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Lateral flow assays are valuable rapid diagnostic tests, but low sensitivity can hinder their precision. Here, the authors report an enrichment method using nanoporous AAO and red blood cell membranes, which when applied to patient samples prior to analysis can improve sensitivity up to 20-fold.

AIM: To determine the prevalence of focal lamina cribrosa (LC) defect among patients with pachychoroid disease spectrum (PDS) in the absence of peripapillary retinoschisis. METHODS: This retrospective, cross-sectional study comprised of 180 patients with PDS, including polypoidal choroidal vasculopathy (PCV), central serous chorioretinopathy, and pachychoroidal neovasculopathy. Medical records and optic nerve head evaluations conducted using spectral-domain optical coherence tomography with enhanced depth imaging were reviewed. As a control group, 236 patients who underwent ophthalmologic evaluation for vitreous floaters, without obvious ocular disease, were also included. RESULTS: The mean age of the PDS group, which included 118 male patients (65.6%), was 57.4±11.1y. There was no significant difference between the two groups in age (P=0.710) or sex (P=0.248). Six patients (3.3%) in the PDS group and none in the control group showed focal LC defect (P=0.318). Among the six patients with focal LC defect in the PDS group, four eyes had PCV, one eye was the fellow eye of a PCV eye, and one eye had pachychoroidal neovasculopathy. CONCLUSION: Focal LC defect can be defected in patients with PDS in the absence of peripapillary retinoschisis. However, the prevalence of focal LC defect was not different significantly between PDS patients and those who did not have PDS.

A sample preconcentration technique that exceeds a microfluidic device’s limited processing volume (up to microliters) is critical for real sample pretreatment applications. Here, we have developed a 3D-printed preconcentrator with a pillar structure (3DP2) to enrich the biological samples up to hundreds of microliter scales (700 μL) within 20 min by utilizing ion concentration polarization (ICP). We designed three-dimensional ready-to-pick reservoirs serially connected with a pillar-structured channel to enable large-volume preconcentration by balancing the preconcentrating forces (depletion, electrophoretic, and electroosmotic force) generated by ICP. Using the I-t and I-V curves, we confirmed that ICP performance was enhanced due to a pillar structure’s suppression of the vortex. Finally, we preconcentrated bovine serum albumin (BSA) and micro ribonucleic acid-21 (miRNA-21) two-fold. Moreover, depending on their size and charge, these were concentrated at different locations and could be extracted easily using pipettes. We believe that this study provides a novel strategy for downstream applications.

AIM: To investigate sectoral changes in the mean peripapillary choroidal thickness (PCT) in patients with unilateral branch retinal vein occlusion (BRVO). METHODS: This retrospective, interventional study included 41 patients with acute, unilateral BRVO without macular edema. All patients completed at least a 6-month follow-up period. The PCT was measured at eight locations (temporal, superotemporal, superior, superonasal, nasal, inferonasal, inferior, and inferotemporal). In addition to calculating the average of all locations, the peripapillary choroidal area was divided into four sectors: superior (average of superotemporal PCT, superior PCT, and superonasal PCT), temporal, inferior (average of inferotemporal PCT, inferior PCT, and inferonasal PCT), and nasal. RESULTS: In the BRVO-affected eyes, the mean PCT was 177.7±69.8 μm (range, 70.1-396.0 μm) at baseline and 127.8±54.8 μm (range, 56.4-312.1 μm) at 6mo (P

Background/Aims To investigate the treatment efficacy and renal safety of long-term tenofovir disoproxil fumarate (TDF) therapy in chronic hepatitis B (CHB) patients with preserved renal function. Methods : The medical records of 919 CHB patients who were treated with TDF therapy were reviewed. All patients had preserved renal function with an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2. Results : A total of 426 patients (184 treatment-naïve and 242 treatment-experienced) were included for analysis. A virologic response (VR) was defined as achieving an undetectable serum hepatitis B virus (HBV) DNA level, and the overall VR was 74.9%, 86.7%, and 89.4% at the 1, 2, and 3-year follow-ups, respectively. Achieving a VR was not influenced by previous treatment experience, TDF combination therapy, or antiviral resistance. In a multivariate analysis, being hepatitis B e antigen positive at baseline and having a serum HBV DNA level ≥2,000 IU/mL at 12 months were associated with lower VR rates during the long-term TDF therapy. The overall renal impairment was 2.9%, 1.8%, and 1.7% at the 1, 2, and 3-year follow-ups, respectively. With regard to renal safety, underlying diabetes mellitus (DM) and an initial eGFR of 60 to 89 mL/min/1.73 m2 were significant independent predictors of renal impairment. Conclusion : s TDF therapy appears to be an effective treatment option for CHB patients with a preserved GFR. However, patients with underlying DM and initial mild renal dysfunction (eGFR, 60 to 89 mL/min/1.73 m2) have an increased risk of renal impairment.

Graphene quantum dots (GQDs) can be highly beneficial in various fields due to their unique properties, such as having an effective charge transfer and quantum confinement. However, defects on GQDs hinder these properties, and only a few studies have reported fabricating high-quality GQDs with high crystallinity and few impurities. In this study, we present a novel yet simple approach to synthesizing high-quality GQDs that involves annealing silicon carbide (SiC) under low vacuum while introducing hydrogen (H) etching gas; no harmful chemicals are required in the process. The fabricated GQDs are composed of a few graphene layers and possess high crystallinity, few defects and high purity, while being free from oxygen functional groups. The edges of the GQDs are hydrogen-terminated. High-quality GQDs form on the etched SiC when the etching rates of Si and C atoms are monitored. The size of the fabricated GQDs and the surface morphology of SiC can be altered by changing the operating conditions. Collectively, a novel route to high-quality GQDs will be highly applicable in fields involving sensors and detectors.

Sphingomonas paucimobilis is an aerobic Gram-negative bacillus found in soil and water. Knowledge regarding the role of this infectious agent is limited because it is rarely isolated from human material. Furthermore, it is an unusual pathogen in cases of peritoneal dialysis (PD)-associated peritonitis. The clinical courses and outcomes of peritonitis caused by S. paucimobilis are variable. Whereas some patients were cured with appropriate antibiotic therapy, others required catheter removal. Cases of PD-associated peritonitis caused by S. paucimobilis have been reported worldwide, and there was a case report of coinfection with S. paucimobilis and Chryseobacterium indologenes in Korea. However, there has been no case caused by S. paucimobilis as a single pathogen. We report a case of PD-associated peritonitis due to S. paucimobilis in which the patient recovered after catheter removal.

Objective: Accumulating evidence from other countries indicates potential associations between gout and cardiovascular diseases; however, the associations of gout with cardiovascular diseases, particularly stroke, ischemic heart disease, and heart failure, remain ambiguous in the Korean population. We hypothesized that individuals with gout are at a higher likelihood of stroke, ischemic heart disease, or heart failure. This study expands upon previous research by ensuring a comparable baseline between patient and control groups and analyzing 16 years of data derived from an extensive healthcare database. Methods: We selected 22,480 patients with gout and 22,480 control individuals from the Korean National Health Insurance Service-Health Screening Cohort database (2002-2019), and matched them at a 1:1 ratio according to sex, age, income, and residence. A Cox proportional hazard model with weighted overlap was employed to examine the relationship between gout and the risk of stroke, ischemic heart disease, or heart failure after adjustment for several covariates. Results: The incidences of stroke, ischemic heart disease, or heart failure in participants with gout were slightly higher than those in controls (stroke: 9.84 vs. 8.41 per 1000 person-years; ischemic heart disease: 9.77 vs. 7.15 per 1000 person-years; heart failure: 2.47 vs. 1.46 per 1000 person-years). After adjustment, the gout group had an 11% (95% confidence interval [CI] = 1.04- 1.19), 28% (95% CI = 1.19-1.37), or 64% (95% CI = 1.41-1.91) higher likelihood of experiencing stroke, ischemic heart disease, or heart failure, respectively, than the control group. Conclusion: The present findings suggest that individuals with gout in the Korean population, particularly those aged = 60 years, were more likely to have stroke, ischemic heart disease, or heart failure. [ABSTRACT FROM AUTHOR]

A data acquisition and monitoring system was developed for an automated system of a smart fish farm. The fish farm is located in Jang Hang, South Korea, and was designed as circulation filtration system. Information of every aquaculture pool was automatically measured by pH sensors, dissolved oxygen sensors, and water temperature sensors and the data were stored in the database in a remoted server. Modbus protocol was used for gathering the data which were further used to optimize the pool water quality to predict the rate of growth and death of fish, and to deliver food automatically as planned by the fish farmer. By using JSON protocol, the collected data was delivered to the user's PC and mobile phone for analysis and easy monitoring. The developed monitoring system allowed the fish farmers to improve fish productivity and maximize profits. [ABSTRACT FROM AUTHOR]

Background. There are various types of adipose tissue in the human body, and their morphology is known to be closely related to cell function and metabolism. However, the functional differences among the mesenchymal stromal cells (MSCs) of different abdominal adipose tissues have not been clearly elucidated. Methods. MSCs were isolated from different abdominal adipose tissues according to their regional distribution and included superficial subcutaneous, deep subcutaneous, omentum, mesentery and retroperitoneal MSCs. The immunophenotype, proliferative ability and angiogenic function of these MSCs were compared based on flow cytometry analysis, CCK-8 proliferation, in vitro differentiation, tubule formation and in vivo plug assay. Results. The plastic adherence, cell morphology and general immunophenotype are similar among the MSCs. However, subcutaneous adipose tissue-derived MSCs have a faster growth rate and a higher level of CD146 expression than the other MSCs. Moreover, according to the fluorescence-activated cell sorting (FACS) enrichment procedure, the expression level of CD146 is positively related to the growth rate and angiogenic capability of MSCs. Discussion. MSCs in adipose tissue showed slightly different characteristics depending on their location of origin, and they possessed different angiogenic abilities that were mediated by the expression of CD146. This study provides evidence that subcutaneous adipose tissue is the most appropriate source of MSCs for therapeutic cell transplantation in vascular disease. [ABSTRACT FROM AUTHOR]

ABA-type amphiphiles bearing a triazole-based aromatic block were easily synthesized using click chemistry, which act as fluorescent turn-off Hg2+-chemoprobes in an aqueous solution. Interestingly, the metal-binding process of amphiphiles induced nanoassemblies even below the CMCs, and the binding stoichiometry affected the morphologies of the resultant nanostructures. [ABSTRACT FROM AUTHOR]

We prepared pyrene-labeled peptide amphiphiles (PAs) consisting of a hydrophobic linear- or branchedalkyl chain (for 1 or 2, respectively) and a hydrophilic histidine-rich peptide of HGGGHGHGGGHG (HG12). Both peptides have a strong tendency to form nanofibrils (NFs) in aqueous media. The resulting histidine-coated NFs show a great binding affinity to Cu2+ as a fluorescence "light-off" sensor. Interestingly, the emission spectra of the pyrene probe show that the different supramolecular assemblies between 1 and 2 can significantly affect the binding affinity to specific metal ions. In particular, "light-up" fluorescent Ag+ detection of NFs of 2 through inhibition of photoinduced electron transfer (PET) was observed even at a low concentration of PA solution. As a means to determine the biological responsibility of 2 to Ag+, intracellular detection using the "turn-on" response was performed. A considerable enhancement of fluorescence in NF-loaded HeLa cells was observed. In addition, the NFs were used as a template scaffold for the production of Ag nanoparticles (AgNPs) with high monodispersity and stability. The NFs decorated with AgNPs are shown to possess highly effective and long-term antibacterial activity against both Gram-negative and -positive bacteria. [ABSTRACT FROM AUTHOR]

This article presents information on a study on the use of CTAB micelles for the surface modification of citrate-capped gold nanoparticles. It discusses the characterization of gold nanoparticles, the molecule chosen for converting the surface charge from negative to positive, and the changes in color and ultraviolet-vis spectra of the gold nanoparticles.

Meniere’s disease (MD) is a chronic inner ear disorder characterized by tinnitus, ear fullness, episodic vertigo, and fluctuating hearing loss, which significantly impacts quality of life and poses management challenges. Recent evidence suggests that upper respiratory infections (URIs) may contribute to MD’s onset. This study examines the potential link between URIs and MD using data from the Korean National Health Insurance Service-National Sample Cohort (2002–2019). We analyzed 19,721 individuals with MD and 78,884 matched controls, adjusting for demographic factors and comorbidities using propensity score matching. Our results showed that individuals with a URI within one year prior to the index date exhibited a 2.01-fold greater likelihood of developing MD (95% confidence interval [CI] = 1.91–2.11, p < 0.001), while those with URIs within two years demonstrated a 1.54-fold higher probability (95% CI = 1.50–1.59, p < 0.001). Furthermore, we found that even remote URIs occurring up to two years before the index date significantly increased the risk of developing MD, underscoring the need for long-term patient follow-up. Overall, our study suggests that individuals with a history of URI may have an elevated risk of developing MD over multiple time frames, regardless of demographic or health profiles.

Despite growing interest in the preventive effects of statins, as lipid-lowering agents, on migraine attacks, comprehensive nationwide studies comparing migraine likelihood between statin users and controls are lacking. Our nested case–control study within the Korean National Health Insurance Service-Health Screening Cohort (2002–2019) investigated this association using 38,957 migraine patients and 155,828 controls, considering migraine subtypes (with/without aura) and statin types (lipophilic vs. hydrophilic). Using propensity score matching and adjusting for confounders, statin use was linked to reduced migraine likelihood overall (odds ratio (OR) 0.93), particularly for migraines with aura (OR 0.75) and without aura (OR 0.94). Lipophilic statins were effective for both subtypes, while hydrophilic statins mainly reduced the likelihood of migraines without aura. Subgroup analyses showed consistent benefits across demographics, but varied effectiveness based on weight, smoking, alcohol use, hemoglobin levels, and dyslipidemia history. In summary, this nationwide cohort study suggests that statin use may reduce migraine likelihood among Korean adults across diverse demographics and clinical profiles, but varied effectiveness based on certain lifestyle and comorbidity factors underscores the importance of considering individual patient profiles when assessing the potential benefits of statin therapy for migraine prevention.

Growing research has proposed that rheumatoid arthritis (RA) and chronic periodontitis (CP) share similar pathophysiological mechanisms involving inflammation and tissue destruction. However, the potential correlation of CP as a contributing factor for the occurrence of RA warrants validation in the Korean population, where both diseases are prevalent, especially considering the increasingly aging demographic in Korea. This study examined 5139 RA cases and 509,727 matched controls from a Korean national cohort dataset (2002–2019) by carefully employing propensity score matching to ensure comparability between groups. Baseline characteristics were compared using standardized differences, and logistic regression was employed to estimate the impact of CP history on RA likelihood while controlling for covariates. We fully examined medical records documenting CP occurrences within the two-year period leading up to the index date, conducting comprehensive subgroup analyses. While a 1-year history of CP did not show a significant association with likelihood of RA, a 2-year history of CP increased RA likelihood by 12%, particularly among older adults, females, rural residents, and those with certain comorbidities such as hypercholesterolemia. Interestingly, this association persisted even among individuals with non-smoking habits, normal weight, and infrequent alcohol consumption. These findings suggest that chronic CP exposure for at least 2 years may independently elevate RA risk in Korean adults. The association in certain subgroups appears to suggest a predisposition toward genetic susceptibilities over lifestyle and environmental factors. Predicting RA in CP patients may be challenging, emphasizing the importance of regular RA screening, especially in high-risk subgroups.

Recent research suggests a potential relevance between chronic periodontitis (CP) and Parkinson’s disease (PD), raising concerns about comorbid PD among elderly CP patients. However, the epidemiologic basis for this association remains unclear. Employing a nested case-control design, this study explored the association between CP and subsequent PD occurrences in Korean adults, leveraging a validated national population-based dataset covering the period from 2002 to 2019. It included 8794 PD patients and 35,176 matched control individuals, established through propensity score matching for age, sex, residential area, and income. Baseline characteristics were compared using standardized differences, and logistic regression was employed to assess the impact of CP histories on PD likelihood while controlling for covariates. We performed a thorough examination of CP events within both 1-year and 2-year intervals preceding the index date, incorporating subgroup analyses. Our analysis revealed no statistically significant association between CP history and PD development overall. However, subgroup analysis revealed a slightly increased likelihood of PD development among CP individuals with a high disease burden (Charlson Comorbidity Index score ≥ 2). In conclusion, although our study did not find a significant overall association between CP history and PD development, the elevated likelihood of PD in subgroups with high disease burden may suggest that comorbidities influence PD probability among certain CP patients. Considering comorbid conditions in PD screening for some individuals with CP may be also important.

Abstract Immune checkpoint inhibitor (ICI) clinically benefits cancer treatment. However, the ICI responses are only achieved in a subset of patients, and the underlying mechanisms of the limited response remain unclear. 160 patients with non‐small cell lung cancer treated with anti‐programmed cell death protein‐1 (anti‐PD‐1) or anti‐programmed death ligand‐1 (anti‐PD‐L1) are analyzed to understand the early determinants of response to ICI. It is observed that high levels of intracellular adhesion molecule‐1 (ICAM‐1) in tumors and plasma of patients are associated with prolonged survival. Further reverse translational studies using murine syngeneic tumor models reveal that soluble ICAM‐1 (sICAM‐1) is a key molecule that increases the efficacy of anti‐PD‐1 via activation of cytotoxic T cells. Moreover, chemokine (CXC motif) ligand 13 (CXCL13) in tumors and plasma is correlated with the level of ICAM‐1 and ICI efficacy, suggesting that CXCL13 might be involved in the ICAM‐1‐mediated anti‐tumor pathway. Using sICAM‐1 alone and in combination with anti‐PD‐1 enhances anti‐tumor efficacy in anti‐PD‐1‐responsive tumors in murine models. Notably, combinatorial therapy with sICAM‐1 and anti‐PD‐1 converts anti‐PD‐1‐resistant tumors to responsive ones in a preclinical study. These findings provide a new immunotherapeutic strategy for treating cancers using ICAM‐1.

Background: Gintonin is a ginseng-derived exogenous G-protein–coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood–brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

Background: Ginseng has been widely used as a health-promoting tonic. Gintonin present in ginseng acts as a lysophosphatidic acid (LPA) receptor ligand that activates six LPA receptor subtypes. The LPA6 subtype plays a key role in normal hair growth, and mutations in the LPA6 receptor impair normal human hair growth. Currently, human hair loss and alopecia are concerning issues that affect peoples' social and day-to-day lives. Objective: We investigated the in vitro and in vivo effects of a gintonin-enriched fraction (GEF) on mouse hair growth. Methods: Human hair follicle dermal papilla cells (HFDPCs) and six-week-old male C57BL/6 mice were used. The mice were divided into the four groups: control, 1% minoxidil, 0.75% GEF, and 1.5% GEF. The dorsal hair was removed to synchronize the telogen phase. Each group was treated topically, once a day, for 15 days. We analyzed hair growth activity and histological changes. Results: GEF induced transient [Ca2+]i, which stimulated HFDPC proliferation and caused 5-bromo-2′-deoxyuridine (BrdU) incorporation in a concentration-dependent manner. GEF-mediated HFDPC proliferation was blocked by the LPA receptor antagonist and Ca2+ chelator. HFDPC treatment with GEF stimulated vascular endothelial growth factor release. Topical application of GEF and minoxidil promoted hair growth in a dose-dependent manner. Histological analysis showed that GEF and minoxidil increased the number of hair follicles and hair weight. Conclusion: Topical application of GEF promotes mouse hair growth through HFDPC proliferation. GEF could be one of the main components of ginseng that promote hair growth and could be used to treat human alopecia. Keywords: Ginseng, Gintonin-enriched fraction, Hair growth, Human hair follicle dermal papilla cells, Mouse

Background: Recently, gintonin and gintonin-enriched fraction (GEF) have been isolated from ginseng, a herbal medicine. Gintonin induces [Ca2+]i transition in cultured hippocampal neurons and stimulates acetylcholine release through LPA receptor activation. Oral administration of GEF is linked to hippocampus-dependent cognitive enhancement and other neuroprotective effects; however, effects of its long-term administration on hippocampal gene expression remains unknown. Here, we used next-generation sequence (NGS) analysis to examine changes in hippocampal gene expressions after long-term oral administration of GEF. Methods: C57BL/6 mice were divided into three groups: control group, GEF50 (GEF 50 mg/kg, p.o.), and GEF100 (GEF 100 mg/kg, p.o.). After 22 days, total RNA was extracted from mouse hippocampal tissues. NGS was used for gene expression profiling; quantitative-real-time PCR and western blot were performed to quantify the changes in specific genes and to confirm the protein expression levels in treatment groups. Results: NGS analysis screened a total of 23,282 genes, analyzing 11-related categories. We focused on the neurogenesis category, which includes four genes for candidate markers: choline acetyltransferase (ChAT) gene, β3-adrenergic receptor (Adrb3) gene, and corticotrophin-releasing hormone (Crh) gene, and tryptophan 2,3-dioxygenase (Tdo2) gene. Real-time PCR showed a marked overexpression of ChAT, Adrb3, and Crh genes, while reduced expression of Tdo2. Western blot analysis also confirmed increased ChAT and decreased Tdo2 protein levels. Conclusion: We found that GEF affects mouse hippocampal gene expressions, associated with memory, cognitive, anti-stress and anti-anxiety functions, and neurodegeneration at differential degree, that might explain the genetic bases of GEF-mediated neuroprotective effects.

Background: Gintonin is a ginseng-derived exogenous ligand of the G protein-coupled lysophosphatidic acid (LPA) receptor. We previously reported that gintonin stimulates gliotransmitter release in primary cortical astrocytes. Astrocytes play key roles in the functions of neurovascular systems. Although vascular endothelial growth factor (VEGF) is known to influence the normal growth and maintenance of cranial blood vessels and the nervous system, there is little information about the effect of gintonin on VEGF regulation in primary astrocytes, under normal and hypoxic conditions. Methods: Using primary cortical astrocytes of mice, the effects of gintonin on the release, expression, and distribution of VEGF were examined. We further investigated whether the gintonin-mediated VEGF release protects astrocytes from hypoxia. Results: Gintonin administration stimulated the release and expression of VEGF from astrocytes in a concentration- and time-dependent manner. The gintonin-mediated increase in the release of VEGF was inhibited by the LPA1/3 receptor antagonist, Ki16425; phospholipase C inhibitor, U73122; inositol 1,4,5-triphosphate receptor antagonist, 2-APB; and intracellular Ca2+ chelator, BAPTA. Hypoxia further stimulated astrocytic VEGF release. Gintonin treatment stimulated additional VEGF release and restored cell viability that had decreased due to hypoxia, via the VEGF receptor pathway. Altogether, the regulation of VEGF release and expression and astrocytic protection mediated by gintonin under hypoxia are achieved via the LPA receptor–VEGF signaling pathways. Conclusion: The present study shows that the gintonin-mediated regulation of VEGF in cortical astrocytes might be neuroprotective against hypoxic insults and could explain the molecular basis of the beneficial effects of ginseng on the central nervous system. Keywords: Astrocytes, Gintonin, Hypoxia, Lysophosphatidic acid receptor, Vascular endothelial growth factor