Diabetic retinopathy (DR) is a serious complication of diabetes caused by long-term hyperglycemia that leads to microvascular and neuronal damage in the retina. The molecular mechanisms of DR involve oxidative stress, inflammatory responses, neurodegenerative changes, and vascular dysfunction triggered by hyperglycemia. Oxidative stress activates multiple metabolic pathways, such as the polyol, hexosamine, and protein kinase C (PKC) pathways, resulting in the production of, which in turn promote the formation of advanced glycation end products (AGEs). These pathways exacerbate vascular endothelial damage and the release of inflammatory factors, activating inflammatory signaling pathways such as the NF-κB pathway, leading to retinal cell damage and apoptosis. Additionally, DR involves neurodegenerative changes, including the activation of glial cells, neuronal dysfunction, and cell death. Research on the multiomics molecular markers of DR has revealed complex mechanisms at the genetic, epigenetic, and transcriptional levels. Genome-wide association studies (GWASs) have identified multiple genetic loci associated with DR that are involved in metabolic and inflammatory pathways. Noncoding RNAs, such as miRNAs, circRNAs, and lncRNAs, participate in the development of DR by regulating gene expression. Proteomic, metabolomic and lipidomic analyses have revealed specific proteins, metabolites and lipid changes associated with DR, providing potential biomarkers for the early diagnosis and treatment of this disease. This review provides a comprehensive perspective for understanding the molecular network of DR and facilitates the exploration of innovative therapeutic approaches.

It has been widely established that DNA methyl transferase 1 has a role in the epigenetic regulation of numerous complications including diabetes and inhibition of the same is widely being seen as a potential therapeutic mechanism to treat these complications. Fucoxanthin is a carotenoid that has widely been reported to have a wealth of biological functions. Fucoxanthin is believed to be involved in a broad spectrum of pathways to produce anti-cancer, anti-obesity and antioxidant effects. In this study, fucoxanthin was encapsulated within myristic acid and BSA particles. These particles were tested for their physicochemical properties and fucoxanthin encapsulated within these particles exhibited superior thermal and storage stability. In-vitro digestion tests were carried out further confirming the ability of the encapsulation process to enhance the biological activity of fucoxanthin. The efficacy of fucoxanthin encapsulated particles were evaluated at in-vivo level using diabetic wound models in wistar rats. Fucoxanthin when delivered as an oral supplement in combination with linseed polysaccharide gel as wound dressing managed to significantly accelerate wound healing progression when compared with control and treatment groups. Fucoxanthin when delivered orally also managed to significantly inhibit DNA methyl transferase 1 leading to Angiopoietin 1 upregulation eventually resulting in accelerated wound healing.

Organoids provide 3D structures that replicate native tissues in biomedical research. The development of vascular networks within organoids enables oxygen and nutrient delivery while facilitating metabolic waste removal, which supports organoid growth and maturation. Recent studies demonstrate that vascularized organoid models offer insights into tissue interactions and promote tissue regeneration. However, the current limitations in establishing functional vascular networks affect organoid growth, viability, and clinical translation potential. This review examines the development of vascularized organoids, including the mechanisms of angiogenesis and vasculogenesis, construction strategies, and biomedical applications. The approaches are categorized into in vivo and in vitro methods, with analysis of their specific advantages and limitations. The review also discusses emerging techniques such as bioprinting and gene editing for improving vascularization and functional integration in organoid-based therapies. Current developments in organoid vascularization indicate potential applications in modeling human diseases and developing therapeutic strategies, contributing to advances in translational research.

Endothelial cells (ECs) play pivotal roles in the development and maintenance of tissue homeostasis. During development, vasculature actively involves in organ morphogenesis and functional maturation, through the secretion of angiocrine factors and extracellular matrix components. Islets of Langerhans, essential functional units of glucose homeostasis, are embedded in a dense endothelial capillary network. Islet vasculature not only supplies nutrients and oxygen to endocrine cells but also facilitate the rapid delivery of pancreatic hormones to target tissues, thereby ensuring precise glucose regulation. Diabetes mellitus is a major disease burden and is caused by islet dysfunction or depletion, often accompanied by vessel loss and dysregulation. Therefore, elucidating the regulatory mechanisms of ECs within islets hold profound implications for diabetes therapy. This review provides an overview of recent research advancements on the functional roles of ECs in islet biology, transplantation, and in vitro islet organoid culture.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

This pilot phase II study evaluated the combination of lenvatinib, a multi-kinase inhibitor, and eribulin, a microtubule inhibitor, in patients with advanced solid tumors, including breast carcinoma, lung carcinoma, and sarcoma. Tumor angiogenesis and resistance mechanisms to anti-angiogenic therapies were primary motivations for combining these agents. The trial enrolled 29 patients, heavily pretreated with at least three prior lines of chemotherapy, and aimed to assess the efficacy and safety of the combination therapy. Overall response rate (ORR) was 24% with the highest responses observed in breast cancer (29%) and lung cancer (33%) patients. Median progression-free survival (PFS) was 7.4 months (95% CI 4.5, NA), and overall survival (OS) was 8.2 months (95% CI 6.4 to 14.9). A significant improvement in both OS and PFS was found in vimentin-negative patients, suggesting that vimentin expression may be a predictor of treatment response. The most common treatment-related adverse events (TRAEs) were oral mucositis, fatigue, neutropenia, and nausea. Grade ≥3 TRAEs included neutropenia (34.5%), febrile neutropenia (17.2%), and hypertension (13.8%), with one fatal case of sepsis reported. While the study demonstrated the potential of lenvatinib and eribulin in advanced solid tumors, particularly breast and lung cancers, it also highlighted the need for further investigation into biomarkers like vimentin to predict therapeutic outcomes. The combination therapy was manageable in terms of safety and toxicity, with a predictable safety profile. These findings suggest that lenvatinib and eribulin represent a promising treatment strategy for advanced, heavily pretreated solid tumors, warranting further exploration in larger clinical studies.

This study aimed to identify the anatomical course of collateral vessels in chronic lower-extremity arterial occlusive disease to optimize intramuscular injection sites for angiogenesis therapy.

We retrospectively analyzed 35 limbs with superficial femoral artery (SFA) occlusion and 17 limbs with 3 crural artery occlusion using 1-mm slice contrast-enhanced computed tomography. Collateral vessels (≥1 mm) connecting the common femoral to popliteal arteries, and popliteal to foot arteries were identified. Donor and recipient arteries, and vessel courses were documented.

In SFA occlusion, 49 collateral vessels were identified. The deep femoral artery was the sole donor. Recipient arteries were predominantly the lateral (94%) and medial (6%) superior genicular arteries. Seventy-one percent (35 of 49) of collaterals ran within the short head of the biceps femoris. In crural artery occlusion, 17 collaterals were found. Donor arteries included the peroneal (29%), posterior tibial (24%), and combinations thereof. Recipient arteries were the anterior tibial (53%), plantar (29%), and dorsalis pedis (18%). All collaterals coursed through the soleus muscle, with 35% traversing the posterior tibial muscle.

Collateral vessels in chronic lower-extremity arterial occlusive disease exhibit preferential development within specific muscles. In SFA occlusion, collaterals develop predominantly within the short head of the biceps femoris, while in crural artery occlusion, collaterals develop within the soleus muscle. These findings suggest that targeted intramuscular injections, guided by anatomical knowledge of collateral pathways, may enhance angiogenesis therapy efficacy.

Drugs that inhibit tumor angiogenesis, promote vascular normalization and improve the tumor microenvironment. However, their application is limited by adaptive or compensatory resistance. Chondroitin sulfate (CS) regulates numerous proteins including pro-angiogenic growth factors, for whom binding affinity depends on sulfation of CS. In this study, we aimed to determine how sulfation of natural tetrasaccharides and hexasaccharides of CS affected binding to the vascular endothelial growth factor (VEGF-A) and fibroblast growth factor 2 (FGF-2). Twenty-eight CS oligosaccharide isomers were obtained by preparative HPLC, tagged with the AEAB fluorescent linker, and identified using an improved chemical derivatization strategy combined with tandem mass spectrometry. CS oligosaccharide microarrays revealed that VEGF-A and FGF-2 bound preferentially to highly sulfated CS, and the GalNAc(4S)GlcA(2S)GalNAc(6S) sequence was found to be indispensable for binding to these proteins. By integrating glycan microarrays with computational modeling, this study revealed the relationship between the structure of CS and its interactions with pro-angiogenic factors. The degree and the specific sulfation patterns on CS should be taken into account when designing anti-angiogenic drugs.

Age-related macular degeneration (AMD) poses a significant threat to visual health among the elderly, necessitating urgent preventive measures as the global population ages. Extensive research has implicated oxidative stress (OS)-induced retinal damage as a primary contributor to AMD pathogenesis, prompting investigations into potential therapeutic interventions. Among the various nutrients studied for their potential in AMD risk reduction, antioxidants have shown promise, with initial findings from the Age-Related Eye Disease Study suggesting a correlation between antioxidant supplementation and decreased AMD progression. This article explores the scientific foundation supporting the therapeutic efficacy of tocotrienol-rich fraction (TRF) as a viable candidate for slowing AMD progression, based on interventional studies. AMD is characterized by OS, inflammation, dysregulated lipid metabolism, and angiogenesis, all of which TRF purportedly addresses through its potent anti-inflammatory, lipid-lowering, antiangiogenic, and antioxidant properties. The review underscores TRF's promising attributes, aiming to deepen understanding of AMD pathogenesis and advocate for TRF-based pharmacological interventions to enhance therapeutic outcomes. Given the pressing need for effective AMD treatments, TRF represents a promising avenue for intervention, offering hope for improved vision outcomes and enhanced quality of life for individuals affected by this debilitating condition.

Rheumatoid arthritis (RA) involves synovial tissue proliferation, inflammation, and angiogenesis, and contributes to joint destruction. Angiogenesis is a key therapeutic target for the treatment of RA, and Janus kinase (JAK) inhibitors have emerged as a promising therapy. In this study, we compared the inhibitory effects of five JAK inhibitors, including tofacitinib (TOF), baricitinib, peficitinib, upadacitinib, and filgotinib, on interleukin (IL)-6-induced inflammation in RA synovial tissues. All five inhibitors effectively suppressed IL-6-induced inflammatory and angiogenic factors, including vascular endothelial growth factor, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, by inhibiting the phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. Overall, the results suggest that while all five JAK inhibitors are effective in reducing IL-6-induced inflammatory and angiogenic factors, their efficacy may differ owing to specific molecular mechanisms and pharmacological properties.

The emergence of tissue engineering (TE) has provided new vital means for human body tissue/organ repair. TE scaffolds can provide temporary structural support for cell attachment, growth, and proliferation, until the body restores the mechanical and biological properties of the host tissues. Since native tissues are inhomogeneous and in many situations are graded structures for performing their unique functions, graded scaffolds have become increasingly attractive for regenerating particular types of tissues, which aim to offer a more accurate replication of native interactions and functions. Importantly, the advances introduced by additive manufacturing (AM) have now enabled more design freedom and are capable of tailoring both structural and compositional gradients within a single scaffold. In this context, graded TE scaffolds fabricated by AM technologies have been attracting increasing attention. In this review, we start with an introduction of common graded structures in the human body and analyse the advantages and strengths of AM-formed graded scaffolds. Various AM technologies that can be leveraged to produce graded scaffolds are then reviewed based on non-cellular 3D printing and cell-laden 3D bioprinting. The comparisons among various AM technologies for fabricating graded scaffolds are presented. Subsequently, we propose several types of gradients, structural, material, biomolecular and multi-gradients for scaffolds, and highlight the design methods, resulting mechanical properties and biological responses. Finally, current status, challenges and perspectives for AM in developing graded scaffolds are exhibited and discussed.

The tumor microenvironment is composed of tumor cells and various stromal cell types, such as immune cells, fibroblasts, and vascular cells. Signaling interactions between tumor and stromal cells orchestrate the tumor microenvironment's contribution to tumor progression. Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies indicate that tumor cell-derived ANGPTL2 serves as a tumor promoter. However, recent studies suggest that tumor stroma-derived ANGPTL2 shows tumor-suppressive activity by enhancing anti-tumor immune responses, supporting a dual function for ANGPTL2 in cancer pathology. Such complexity can complicate development of effective therapeutic strategies targeting ANGPTL2. In this Review, we focus on ANGPTL2 activity in the tumor microenvironment and its function in anti-cancer immunity.

To study the real-world outcomes of intravitreal faricimab (IVF) in long-standing neovascular age-related macular degeneration (nAMD) over a 1-year study period.

Retrospective single-center cohort study of patients with previously treated nAMD receiving IVF with at least 12 months of follow-up. Main outcome measures include injection intervals, visual acuity (VA), and optical coherence tomography features.

A total of 263 eyes from 217 patients received 6.4 ± 2.3 IVF injections over 1 year. Injection interval increased after switching to IVF (5.9 ± 1.8 vs. 7.6 ± 2.4 weeks) ( P < 0.01). There was no improvement in VA after switching to IVF at any time period ( P > 0.15). Average CST decreased after the first IVF injection and was sustained for 1 year (313.7 ± 96.0 vs. 288.2 ± 80.6 µ m) ( P < 0.01). There was a statistically significant resolution of subretinal fluid but not IRF at all time points (40.8%-50.4%; P < 0.01). Persistent fluid after the first IVF injection was resolved in 34.4% (n = 45) by 1 year. IVF was discontinued in 31 eyes (11.8%), four (1.6%) that experienced intraocular inflammation.

Long-standing nAMD eyes switched to IVF experienced a significant extension in injection interval, stable visual acuity, improvement in CST, and resolution of fluid on OCT in many patients over 1 year.

The purpose of this study was to assess whether diabetic NV is perfused by the arterial or the venous circulation.

This is a retrospective, consecutive case series evaluating patients with proliferative diabetic retinopathy (PDR) imaged with ultrawide-field (UWF) fluorescein angiography (FA). Areas of neovascularization elsewhere (NVE) and neovascularization of the disc (NVD) were assessed. Perfusion was defined as arterial, arteriovenous, or venous if the area of diabetic neovascularization (NV) began to hyperfluoresce either prior, during, or after laminar venous flow, respectively.

A total of 180 eyes from 176 patients with 928 NV were identified (830 NVE, 98 NVD). Of those, 5.1% of NVE were classified as arterial and 58.2% of NVD were classified as arterial. The remaining NV were classified as arteriovenous except for a small subset (6.1%) which were indeterminate. None of the NV were classified as venous. Noteworthy examples demonstrated NV that nearly fully perfused prior to any detectable fluorescence within nearby veins as well as clear shunting of blood from a feeding artery to a draining vein.

UWF FA images suggest that some NV is perfused by retinal arteries. This may be useful in devising strategies for early detection and treatment of NV precursors.

What is known • Diabetic retinal neovascularization has long been thought to be perfused by the retinal venous circulation. • Vascular endothelial growth factor has been shown to play key roles in both angiogenesis and arteriogenesis. What is new • Ultrawide-field fluorescein angiography demonstrates that at least some diabetic neovascularization is perfused by the retinal arterial circulation. • This supports the hypothesis that diabetic neovascularization may arise from arterially-perfused intraretinal microvascular abnormalities in the capillary bed.

Gastric-type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high-risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti-angiogenic regimens in real-world GEA patients.

Patients with GEA were enrolled between February 2012 and March 2023, and their clinicopathological characteristics were collected from their medical records. The patients were categorized into groups based on whether they received anti-angiogenic treatments or not. Survival analysis was conducted using the Kaplan-Meier method.

A total of 43 GEA patients were enrolled in this study, with 23 cases who received anti-angiogenic drugs (nine received them as the primary treatment, 12 as first-line therapy after recurrence/metastasis, and two as second-line therapy) as the observation group. The other 20 patients who received similar treatments without the anti-angiogenic regimens serve as the control group. Compared to the control group, the addition of anti-angiogenic drugs as the primary treatment mildly extended progression-free survival (PFS) while not being statistically significant (16 months vs 11 months, p = 0.744). The negative results were also observed in 12 patients who started anti-angiogenic therapy as first-line therapy after recurrence/metastasis (8.5 months vs 9 months, p = 0.518). As for the overall survival (OS), no benefits were detected in either patients who started the anti-angiogenic therapy as primary or subsequent treatments (p = 0.499 and 0.450, respectively).

We firstly evaluated the efficacy of anti-angiogenic drugs in treating patients with GEA. Although with a small sample size, our preliminary results clearly proposed that the anti-angiogenic therapy failed in suppressing tumors and should not be a preferred choice for GEA. As a much rarer tumor without standard treatments, we herein warned of a pitfall for gynecologic oncologists when facing this malignancy.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

Vascularization is a critical component of tissue engineering research and is essential for enhancing the success rate of tissue construction and function. Over the past decade, researchers have explored various methods to construct in vitro vascular networks, including 3D printing, cell sphere technology, and microfluidics. Microfluidic technology has garnered significant attention due to its notable advantages in precision, controllability, flexibility, and applicability. It can be primarily classified into two modes: (i) the pre-designed mode, which involves creating vascular networks by pre-designing vascular channels and seeding endothelial cells, encompassing microfluidic chips and microfluidic spinning technologies; and (ii) the self-assembly mode, where cell spheres are fabricated using microfluidic technology and subsequently self-assemble into vascular networks. In this review, we first provide a brief overview of the normal physiological and pathological characteristics of vascular networks, followed by a discussion of the factors to be considered in designing in vitro vascular networks, and conclude with an examination of the classification of technologies for the preparation of microfluidic vascular networks and recent advancements. It is anticipated that in vitro vascular network models will soon be successfully applied in regenerative medicine and drug development.

A correlation between inflammation and cerebral small vessel disease (CSVD) has been hypothesized by earlier observational research, while this correlation has not been well established. Considering the significant clinical value of this causality determination, Mendelian randomization (MR) was implemented to investigate the causality between inflammatory cytokines and CSVD radiological lesions.

Using the publicly available Genome-Wide Association Study (GWAS) datasets, a bidirectional two-sample MR analysis was employed to infer causality between 91 inflammatory cytokines and CSVD phenotypes [white matter hyperintensity (WHM), fractional anisotropy (FA), mean diffusivity (MD), cerebral microbleeds (CMBs), and lacunar stroke]. A set of methods was used for sensitivity analysis, including Cochran's Q test, MR-Egger intercept method, and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Furthermore, the strength of causality was assessed using the Bonferroni correction.

Our research discovered a mutually predictive bidirectional link between CSVD phenotypes and inflammatory cytokines. Following the application of the Bonferroni correction, fibroblast growth factor 21 (FGF-21) was significantly inversely correlated with an increased risk of CMBs (OR = 0.579, 95 % CI = 0.425-0.789, P = 0.00055). Using sensitivity analysis, heterogeneity, and horizontal pleiotropy were not detected.

In this investigation, we established the causality between CSVD and inflammatory cytokines, with FGF-21 in particular significantly reducing the risk of CMBs. With further validation, these findings may provide new targets for the prevention, detection, and intervention of CSVD.

Highly specialized gap junctions play an important role in the interaction between endothelial (EC) and multipotent mesenchymal stromal cells (MSC). Inhibition of gap junctions with a specific inhibitor carbenoxolone attenuates the effects of the medium conditioned by MSC-EC co-culture on proliferation and migration of cultured EC. In conditioned medium from co-culture, the levels of angiogenic mediators (VEGF-A, FGF-2, MCP-1, etc.) were decreased, which apparently determines lower angiogenic effect of the conditioned medium on the growth of the vascular network in the chorioallantois membrane of quail embryo in ovo. Suppression of communication through gap junctions in associations of MSC and EC, the structural and functional units of physiological and reparative angiogenesis, can directly reduce the level of proangiogenic mediators in the microenvironment, which, in turn, can help to control the regulation of vascular function in pathologies.

Deep partial-thickness burns have a significant impact on both the physical and mental health of patients. Our previous study demonstrated human Umbilical Cord Mesenchymal stem cells (hUCMSCs) could enhance the healing of severe burns in small animal burn models, such as rats. Furthermore, our team has developed a deep partial-thickness burn model in Bama miniature pigs, which can be utilized for assessing drug efficacy in preclinical trials for wound healing. Therefore, this study further determine the optimal dosage of hUCMSCs in future clinical practice by comparing the efficacy of low-to-high doses of hUCMSCs on deep partial-thickness burn wounds in Bama miniature pigs.

The male Bama miniature pigs (N = 8, weight: 23-28 kg and length: 71-75 cm) were used to establish deep partial-thickness burn models, which used a continuous pressure of 1 kg and contact times of 35 s by the invented electronic burn instrument at 100℃ to prepare 10 round burn wounds with diameter of 5 cm according to our previous report. And then, 0 × 10^7, 1 × 10^7, 2 × 10^7, 5 × 10^7 and 1 × 10^8 doses of hUCMSCs were respectively injected into burn wounds of their corresponding groups. After treatment for 7, 14 and 21 days, the burned wound tissues were obtained for histological evaluation, including HE staining for histopathological changes, immunohistochemistry for neutrophil (MPO+) infiltration and microvessel (CD31+) quantity, as well as Masson staining for collagen deposition. The levels of inflammatory factors TNF-α, IL-1β, IL-10 and angiogenesis factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), as well as collagen type-I/type-III of the wound tissues were quantified by ELISA.

All of doses hUCMSCs can significantly increase wound healing rate and shorten healing time of the deep partial-thickness burn pigs in a dose-dependent manner. Furthermore, all of doses hUCMSCs can significantly promote epithelialization and decreased inflammatory reaction of wound, including infiltration of inflammatory cells and levels inflammatory factors. Meanwhile, the amounts of microvessel were increased in all of doses hUCMSCs group than those in the burn group. Furthermore, the collagen structure was disordered and partially necrotized, and ratios of collagen type-I and type-III were significantly decreased in burn group (4:1 in normal skin tissue), and those of all hUCMSCs groups were significantly improved in a dose-dependent manner. In a word, 1 × 10^8 dose of hUCMSCs could regenerate the deep partial-thickness burn wounds most efficaciously compared to other dosages groups and the burn group.

This regenerative cell therapy study using hUCMSCs demonstrates the best efficacy toward a high dose, that is dose of 1 × 10^8 of hUCMSCs was used as a reference therapeutic dose for treating 20 cm2 deep partial-thickness burns wound in future clinical practice.

In the body, capillary beds fulfill the metabolic needs of cells by acting as the sites of diffusive transport for vital gasses and nutrients. In artificial tissues, replicating the scale and complexity of capillaries has proved challenging, especially in a three-dimensional context. In order to better develop thick artificial tissues, it will be necessary to recreate both the form and function of capillaries. Here we demonstrate a top-down method of patterning hydrogels using sacrificial templates formed from thermoresponsive microfibers whose size and architecture approach those of natural capillaries. Within the resulting microchannels, we cultured endothelial monolayers that remain viable for over three weeks and exhibited functional barrier properties. Additionally, we cultured endothelialized microchannels within hydrogels containing fibroblasts and characterized the viability of the co-cultures to demonstrate this approach's potential when applied to cell-laden hydrogels. This method represents a step forward in the evolution of artificial tissues and a path towards producing viable capillary-scale microvasculature for engineered organs.

Retinal vascular diseases encompass several retinal disorders, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and retinal vascular occlusion; these disorders are classified as similar groups of disorders due to impaired retinal vascularization. The aim of this review is to address the main signaling pathways involved in the pathogenesis of retinal vascular diseases and to identify crucial molecules and the importance of their interactions. Vascular endothelial growth factor (VEGF) is recognized as a crucial and central molecule in abnormal neovascularization and a key phenomenon in retinal vascular occlusion; thus, anti-VEGF therapy is now the most successful form of treatment for these disorders. Interaction between angiopoietin 2 and the Tie2 receptor results in aberrant Tie2 signaling, resulting in loss of pericytes, neovascularization, and inflammation. Notch signaling and hypoxia-inducible factors in ischemic conditions induce pathological neovascularization and disruption of the blood-retina barrier. An increase in the pro-inflammatory cytokines-TNF-α, IL-1β, and IL-6-and activation of microglia create a persistent inflammatory milieu that promotes breakage of the blood-retinal barrier and neovascularization. Toll-like receptor signaling and nuclear factor-kappa B are important factors in the dysregulation of the immune response in retinal vascular diseases. Increased production of reactive oxygen species and oxidative damage follow inflammation and together create a vicious cycle because each factor amplifies the other. Understanding the complex interplay among various signaling pathways, signaling cascades, and molecules enables the development of new and more successful therapeutic options.

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5'-GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti-inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3',5'-cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease-modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field.

JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis.

RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining.

Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures.

The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors.

The vascular endothelial growth factor receptor (VEGFR) system is the key component for controlling angiogenesis in cancer cells. Blocking vascular endothelial growth factor receptor 2 (VEGFR2) signalling is one of the most promising approaches to hindering angiogenesis and the subsequent growth of cancer cells. The USFDA-approved small-molecule drugs targeting VEGFR-2 are developing drug resistance over the course of chemotherapy, and cardiac-related side effects are consistently being reported; hence, there is an urgent need for more safe and effective anticancer molecules. The present review focuses on the structure and physiology of VEGFR-2 and its involvement in the progression of cancer cells. The recent updates from the last five years through papers and patents on structure-activity relationships, pharmacophoric attributes, molecular docking interactions, antiangiogenic assays, cancer cell line studies, and the potencies (IC50) of VEGFR-2 inhibitors are discussed herein. The common structural framework requirements, such as the Asp-Phe-Gly (DFG) motif of VEGFR-2 interacting with the HBD-HBA region in the ligand molecules, the central aryl ring occupying the linker region, and a variety of bio-isosteres, can enhance activity against VEGFR-2. At one end, the heteroaryl moiety is essential for interaction within the ATP-binding site of VEGFR-2, while the terminal hydrophobic tail occupies the allosteric binding site. Three to five bond spacers between the heteroaryl and HBD-HBA regions provided a better result towards VEGFR-2 inhibition, mirroring the behaviors of standard drugs. The in-depth analysis of recent updates on VEGFR-2 inhibitors presented in this paper will help prospective synthetic and medicinal chemists to discover new lead molecules for the treatment of various cancers.

Fucoxanthin, a dietary carotenoid, is predominantly found in edible brown algae and is commonly consumed worldwide. Fucoxanthin has been shown to possess beneficial health activities such as antidiabetic, anti-inflammatory, antimutagenic, and antiobesity; however, the effects of fucoxanthin on VEGF-mediated angiogenesis and its possible binding with VEGF are unknown. Here, different lines of evidence supported the suppressive roles of fucoxanthin in VEGF-mediated angiogenesis. In human umbilical vein endothelial cells, fucoxanthin remarkedly suppressed VEGF-mediated cell proliferative, migration, and invasive abilities, as well as tube formation, without cytotoxicity. In addition, fucoxanthin inhibited the subintestinal vessel formation of zebrafish in vivo. In signaling cascades, fucoxanthin was proposed to interact with VEGF, thus attenuating VEGF's functions in activating the VEGF receptor and its related downstream signaling, i.e., phosphorylations of MEK and Erk. Fucoxanthin also significantly blocked VEGF-triggered ROS formation. Furthermore, the outcomes of applying fucoxanthin in cancer cells were identified, which included (i) inhibiting VEGF-mediated cell proliferation and migration and (ii) inhibiting NF-κB translocation via limiting MMP2 expression. These lines of investigations supported the antiangiogenic roles of fucoxanthin, as well as reviewing its signaling mechanisms, in blocking the VEGF-triggered responses. The results would benefit the potential development of fucoxanthin for the prevention and treatment of angiogenesis-related diseases.

Angiogenesis, the biological mechanism by which new blood vessels are generated from existing ones, plays a vital role in growth and development. Effective preclinical screening is necessary for the development of medications that may enhance or inhibit angiogenesis in the setting of different disorders. Traditional in vitro and, in vivo models of angiogenesis are laborious and time-consuming, necessitating advanced infrastructure for embryo culture.

A challenge encountered by researchers studying angiogenesis is the lack of appropriate techniques to evaluate the impact of regulators on the angiogenic response. An ideal test should possess reliability, technical simplicity, easy quantifiability, and, most importantly, physiological relevance. The CAM model, leveraging the extraembryonic membrane of the chicken embryo, offers a unique combination of accessibility, low cost, and rapid development, making it an attractive option for angiogenesis assays. This review evaluates the strengths and limitations of the CAM model in the context of its anatomical and physiological properties, and its relevance to human pathophysiological conditions. Its abundant capillary network makes it a common choice for studying angiogenesis. The CAM assay serves as a substitute for animal models and offers a natural setting for developing blood vessels and the many elements involved in the intricate interaction with the host. Despite its advantages, the CAM model's limitations are notable. These include species-specific responses that may not always extrapolate to humans and the ethical considerations of using avian embryos. We discuss methodological adaptations that can mitigate some of these limitations and propose future directions to enhance the translational relevance of this model. This review underscores the CAM model's valuable role in angiogenesis research and aims to guide researchers in optimizing its use for more predictive and robust preclinical studies.

The highly vascularized chorioallantoic membrane (CAM) of fertilized chicken eggs is a cost-effective and easily available method for screening angiogenesis, in comparison to other animal models.

Angiogenesis plays a pivotal role in the growth and metastasis of tumors, including the development and progression of cutaneous lymphomas. The chick embryo CAM model has been utilized in various studies to assess the growth rate, angiogenic potential, and metastatic capability of different tumor types and malignant cell lines. However, the precise mechanisms of angiogenesis in CTCL and the influence of Ruxolitinib or Resminostat on angiogenesis in hematological malignancies and solid tumors are not well understood. Recent in vitro and in vivo data have demonstrated the synergistic inhibition of tumorigenesis and metastasis in experimental models of CTCL when using the combination of Resminostat (HDACi) with Ruxolitinib (JAKi). The present work aims to elucidate the effects of this combination on the tumor microenvironment's vascular components. We investigated the effects of Ruxolitinib (JAKi) in combination with Resminostat (HDACi) treatment in transendothelial migration of CTCL cells (106 MyLa and SeAx) by using a transwell-based transendothelial migration assay and tumor angiogenesis in vivo. We used the CTCL chick embryo CAM model with xenografted tumors derived from implanted MyLa and SeAx cells and administered topically 15 μM ruxolitinib and 5 μM Resminostat every two days during a 5-day period. JAKi and HDACi inhibited CTCL cell transendothelial migration by 75% and 82% (p < 0.05) in both CTCL engrafted cells (MyLa and SeAx, respectively) compared to the untreated group. Moreover, the combination of ruxolitinib with resminostat blocked angiogenesis by significantly reducing the number of blood vessel formation by 49% and 34% in both MyLa and SeAx, respectively (p < 0.05), indicating that the proposed combination exerted significant anti-angiogenic effects in the CAM CTCL model. Overall, these data provide valuable insights into potential therapeutic strategies targeting angiogenesis in CTCL, paving the way for more effective treatment approaches in the future.

Injectable, tissue mimetic, bioactive, and biodegradable hydrogels offer less invasive regeneration and repair of tissues. The monitoring swelling and in vitro degradation capacities of hydrogels are highly important for drug delivery and tissue regeneration processes. Bioactivity of bone tissue engineered constructs in terms of mineralized apatite formation capacity is also pivotal. We have previously reported in situ forming chitosan-based injectable hydrogels integrated with hydroxyapatite and heparin for bone regeneration, promoting angiogenesis. These hydrogels were functionalized by glycerol and pH to improve their mechano-structural properties. In the present study, functionalized hybrid hydrogels were investigated for their swelling, in vitro degradation, and bioactivity performances. Hydrogels have degraded gradually in phosphate-buffered saline (PBS) with and without lysozyme enzyme. The percentage weight loss of hydrogels and their morphological and chemical properties, and pH of media were analyzed. The swelling ratio of hydrogels (55%-68%(wt), 6 h of equilibrium) indicated a high degree of cross-linking, can be suitable for controlled drug release. Hydrogels have gradually degraded reaching to 60%-70% (wt%) in 42 days in the presence and absence of lysozyme, respectively. Simulated body fluid (SBF)-treated hydrogels containing hydroxyapatite-induced needle-like carbonated-apatite mineralization was further enhanced by heparin content significantly.

Due to its anti-angiogenic properties, trebananib is frequently employed in the treatment of cancer patients, particularly those with ovarian cancer. We conducted a meta-analysis to assess the efficacy and safety profile of trebananib in combination with other drugs for treating both ovarian and non-ovarian cancer patients.

Our search encompassed PubMed, Medline, Cochrane, and Embase databases, with a focus on evaluating study quality. Data extraction was conducted from randomized controlled trials (RCTs), and RevMan 5.3 facilitated result analysis.

Combining trebananib with other drugs extended progression-free survival (PFS) [HR 0.81, (95%CI: 0.65, 0.99), p = 0.04] and overall survival (OS) [HR 0.88, (95%CI: 0.79, 1.00), p = 0.04] in ovarian cancer patients. Ovarian cancer patients exhibited a higher objective response rate (ORR) with trebananib compared to non-ovarian cancer cohorts. Moreover, the incorporation of trebananib into the standard treatment regimen for malignant tumors did not significantly elevate drug-related adverse events [RR 1.05, (95% CI: 1.00, 1.11), p = 0.05].

Trebananib plus other drugs can improve the PFS, OS and ORR in patients with cancer, especially ovarian cancer. Our recommendation is to use trebananib plus other drugs to treat advanced cancer, and to continuously monitor and manage drug-related adverse events.

PROSPERO (No. CRD42023466988).

Glioblastoma (GBM) is the most prevalent central nervous system tumour (CNS). Patients with GBM have a dismal prognosis of 15 months, despite an intensive treatment schedule consisting of surgery, chemoradiation and concurrent chemotherapy. In the last decades, many trials have been performed investigating small molecule inhibitors, which target specific genes involved in tumorigenesis. So far, these trials have been unsuccessful, and standard of care for GBM patients has remained the same since 2005. This review gives an overview of trials investigating small molecule inhibitors on their own, combined with chemotherapy or other small molecule inhibitors. We discuss possible resistance mechanisms in GBM, focussing on intra- and intertumoral heterogeneity, bypass mechanisms and the influence of the tumour microenvironment. Moreover, we emphasise how combining inhibitors can help overcome these resistance mechanisms. We also address strategies for improving trial outcomes through modifications to their design. In summary, this review aims to elucidate different resistance mechanisms against small molecule inhibitors, highlighting their significance in the search for novel therapeutic combinations to improve the overall survival of GBM patients.

Rheumatoid arthritis (RA) is one of the most common forms of arthritis. Extracorporeal shockwave therapy (ESWT) has been identified as a viable alternative therapeutic approach in light of the present protracted clinical course of pharmacological treatment, and changes in levels of marker proteins in the blood samples of RA patients can be utilized to assess treatment outcomes.

A randomized controlled trial was conducted involving forty patients diagnosed with rheumatoid arthritis (RA) who were assigned randomly to two groups. The first group received a combination of diclofenac and methotrexate (MTX) consisting of 25 mg of diclofenac administered thrice daily and 15 mg of MTX administered once weekly. Individual follow-up assessments were carried out after 7 and 14 days. Meanwhile, patients in the second group underwent two sessions of Extracorporeal Shockwave Therapy (ESWT), with a 7-day interval between sessions. Evaluations were conducted on day 7 and day 14. Patients who displayed pain control and stability were advised to continue the treatment, whereas those who had inflammation and discomfort were administered specific medications, and their progress was closely monitored until day 28. Blood samples were collected from both groups prior to treatment, after the first treatment, and after the second treatment. Four marker proteins (NRP-1, CELF-6, COX-2, and RGS-1) and two inflammatory cytokines (IL-6 and IL-17) were measured using western blot and RT-PCR techniques. A statistical analysis was conducted on the levels of specific proteins and inflammatory factors before and after treatment to evaluate its impact.

Both groups exhibited statistically significant differences in the serum level of target biomarkers before and after the intervention. However, the ESWT group demonstrated a more noticeable effect, while the diclofenac + MTX group exhibited a delayed anti-inflammatory effect compared to ESWT.

Both treatments significantly improved joint function, relieved pain, and reduced inflammation in patients. However, ESWT demonstrated a more prominent clinical analgesic effect compared to the combination treatment of diclofenac and MTX. Furthermore, ESWT produced a more immediate and noteworthy anti-inflammatory impact by regulating NRP-1 expression, a trophic factor receptor that facilitates vascular endothelial cell migration and tissue repair through angiogenesis, and regulating RGS-1 to limit inflammatory signal transmission and immune cell activation.

This study targeted to explore circUQCRC2's role and mechanism in childhood asthma. A mouse model of ovalbumin-induced asthma was established to evaluate the effects of circUQCRC2 on childhood asthma in terms of oxidative stress, inflammation, and collagen deposition. The effects of circUQCRC2 on platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cells (SMCs) were evaluated, the downstream mRNA of miRNA and its associated pathways were predicted and validated, and their effects on asthmatic mice were evaluated. circUQCRC2 levels were upregulated in bronchoalveolar lavage fluid of asthmatic mice and PDGF-BB-treated SMCs. Depleting circUQCRC2 alleviated tissue damage in asthmatic mice, improved inflammatory levels and oxidative stress in asthmatic mice and PDGF-BB-treated SMC, inhibited malignant proliferation and migration of SMCs, and improved airway remodeling. Mechanistically, circUQCRC2 regulated VEGFA expression through miR-381-3p and activated the NF-κB cascade. circUQCRC2 knockdown inactivated the NF-κB cascade by modulating the miR-381-3p/VEGFA axis. Promoting circUQCRC2 stimulates asthma development by activating the miR-381-3p/VEGFA/NF-κB cascade. Therefore, knocking down circUQCRC2 or overexpressing miR-381-3p offers a new approach to treating childhood asthma.

This study investigate the histopathological changes and VEGF, IL-1β, and IL-6 immunoreactivities in cornea treated with Coenzyme Q10 (CoQ10) in a Streptozocin (STZ) induced diabetic rat model.

A total of 20 male Wistar Albino rats including a group of STZ diabetic rats, diabetic rats treated with CoQ10, rats were given CoQ10 without being diabetic and a Control group were included the study. The groups were followed up for 2 months. Eye tissues were stained with Hematoxylin-Eosin (HE), Periodic Acid-Schiff (PAS), and immunohistochemical staining (IHC).

The mean corneal thickness was found to be lower in the group with DM (126,62 ± 18,1) compared to the other groups. However, this decrease was found to be significant only in comparison with the control group (181,75 ± 13,87) (p = 0.000). In diabetic corneas, PAS positivity was observed in in Descemet's membrane (p = 0.021). Staining with VEGF, IL-1β, IL-6antibodies was found to be lower in the DM+CoQ10 group compared to the group with DM (p < 0.001, p < 0.001, p < 0.001).

We observed that diabetes increases inflammation and tendency to angiogenesis in the corneal tissue, and CoQ10 treatment reduces the corneal thickness, inflammation, and tendency to angiogenesis caused by diabetes.

Investigating the potential role of CYR61 in recurrent pregnancy loss is critical for developing diagnostic approaches and treatments for recurrent pregnancy loss.

In this prospective case-control study, we have investigated the expression patterns of CYR61 in blood samples from participants with recurrent pregnancy loss in their medical history and control group (n=20 vs n=10). Peripheral blood mononuclear cells from study and control groups were isolated and the expression patterns of the CYR61 gene were determined by real-time semi-quantitative reverse transcriptase PCR.

A significant decrease in CYR61 gene expression was demonstrated in patients with two or more clinically recognized miscarriages compared with patients without miscarriages or with a history of miscarriage (p<0.01), which may make the CYR61 gene a potential candidate for predicting the risk of recurrent pregnancy loss.

This study provides a basis for a detailed investigation of candidate biomarkers and molecular players involved in the development of recurrent pregnancy loss and for the development of potential treatment approaches to prevent recurrent pregnancy loss.

Angiopoietin-2 (Ang-2) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRASQ61R mutation has been found in the lesions of KLA patients.

Our study tested the hypothesis that the NRASQ61R mutation drives elevated Ang-2 expression in endothelial cells. Ang-2 was measured in human endothelial progenitor cells (EPC) expressing NRASQ61R and a genetic mouse model with endothelial targeted NRASQ61R. To determine the signaling pathways driving Ang-2, NRASQ61R EPC were treated with signaling pathway inhibitors.

Ang-2 levels were increased in EPC expressing NRASQ61R compared to NRASWT by Western blot analysis of cell lysates and ELISA of the cell culture media. Ang-2 levels were elevated in the blood of NRASQ61R mutant mice. NRASQ61R mutant mice also had reduced platelet counts and splenomegaly with hypervascular lesions, like some KLA patients. mTOR inhibitor rapamycin attenuated Ang-2 expression by NRASQ61R EPC. However, MEK1/2 inhibitor trametinib was more effective blocking increases in Ang-2.

Our studies show that the NRASQ61R mutation in endothelial cells induces Ang-2 expression in vitro and in vivo. In cultured human endothelial cells, NRASQ61R drives elevated Ang-2 through MAP kinase and mTOR-dependent signaling pathways.

Oral squamous cell carcinoma (OSCC) is a serious health disease that can lead to a reduced quality of life or even death. It ranks sixth in terms of cancer expansion. It is one of India's primary causes of natural death. In OSCC such potentially malignant Disorders (PMDs) are precancerous lesions with such a high risk of progression. Tumor angiogenesis is a one of the basic biomarkers that may influence the proliferation of a precancerous lesion into the cancerous lesion. Tropomyosin receptor kinase B (TrkB), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) also play important roles in carcinogenesis by promoting angiogenesis. The construction of new vessels of blood from existing vasculature is referred as angiogenesis.

To get deep insights of immunohistochemistry expression of VEGF, BDNF, and TRKB in oral epithelial dysplasia (OED), verrucous carcinoma (VC), and OSCC.

The study included 100 formalin-fixed paraffin-embedded tissue blocks from 20 cases of OED, 20 cases of VC, and 60 cases of OSCC [20 cases of well-differentiated oral squamous cell carcinoma (WD-OSCC), 20 cases of moderately differentiated oral squamous cell carcinoma (MD-OSCC), and 20 cases of poorly differentiated oral squamous cell carcinoma (PD-OSCC). The staining intensity and distribution of VEGF, BNDF, and TrkB were examined and statistically analyzed using analysis of variance (ANOVA), post hoc Bonferroni test, independent t-test, Pearson's Chi-square test, and Pearson's correlation coefficient test.

The immunoexpression of VEGF, BDNF, and TrkB was found to be elevated in the order of OEDs, VC, and OSCC. The percentage of positive was highest in PD-OSCC, followed by MD-OSCC and WD-OSCC.

Based on our findings, angiogenesis plays a significant role in tumor growth and metastasis. A substantial relationship was discovered between VEGF, BDNF, TrkB expression, and increases in vascularity throughout the transition from OEDs to VCs and OSCCs.

Ultrasound (US) imaging has been observed to underestimate tumor size in clinical practice. This study aims to compare the size measurements of breast cancer and benign tumors using two-dimensional ultrasound (2DUS) and contrast-enhanced ultrasound (CEUS).

The study included 42 clinically confirmed breast cancer and 47 benign breast tumors. Two experienced physicians independently measured the maximal longitudinal and transverse diameters of the masses in 2DUS and CEUS. All analyses were performed in R (4.2.2) and GraphPad Prism 6.

The maximal longitudinal and transverse diameters of breast cancer measured by CEUS were 26.61 ± 0.21% and 26.24 ± 0.19% larger compared with 2DUS, and benign breast tumors had an 11.74 ± 0.21% and 11.06 ± 0.14% increase in size compared with 2DUS. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) for the difference between 2DUS and CEUS was 0.870 for longitudinal diameters (95% CI: 0.795-0.945, sensitivity 0.842, specificity 0.783, threshold value 0.215), and 0.863 for transverse diameters (95% CI: 0.785-0.942, sensitivity 0.667, specificity 0.936, threshold value 0.203).

The size measurements of both breast cancer and benign tumors were larger in CEUS compared with 2DUS, with CEUS measurements of breast cancer being more pronounced than those of benign breast tumors. These findings suggest that CEUS may provide a more precise assessment of tumor size, which is crucial for determining optimal treatment strategies and improving patient outcomes in breast cancer management.

Endometrial cancer (EC) is a significant cause of cancer-related deaths in women. MicroRNAs (miRs) play a role in cancer development, acting as oncogenes or tumor suppressors. This study evaluated the diagnostic potential of hsa-miR-185-5p and hsa-miR-191-5p in EC and their correlation with clinical and histopathological features. A cross-sectional study analyzed formalin-fixed, paraffin-embedded tissue samples from 59 patients: 18 with EC, 21 with endometrial hyperplasia (EH), 17 with normal endometrium (NE), and 3 with endometrial polyps (EPs). Quantitative reverse transcription-polymerase chain reaction and TaqMan probes were used for miR expression analysis. The Shapiro-Wilk test was used to analyze the normal distribution of the data. Subsequently, parametric or non-parametric tests were used to evaluate the associations between the expression levels of each miR and clinical parameters. Both miRs were underexpressed in some precursor and malignant lesions compared to certain NE subtypes and benign lesions. Specifically, hsa-miR-185-5p showed underexpression in grade 3 EC compared to some NE and EH subtypes (FC: -57.9 to -8.5, p < 0.05), and hsa-miR-191-5p was underexpressed in EH and EC compared to secretory endometrium and EPs (FC: -4.2 to -32.8, p < 0.05). SETD1B, TJP1, and MSI1 were common predicted target genes. In conclusion, hsa-miR-185-5p and hsa-miR-191-5p are underexpressed in EC tissues, correlating with histopathological grades, highlighting their potential as diagnostic biomarkers and their role as tumor suppressors in EC.

To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME).

Randomized, double-masked, noninferiority phase 3 trials.

Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME.

Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change.

Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100.

In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept.

Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.