic nerve glymphatic clearance rates. Immunofluorescence was used to quantify MGC expression of glial fibrillary acidic protein (GFAP) to quantify gliosis and aquaporin‐4 (AQP4), which is the main molecular driver of glymphatic clearance in both the brain and the eye. To observe glymphatic clearance in the anterograde direction (from eye toward brain), we performed intravitreal injections of fluorescent human Aβ40 as well as fluorescent cadaverine to observe extracellular fluid transport. Results: AQP4 demonstrated a robust upregulation across all retina layers in 5xFAD mice, marked by enhanced perivascular localization and increased expression in the neuropil. GFAP levels were notably elevated in the peripheral retina of 5xFAD mice, suggesting potential reactive gliosis and glymphatic disruptions originating in these regions. Importantly, the study observed consistent anterograde glymphatic transport of fluorescent Aβ or cadaverine tracers via the optic nerve, indicating maintained transport efficiency in this pathway. Conclusions: These findings reinforce and expand on prior evidence that Müller glial cell (MGC) biology undergoes significant changes in the early stages of AD, potentially preceding clinical symptoms. The identification of the peripheral retina as a critical yet underexplored region in understanding retinal AD pathology highlights its potential as an accessible biomarker and a potential target for early intervention. Further research will dissect the complex interplay between local Aβ production and clearance to clarify the retina's role in AD progression, paving the way for novel diagnostic and therapeutic strategies.

Background: Retinal amyloid-β (Aβ) accumulation has been detected in Alzheimer's disease (AD) and correlates with brain Aβ deposition, suggesting that the retina may reflect central disease processes. Impaired Aquaporin-4 (AQP4)-mediated glymphatic clearance contributes to Aβ accumulation in AD brains, but whether similar mechanisms affect the retina remains unclear. Objective: This study investigated glymphatic transport and Müller glia cell (MGC) remodeling in 3-month-old female 5xFAD mice. Methods: Fluorescent immunostaining of 5xFAD and wild-type (WT) retinas (n = 5 for each) of AQP4, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS) were performed to evaluate MGC function. To evaluate bulk glymphatic clearance rates along the optic nerve, intravitreal injections of fluorescent Aβ and cadaverine (interstitial fluid indicator) were performed (n = 5 for each WT, AD). Results: 5xFAD retinas showed upregulated AQP4 across all retina layers with increased perivascular localization, particularly in the peripheral retina. Indicators of more efficient perivascular Aβ clearance were observed in peripheral versus the central retina. Elevated GFAP in 5xFAD peripheral retinas indicated glial activation. Despite these changes, tracer-based assays showed no significant differences in bulk glymphatic flow. Conclusions: These findings suggest that retinal Aβ accumulation at this disease stage is unlikely driven by impaired glymphatic clearance but may result from enhanced local Aβ production. While later glymphatic dysfunction cannot be excluded, our results highlight the spatiotemporal dynamics of MGC remodeling and underscore the importance of a) focusing diagnostic imaging studies on the retinal periphery, and b) longitudinal evaluation of retinal amyloid plaque formation mechanisms.