Blood Vessel Growth Research Articles

Efficient vascular and neural engraftment of stem cell-derived islets.

Pluripotent stem cell-derived islets (SC-islets) now emerge as a new source for beta-cell replacement therapy. While the function of human islet transplants is hampered by excessive cell death post-transplantation, contributing factors include inflammatory reactions, insufficient revascularization and islet amyloid formation, there is a gap in knowledge on the engraftment process of the SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at three months post-transplantation, and observed that the cell apoptosis rates were lower, but the vascular density was similar in SC-islets to that of human islets. While the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. The oxygenation of the SC-islet grafts was twice as high as in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, also the reinnervation of the SC-islets was four- to five-fold higher than the human islets. Both SC-islets and the human islets contained amyloid at one and three months post-transplantation. We conclude that the vascular and neural engraftment of SC-islets is superior to human islets, but that grafts of both origins develop amyloid with potential long-term consequences.

Abstract LB387: Microphysiological modeling of gastric cancer vasculature using iPSC-derived endothelial cells

Abstract Generated induced pluripotent stem cells (iPSCs) from the blood of patients with advanced gastric cancer, differentiating them into endothelial cells and fibroblasts. Utilizing microfluidic 3D cell culture, we intricately reconstructed the observed abnormal blood vessels in gastric cancer patients in a three-dimensional format, capturing real-time neovasculature. Applying deep learning techniques, we virtually labeled the growing blood vessels with fluorescence, unveiling thin and tortuous morphological characteristics specific to patient iPSCs, distinct from those derived from human umbilical cord endothelial cells. The development of a tumor model, vascularized with cancer cells from the same donor, establishes a versatile testbed for evaluating personalized cancer vascular models. Through comprehensive morphological and functional assessments, this platform facilitates screening for patient-specific combination therapies and holds promise as a model for immune response testing. Citation Format: Jihoon Ko, Noo Li Jeon, Young Sun Oh. Microphysiological modeling of gastric cancer vasculature using iPSC-derived endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB387.

Microglia in retinal angiogenesis and diabetic retinopathy.

Diabetic retinopathy has a high probability of causing visual impairment or blindness throughout the disease progression and is characterized by the growth of new blood vessels in the retina at an advanced, proliferative stage. Microglia are a resident immune population in the central nervous system, known to play a crucial role in regulating retinal angiogenesis in both physiological and pathological conditions, including diabetic retinopathy. Physiologically, they are located close to blood vessels and are essential for forming new blood vessels (neovascularization). In diabetic retinopathy, microglia become widely activated, showing a distinct polarization phenotype that leads to their accumulation around neovascular tufts. These activated microglia induce pathogenic angiogenesis through the secretion of various angiogenic factors and by regulating the status of endothelial cells. Interestingly, some subtypes of microglia simultaneously promote the regression of neovascularization tufts and normal angiogenesis in neovascularization lesions. Modulating the state of microglial activation to ameliorate neovascularization thus appears as a promising potential therapeutic approach for managing diabetic retinopathy.

Bifenox induces hepatotoxicity and vascular toxicity in zebrafish embryos via ROS production and alterations in signaling pathways

Existing evidence shows that currently used pesticides pose toxicological risks to exposed wildlife. Chemically, bifenox belongs to diphenyl ethers, a well-known group of herbicides. Its mechanism of action primarily involves inducing lipid peroxidation and blocking protoporphyrinogen oxidases. Toxicity of diphenyl ether herbicides has been elucidated in animal cells; however, in vivo toxicological evaluations of bifenox are required to determine its unexpected effects. This study aimed to determine the negative effects of bifenox, and its effects on higher eukaryotes. We found that early stages of zebrafish embryo exposed to bifenox demonstrated increased mortality and physiological defects, based on the LC50 value. Bifenox severely inhibited blood vessel growth by reducing key elements of complex connectivity; fluorescently tagged transgenic lines (fli1a:EGFP) showed morphological changes. Additionally, transgenic lines that selectively identified hepatocytes (fabp10a:DsRed) showed reduced fluorescence, indicating that bifenox may inhibit liver development. To evaluate the level of oxidative stress, we used 2′,7′-dichlorofluorescein diacetate (DCFH-DA) probes in zebrafish embryos to identify the underlying mechanisms causing developmental damage. Our findings demonstrate that exposure to bifenox causes abnormalities in the hepatic and cardiovascular systems during zebrafish embryogenesis. Therefore, this study provides new information for the evaluation of toxicological risks of bifenox in vertebrates.

AN OVERVIEW ON THERAPEUTIC SCREENING USING EXPERIMENTAL MODELS OF WOUND HEALING

The complex process of wound healing is how damaged tissue heals itself. It's a process that includes homeostasis, tissue integrity coordination, and the activation of intercellular pathways. The present review was based on the therapeutic screening using experimental models of wound healing. Hemostasis and clot formation are the two main complicated events that take place during this phase. The clot has aggregated platelets encased in a fibrin network. Oxygen is necessary for almost all wound-healing processes and cell metabolism, particularly to produce energy via ATP. It stops wounds from getting infected, stimulates the growth of new blood vessels, raises the differentiation, migration, and re-epithelialization of keratinocytes, boosts the production of collagen and fibroblasts, and encourages wound contraction. Wound healing models include incision, excision and burn model. In conclusion, our understanding of wound pathophysiology will be significantly advanced by combining these strategies with cutting-edge tissue, cell, and molecular "omics" technology. Developing novel therapeutic approaches for enhanced wound care is, in fact, one of the many promising areas of the future.

Strongly Adhesive, Self-Healing, Hemostatic Hydrogel for the Repair of Traumatic Brain Injury.

With wide clinical demands, therapies for traumatic brain injury (TBI) are a major problem in surgical procedures and after major trauma. Due to the difficulty in regeneration of neurons or axons after injury, as well as the inhibition of blood vessel growth by the formation of neural scars, existing treatment measures have limited effectiveness in repairing brain tissue. Herein, the biomultifunctional hydrogels are developed for TBI treatment based on the Schiff base reaction of calcium ion (Ca2+)-cross-linked oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS). The obtained COCS hydrogel exhibits excellent adhesion to wet tissues, self-repair capability, and antimicrobial properties. What's particularly interesting is that the addition of Ca2+ increases the hydrogel's extensibility, enhancing its hemostatic capabilities. Biological assessments indicate that the COCS hydrogel demonstrates excellent biocompatibility, hemostatic properties, and the ability to promote arterial vessel repair. Importantly, the COCS hydrogel promotes the growth of cerebral microvessels by upregulating CD31, accelerates the proliferation of astrocytes, enhances the expression of GFAP, and stimulates the expression of neuron-specific markers such as NEUN and β-tubulin. All of these findings highlight that the strongly adhesive, self-healing, hemostatic hydrogel shows great potential for the repair of traumatic brain injury and other tissue repair therapy.

In Situ injectable photo-crosslinking hydrogel with heterojunction nanoparticles for dual-channel synergistic disinfection and cutaneous regeneration in diabetic chronic wound healing

Recurrent inflammation, intense bacterial infections, and inadequate blood vessel growth make diabetic wounds non-healing. Under pathological environment, cellular functions are also inhibited. In this paper, we developed a novel in situ injectable photo-crosslinking hydrogel embedded with heterojunction Ag@ZnO nanoparticles (NPs) which exhibit dual-channel synergistic ion release and reactive oxygen species (ROS) production for anti-bacteria and cutaneous regeneration. This novel hydrogel platform can be introduced onto any irregular wound and form gelation with 395 nm UV light irradiation in only 5 s. After being affixed to the wound, Ag+ and Zn2+ can be released as the first interaction for wound healing. Foremost, the heterojunction formed on interface of Ag and ZnO has the ability to capture oxygen and water to instigate the generation of a “ROS storm”, which can disrupt the structural integrity of bacteria, trigger the leakage of bacterial cytoplasmic content, enhance angiogenesis by activating VEGF and CD31 expression, and stimulate the steps of wound healing. The continuous release of Ag+, Zn2+ and “ROS storm” collaboratively drive bacterial deactivation, suppress inflammation, promote cellular proliferation, collagen deposition and angiogenesis. These effects significantly accelerate diabetic chronic wounds healing. Therefore, such dual-channel synergistic hydrogel platform might provide a promising new insight to diabetic chronic wound treatment.

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos.

Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.

Mechanobiological tortuosity of blood vessels with stress-modulated growth and remodeling

The stability of blood vessels is essential for maintaining their functions, while severe blood vessel tortuosity leads to various clinical complications. The growth and remodeling of blood vessels, which are regulated by mechanical and biochemical cues, cause residual stresses that affect vessel stability. In this paper, we combine theory and simulations to study the mechanobiological behavior of blood vessels with stress-modulated growth and remodeling. Effects of the volumetric growth of the matrix and the turnover and reorientation of collagen fibers are accounted for. Linear stability analysis is first carried out to investigate the mechanobiological stability of blood vessels. By developing a finite element method that incorporates stress-modulated growth and remodeling, we validate the theoretical solution of the critical state and further capture the postbuckling evolution of blood vessels. Our results show that an increased internal pressure can lead to the thickening of the vessel wall, which stabilizes the blood vessels mechanically, whereas the effect of internal pressure on the mechanobiological buckling is nonmonotonic. Compared to the mechanical instability, the mechanobiological buckling results in a larger mode number and a shorter wavelength, as usually observed in varicose veins. Vessels during postbuckling may exhibit non-uniform wall thicknesses, in consistency with the experimental observation on tortuous aortas. These findings highlight the crucial role of mechanical remodeling in tissue morphogenesis and could deepen the understanding of mechanobiological mechanisms underlying the formation and development of blood vessel tortuosity.

Nanoengineered oxygen-releasing polymeric scaffold with sustained release of dexamethasone for bone regeneration

Maintaining the continuous oxygen supply and proper cell growth before blood vessel ingrowth at the bone defect site are considerably significant issues in bone regeneration. Oxygen-producing scaffolds can supply oxygen and avoid hypoxia leading to expedited bone regeneration. Herein, first oxygen-producing calcium peroxide nanoparticles (CPO NPs) are synthesized, and subsequently, the various amounts of synthesized CPO NPs (0.1, 0.5, and 1 wt/v%) loaded in the scaffold composite, which is developed by simple physical blending of chitosan (CS) and polycaprolactone (PCL) polymers. To deliver the synergistic therapeutic effect, dexamethasone (DEX), known for its potential anti-inflammatory and osteogenic properties, is loaded into the nanocomposite scaffolds. The extensive physicochemical characterizations of nanocomposite scaffolds confirm the successful loading of CPO NPs, adequate porous morphology, pore size, hydrophilicity, and biodegradability. In vitro, biological studies support the antibacterial, hemocompatible, and cytocompatible (MG-63 and MC3T3-E1 cells) nature of the material when tested on respective cells. Field emission scanning electron microscopy and energy-dispersive x-ray spectroscopy confirm the successful biomineralization of the scaffolds. Scaffolds also exhibit the sustained release of DEX and efficient protein adsorption. This study revealed that a nanoengineered scaffold loaded with CPO NPs (PCL/CS/DEX/CPO 3) is a suitable candidate for bone tissue regeneration.

DHEA promotes ovarian angiogenesis and improves ovarian function in POI rats by up-regulating HIF-1α/VEGF signalling

Research QuestionDehydroepiandrosterone (DHEA) promotes tissue function recovery in different diseases by stimulating angiogenesis; however, its impact on ovarian angiogenesis and function in rats with premature ovarian insufficiency (POI) and the potential mechanisms of action remain uncertain. DesignDHEA was co-cultured with human microvascular endothelial cells (HMEC-1) cells to investigate its effects on cell proliferation, migration, and tube formation. A rat model of POI was established by intraperitoneal injection of cyclophosphamide (CTX), followed by continuous oral administration of DHEA for 28 d. Ovarian angiogenesis, follicular growth, and granulosa cell (GC) survival in ovarian tissues were assessed through haematoxylin-eosin staining, immunohistochemistry, and TUNEL. The effect of DHEA on the fertility of rats with POI was evaluated in pregnant animals. The expression levels of characteristic genes and proteins in the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway was determined using quantitative reverse transcription-PCR and western blotting. ResultsIn vitro experiments revealed that DHEA stimulated the proliferation, migration, and tube formation of HMEC-1 cells. In in vivo studies, DHEA treatment improved the disruption of estrous cycle and hormone imbalances in POI rats. Key genes in the HIF-1α/VEGF pathway exhibited upregulated expression, promoting ovarian angiogenesis in POI rats, and enhancing follicular development and GC survival, thereby restoring fertility in rats. ConclusionsDHEA can potentially restore ovarian function in CTX-induced POI rats by upregulating HIF-1α/VEGF signalling, which promotes the growth of blood vessels in the ovaries.

Effect of Nasal Continuous Positive Airway Pressure on Retinopathy of Prematurity in Preterm Newborns: A Comparative Analysis with Mechanical Ventilation and High-Flow Nasal Cannula Therapy.

BACKGROUND Retinopathy of prematurity (ROP), originally described as retrolental fibroplasia, represents an abnormal growth of blood vessels in the premature retina that can occur in response to oxygen therapy. The association between ROP and invasive mechanical ventilation has been widely studied in the literature; however, the relationships between different types of ventilation and ROP have not been as well documented. This study aimed to compare the association of ROP incidence with mechanical ventilation (MV), nasal continuous positive airway pressure (nCPAP), and high-flow nasal cannula (HFNC) therapies in 130 pre-term infants with gestational ages <32 weeks. MATERIAL AND METHODS The study includes 130 premature newborns, out of which 54 underwent MV therapy, either alone or in combination with nCPAP or HFNC therapy, 63 underwent nCPAP therapy, either alone or in combination with MV or HFNC therapy, and 23 underwent HFNC therapy, either alone or in combination with MV or nCPAP therapy. The relationships between ROP and the 3 types of ventilation were analyzed by univariate followed by multivariate logistic regression. RESULTS When adjusting for covariates, only nCPAP and birth weight were significantly associated with ROP, the former being a strong risk factor, with an adjusted odds ratio (AOR) of 7.264 (95% CI, 2.622-20.120; P<0.001), and the latter being a weak protective factor, with an AOR of 0.998 (95% CI, 0.996-0.999; P<0.05). CONCLUSIONS The results showed nCPAP was a strong ROP risk factor, birth weight was a weak ROP protective factor, and MV and HFNC were not significantly associated with increased ROP risk.

Advances in pathogenesis of preeclampsia.

Preeclampsia is a major cause of health problems for both pregnant women and unborn babies worldwide. However, the underlying causes of preeclampsia are not fully understood, leading to limited effective treatments. The goal of this study is to enhance our knowledge of its causes, devise prevention strategies, and develop treatments. We performed a systematic literature search. Six models regarding the pathogenesis of preeclampsia are discussed in this review. This review focuses on the latest advancements in understanding preeclampsia's origins. Preeclampsia is a complex condition caused by various factors, processes, and pathways. Reduced blood flow and oxygen to the uterus and placenta, heightened inflammatory reactions, immune imbalances, altered genetic changes, imbalanced blood vessel growth factors, and disrupted gut bacteria may contribute to its development. Preeclampsia is thought to result from the interplay of these factors.

Cone cell dysfunction attenuates retinal neovascularization in oxygen-induced retinopathy mouse model.

Aberrant neovascularization is the most common feature in retinopathy of prematurity (ROP), which leads to the retinal detachment and visual defects in neonates with a low gestational age eventually. Understanding the regulation of inappropriate angiogenic signaling benefits individuals at-risk. Recently, neural activity originating from the specific neural activity has been considered to contribute to retinal angiogenesis. Here, we explored the impact of cone cell dysfunction on oxygen-induced retinopathy (OIR), a mouse model commonly employed to understand retinal diseases associated with abnormal blood vessel growth, using the Gnat2cpfl3 (cone photoreceptor function loss-3) strain of mice (regardless of the sex), which is known for its inherent cone cell dysfunction. We found that the retinal avascular area, hypoxic area, and neovascular area were significantly attenuated in Gnat2cpfl3 OIR mice compared to those in C57BL/6 OIR mice. Moreover, the HIF-1α/VEGF axis was also reduced in Gnat2cpfl3 OIR mice. Collectively, our results indicated that cone cell dysfunction, as observed in Gnat2cpfl3 OIR mice, leads to attenuated retinal neovascularization. This finding suggests that retinal neural activity may precede and potentially influence the onset of pathological neovascularization.

Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

The angiogenesis-modulating effects of coumarin-derivatives

Coumarin is a natural compound that is rich in plants. Coumarin and its derivates were reported to have many biological activities, such as anti-bacterial, anti-tumor, and anti-coagulation. In this study, we examined the angiogenic modulating activities of six previously synthesized coumarin derivatives (Compound #1-#6) in zebrafish embryos and further confirmed them in a chick model. According to the survival rate in a zebrafish model, Compound #1 (100 %), #2 (82.5–100 %), and #4 (100 %) showed much less toxicity than Compound #3 (19.2–100 %), #5 (0–100 %), and #6 (0–100 %). Using a green blood vessel fluorescent transgenic fish Tg(fli1:egfp) to record the angiogenesis-modulating effects of Compound #1, #2, and #4, we found that Compound #2 had the highest effects in interfering intersegmental vessel growth, subintestinal vein growth, and caudal vein plexus remodeling. Chick chorioallantoic membrane (CAM) assay also showed that Compound #2 exposure led to a reduction of blood vessel growth. Real-time PCR experiments revealed that Compound #2 significantly changed the expression of vascular growth-related genes flt1, cdh5, and nrp1a in zebrafish. Based on our data from zebrafish and chick models, a new coumarin-derivative (Compound #2) possesses anti-angiogenic activity with low toxicity, but further investigation in mammal models is asked to confirm our findings.

A Multifunctional, Tough, Stretchable, and Transparent Curcumin Hydrogel with Potent Antimicrobial, Antioxidative, Anti-inflammatory, and Angiogenesis Capabilities for Diabetic Wound Healing.

The treatment of diabetic chronic wounds is still faced with great challenges, mainly due to wound infection, excessive inflammation, and peripheral vascular disease in the wound area. Therefore, it is of great importance to develop a novel multifunctional hydrogel with high efficiency to accelerate diabetic wound healing. Curcumin (Cur), a Chinese herbal, has shown great potential in enhancing the healing of diabetic chronic wounds because of its immunomodulatory and pro-angiogenic properties. However, its low aqueous solubility, poor bioavailability, and chemical instability have limited its clinical applications. To address these current bottlenecks, novel poly(vinyl alcohol) (PVA)-chitosan (CS)/sodium alginate (SA)-Cur (PCSA) hydrogels were prepared for the first time, and they demonstrated all of the above intriguing performances by the Michael addition reaction of CS and Cur. PCSA hydrogels show multiple dynamic bonds, which possess strong mechanical properties (tensile stress: ∼0.980 MPa; toughness: ∼258.45 kJ/m3; and compressive strength: ∼7.38 MPa at strain of 80%). These intriguing performances provided an optimal microenvironment for cell migration and proliferation and also promoted the growth of blood vessels, leading to early angiogenesis. Importantly, the experimental results demonstrated that PCSA hydrogels can effectively transform pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages without the need for additional ingredients in vitro. Benefiting from these characteristics, a full-thickness diabetic wound in a rat model demonstrated that PCSA hydrogels can effectively accelerate wound healing via ROS-scavenging, downregulation of IL-1β, and upregulation of CD31 expression, resulting in angiogenesis and collagen deposition. This strategy not only provides a simple and safe Cur-based hydrogel for diabetic wound healing but also highlights the significant potential for the development of high-performance biomaterials for promoting diabetic wound healing using traditional Chinese medicine.

Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation.

Metabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches. Here, we present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. The model explores several immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1). We also explore the efficacy of anti-PD-L1 and sodium bicarbonate buffer agents for treatment. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed "meta-phenotypes"): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose. Fomenting a stronger immune response leads to initial benefits (additional cytotoxicity), but this advantage is offset by increased cell turnover that leads to accelerated evolution and the emergence of aggressive phenotypes. This creates a bimodal therapy landscape: either the immune system should be maximized for complete cure, or kept in check to avoid rapid evolution of invasive cells. These constraints are dependent on heterogeneity in vascular context, microenvironmental acidification, and the strength of immune response. This model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape.

Anti-cancer and anti-angiogenic activities of some synthetic Ni(II) thiosemicarbazone complexes

Synthesis and X-ray structural characterization of three Ni(II) complexes of thiosemicarbazone ligand [Ni(L1)2] (1), [Ni(L2)]2 (2) and [Ni(L3)2] (3) [L1 = 2-ethoxybenzaldehyde-N(4)-diethyl-3-thiosemicarbazone, L2 = o-vanillin-N(4)-diethyl-3-thiosemicarbazone and L3 = 2-benzoylpyridine-N(4)-diethyl-3-thiosemicarbazone] are reported. From the structural characterization data, the metal centers in 1 and 2 are found to have distorted square planar geometries but in 3, the Ni(II) center adopts distorted octahedral geometry. The metal complexes (1, 2 and 3) show anti-cancer and anti-angiogenic activities. The complexes act in dual mode by both inhibiting the growth of the cancer cells directly through inducing intracellular Reactive Oxygen Species (ROS) level and inhibiting the growth of blood vessels which can indirectly retard and inhibit tumor growth and progression. Angiogenesis assay performed in in vivo Chorio-Allantoic Membrane (CAM) assay indicated that the complexes significantly inhibited the blood capillary growth within 24 h. The anti-angiogenic effect was observed to be effective against all the key cells involved in angiogenesis namely endothelial cell, fibroblast and smooth muscle cell of the blood vessel as observed in aortic arch assay where the complexes exhibited inhibitory effect on aortic capillary sprouting.

Classic Choroidal Neovascularization in Young Man

Introduction : Classic choroidal neovascularization (CNV 2) represent a pathological growth of blood vessels and can result in loss of visual function. The most common cause of CNV 2 in elderly patients is age- related macular degeneration, meanwhile in young age it is frequently due to inflammation, high myopia, angioid disks and hereditary disorders. Hence, the presented case reports the characteristic findings as well the management of the disease.&#x0D; Case Illustration : A 37-year-old man had two weeks history of metamorphopsia on both eyes. The left eye (LE) had a worse visual acuity, macular fibrosis with pigment epithelial detachment in funduscopy and Optical Coherence Tomography (OCT). A submacular hemorrhage and exudative lesion were recognized on the right eye (RE) with type 2 choroidal neovascularization. Fundus Fluorescence Angiography (FFA) was also performed. Systemic conditions were unremarkable. Intravitreal anti-VEGF injections on RE were given for three consecutive months and showed significant improvement.&#x0D; Discussion : The etiology of CNV 2 includes high myopia, and inflammation. However, none was found in this patient. Nonetheless, CNV type 2 is still uncommon in young age without predisposing conditions. As most common lesions involve the macula, symptoms shown include metamorphopsia, central scotoma and floaters. FFA is still considered to be the gold standard to differentiate the types of choroidal vascularization. Neovascularization and submacular hemorrhage can be treated with intravitreal injection of anti-VEGF, as previous studies reported significant improvement.&#x0D; Conclusion : This was a case of bilateral CNV type 2 in a young man without any previous predisposing conditions. Three monthly injections of anti-VEGF showed significant improvement.