Wnt/ß-catenin pathway is a key signaling pathway to trastuzumab resistance in gastric cancer cells.

BACKGROUND: Trastuzumab is the only approved target agent for the first-line treatment of human epidermal growth factor receptor-2 (HER-2) positive gastric cancer; however, trastuzumab resistance is a major problem in clinical practice. To comprehend the mechanism of trastuzumab resistance, we focused on the Wnt/ß-catenin signaling pathway and its influence on the phenotypes and behavior of trastuzumab-resistant gastric cancer cells. METHODS: Trastuzumab-resistant NCI-N87R cells were established in vitro from the human gastric cancer cell line NCI-N87 by dose-escalating repeated trastuzumab treatment. We investigated the phenotypes of NCI-N87R cells, including Wnt signaling pathway activity. Gastric cancer organoid cells were incubated with complete medium and Wnt3a-depletion medium, and their resistance to trastuzumab was compared. RESULTS: NCI-N87R exhibited stemness and epithelial-mesenchymal transition (EMT)-like phenotypes, along with decreased levels of the epithelial marker E-cadherin and increased levels of the mesenchymal markers Vimentin and Snail along with an increased Wnt signaling pathway activity. When gastric cancer cells were incubated in Wnt3a-conditioned medium. Wnt signaling pathway activity and resistance to trastuzumab increased. Gastric cancer patient-derived organoids incubated in Wnt3a-depletion medium were more susceptible to dose-dependent inhibition of cell viability by trastuzumab than those incubated in complete medium. CONCLUSIONS: Trastuzumab-resistant gastric cancer cells exhibited EMT-like phenotype, and trastuzumab resistance was promoted by the Wnt/ß-catenin signaling pathway. The Wnt/ß-catenin pathway is a key signaling pathway for trastuzumab resistance in gastric cancer cells.

Development of peptide-based ratiometric fluorescent probe for sensing heparan sulfate and heparin in aqueous solutions at physiological pH and quantitative detection of heparan sulfate in live cells.

Heparan sulfate (HS) plays a critical role in various biological processes as a vital component of the extracellular matrix. In this study, we synthesized three fluorescent probes (1-3) comprising Arg-rich peptides as HS receptors and a fluorophore capable of exhibiting red-shifted emissions upon aggregation. All three probes demonstrated ratiometric responses to HS and heparin in aqueous solutions. Remarkably, probe 3 exhibited a unique ratiometric response to HS in both aqueous solutions at physiological pH and HS proteoglycans on live cells. Probe 3 displayed exceptional sensing properties, including high biocompatibility, water solubility, visible light excitation, a large Stokes shift for ratiometric detection and remarkable selectivity and sensitivity for HS (with a low limit of detection: 720 pM). Binding mode studies unveiled the crucial role of charge interactions between probe 3 and negatively charged HS sugar units. Upon binding, the fluorophore segments of the probes overlapped, inducing green and red emission changes through restricted intramolecular rotation of the fluorophore moiety. Importantly, probe 3 was effectively employed to quantify the reduction of HS proteoglycan levels in live cells by inhibiting HS sulfation using siRNA and an inhibitor. It successfully detected decreased HS levels in cells treated with doxorubicin and irradiation, consistent with results obtained from western blot and immunofluorescence assays. This study presents the first ratiometric fluorescent probe capable of quantitatively detecting HS levels in aqueous solutions and live cells. The unique properties of peptide-based probe 3 make it a valuable tool for studying HS biology and potentially for diagnostic applications in various biological systems.

Risk of all-cause and cause-specific mortality associated with immune-mediated inflammatory diseases in Korea.

Objective: Immune-mediated inflammatory disease (IMID) is associated with an increased risk of mortality. It is unclear whether the higher mortality is attributable to the IMIDs themselves or to the higher prevalence of comorbidities in IMIDs. We aimed to investigate whether IMIDs per se confer a higher risk of mortality. Methods: From the Korean National Health Insurance Service-National Sample Cohort database, this population-based cohort study included 25,736 patients newly diagnosed with IMIDs between January 2007 and December 2017, and 128,680 individuals without IMIDs who were matched for age, sex, income, hypertension, type 2 diabetes, dyslipidemia, and the Charlson comorbidity index. All individuals were retrospectively observed through December 31, 2019. The outcomes included all-cause and cause-specific mortalities. Adjustments for age, sex, and comorbidities were performed using multivariable Cox proportional hazard regression analyses, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the outcomes were estimated. Results: The adjusted risk of all-cause mortality was significantly lower in patients with IMIDs than that in those without (aHR, 0.890; 95% CI, 0.841-0.942). Regarding cause-specific mortality, cancer-specific (aHR, 0.788; 95% CI, 0.712-0.872) and cardiovascular disease-specific (aHR, 0.798; 95% CI, 0.701-0.908) mortalities were the two causes of death that showed significantly lower risks in patients with IMIDs. A similar trend was observed when organ based IMIDs were analyzed separately (i.e., gut, joint, and skin IMIDs). Conclusion: After adjusting for comorbidities, IMIDs were associated with a lower risk of all-cause mortality compared to those without IMIDs. This was attributable to the lower risks of cancer-and cardiovascular disease-specific mortalities.

Risk of Metabolic Syndrome and Fatty Liver Diseases in Gastric Cancer Survivors: A Propensity Score-Matched Analysis.

Background/Aims: To investigate the risk of metabolic syndrome and fatty liver diseases in gastric cancer survivors compared to non-cancer subjects. Methods: The data from the health screening registry of the Gangnam Severance Hospital from 2014-2019 was used. Ninety-one gastric cancer survivors and a propensity-score-matching 445 non-cancer subjects were analyzed. Gastric cancer survivors were divided into those with surgical treatment (OpGC, n=66) and non-surgical treatment (non-OpGC, n=25). Metabolic syndrome, fatty liver by ultrasonography, and metabolic dysfunction-associated fatty liver disease (MAFLD) were assessed. Results: Metabolic syndrome was in 15.4% of gastric cancer survivors (OpGC; 13.6%, non-OpGC; 20.0%). Fatty liver by ultrasonography was in 35.2% in gastric cancer survivors (OpGC; 30.3%, non-OpGC: 48.0%). MAFLD was in 27.5% of gastric cancer survivor (OpGC; 21.2%, non-OpGC; 44.0%). After adjusting for age, sex, smoking, and alcohol, the risk of metabolic syndrome was lower in OpGC than in non-cancer subjects (OR, 0.372; 95% CI, 0.176-0.786, p=0.010). After adjusting, OpGC showed lower risks of fatty liver by ultrasonography (OR, 0.545; 95% CI, 0.306-0.970, p=0.039) and MAFLD (OR, 0.375; 95% CI, 0.197-0.711, p=0.003) than did non-cancer subjects. There were no significant differences in the risks of metabolic syndrome and fatty liver diseases between non-OpGC and non-cancer subjects. Conclusions: OpGC showed lower risks of metabolic syndrome, fatty liver by ultrasonography, and MAFLD than non-cancer subjects, but there were no significant differences in the risks between non-OpGC and non-cancer subjects. Further studies on metabolic syndrome and fatty liver diseases in gastric cancer survivors are warranted.

Nomogram for pre-procedural prediction of non-curative endoscopic resection in patients with early gastric cancer.

BACKGROUND: Non-curative resection (non-CR) after endoscopic submucosal dissection (ESD) requires additional surgery due to the possibility of lymph node metastasis (LNM). Therefore, it is important to accurately predict the risk of non-CR to avoid unnecessary preoperative procedures. Thus, we aimed to develop and verify a nomogram to predict the risk of non-CR prior to ESD. METHODS: Patients who underwent ESD for early gastric cancer (EGC) were divided into CR and non-CR groups based on the present ESD criteria. The pre-procedural factors, such as endoscopic features, radiologic findings, and pathology of the lesion, were compared between the groups to identify the risk factors associated with non-CR. A nomogram was developed using multivariate analysis, and its predictive value was assessed using an external validation group. RESULTS: Among 824 patients, 682 were curative (82.7%) and 142 were non-curative (17.3%). By comparing two groups, endoscopic features including redness, whitish mucosal change, fold convergence, and large lesion size; histologic features such as moderately or poorly differentiated or signet ring cell carcinoma; and abnormal CT findings including non-specific lymph node enlargement and fold thickening were identified as significant predictors of non-CR. The nomogram was developed based on these predictors and showed good predictive performance in the external validation, with an area under the curve of 0.87. CONCLUSIONS: We developed a nomogram to predict the risk of non-CR prior to ESD. These predictive factors in addition to the existing ESD criteria can help provide the best treatment option for patients with EGC.

Association of Waist Circumference with the Risk of Inflammatory Bowel Disease: a Nationwide Cohort Study of 10 Million Individuals in Korea.

BACKGROUND AND AIMS: Metabolic syndrome may share the pathophysiology of adipose tissue dysregulation and inadequate immune response with inflammatory bowel disease [IBD]. We determined the association of abdominal obesity [AO] with the risk of developing IBD. METHODS: We conducted a nationwide population-based cohort study using the Korean National Health Insurance Services database. A total of 10 082 568 participants of the 2009 national health screening programme were enrolled. Newly diagnosed Crohn's disease [CD] and ulcerative colitis [UC] were identified using the International Classification of Diseases 10th Revision and specialized national codes for rare intractable diseases. Waist circumference [WC] was classified into six groups and compared with the reference values of 85.0-89.9 cm for men and 80.0-84.9 cm for women. AO was defined as a WC of ≥90 cm for men and ≥85 cm for women. RESULTS: During a median follow-up of 9.3 years, the incidence rates of CD and UC were 2.11 and 8.40 per 100 000 person-years, respectively. After adjustment for age, sex, lifestyle behaviours, income and body mass index [BMI], the increase in baseline WC was significantly associated with the risk of developing CD, but not UC, compared to the references. The risk of developing CD in subjects with AO increased significantly compared to those without AO [adjusted hazard ratio, 1.40; 95% confidence interval, 1.21-1.61], regardless of obesity based on BMI. CONCLUSIONS: Individuals with AO bore an increased risk of developing CD proportional to WC, but not UC, suggesting that visceral adiposity is related to the pathophysiology of CD.

An Optimal Artificial Intelligence System for Real-Time Endoscopic Prediction of Invasion Depth in Early Gastric Cancer.

We previously constructed a VGG-16 based artificial intelligence (AI) model (image classifier [IC]) to predict the invasion depth in early gastric cancer (EGC) using endoscopic static images. However, images cannot capture the spatio-temporal information available during real-time endoscopy-the AI trained on static images could not estimate invasion depth accurately and reliably. Thus, we constructed a video classifier [VC] using videos for real-time depth prediction in EGC. We built a VC by attaching sequential layers to the last convolutional layer of IC v2, using video clips. We computed the standard deviation (SD) of output probabilities for a video clip and the sensitivities in the manner of frame units to observe consistency. The sensitivity, specificity, and accuracy of IC v2 for static images were 82.5%, 82.9%, and 82.7%, respectively. However, for video clips, the sensitivity, specificity, and accuracy of IC v2 were 33.6%, 85.5%, and 56.6%, respectively. The VC performed better analysis of the videos, with a sensitivity of 82.3%, a specificity of 85.8%, and an accuracy of 83.7%. Furthermore, the mean SD was lower for the VC than IC v2 (0.096 vs. 0.289). The AI model developed utilizing videos can predict invasion depth in EGC more precisely and consistently than image-trained models, and is more appropriate for real-world situations.

Effects of immune-mediated inflammatory diseases on cardiovascular diseases in patients with type 2 diabetes: a nationwide population-based study.

Both type 2 diabetes and immune-mediated inflammatory diseases (IMIDs), such as Crohn's disease (CD), ulcerative colitis, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis (PsO) are risk factors of cardiovascular disease. Whether presence of IMIDs in patients with type 2 diabetes increases their cardiovascular risk remains unclear. We aimed to investigate the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes and IMIDs. Patients with type 2 diabetes without cardiovascular disease were retrospectively enrolled from nationwide data provided by the Korean National Health Insurance Service. The primary outcome was cardiovascular mortality, and the secondary outcomes were myocardial infarction (MI), stroke, and all-cause mortality. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analysis was performed to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for each IMID. Overall 2,263,853 patients with type 2 diabetes were analyzed. CD was associated with a significantly higher risk of stroke (IPTW-adjusted HR: 1.877 [95%CI 1.046, 3.367]). UC was associated with a significantly higher risk of MI (1.462 [1.051, 2.032]). RA was associated with a significantly higher risk of cardiovascular mortality (2.156 [1.769, 2.627]), MI (1.958 [1.683, 2.278]), stroke (1.605 [1.396, 1.845]), and all-cause mortality (2.013 [1.849, 2.192]). AS was associated with a significantly higher risk of MI (1.624 [1.164, 2.266]), stroke (2.266 [1.782, 2.882]), and all-cause mortality (1.344 [1.089, 1.658]). PsO was associated with a significantly higher risk of MI (1.146 [1.055, 1.246]), stroke (1.123 [1.046, 1.205]) and all-cause mortality (1.115 [1.062, 1.171]). In patients with type 2 diabetes, concomitant IMIDs increase the risk of cardiovascular morbidity and mortality. Vigilant surveillance for cardiovascular disease is needed in patients with type 2 diabetes and IMIDs.

Hypoxia-induced ELF3 promotes tumor angiogenesis through IGF1/IGF1R.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers despite a relatively low incidence. Angiogenesis, one of the hallmarks of cancer, is essential for the pathogenesis of EOC, which is related to the induction of angiogenic factors. We found that ELF3 was highly expressed in EOCs under hypoxia and functioned as a transcription factor for IGF1. The ELF3-mediated increase in the secretion of IGF1 and VEGF promoted endothelial cell proliferation, migration, and EOC angiogenesis. Although this situation was much exaggerated under hypoxia, ELF3 silencing under hypoxia significantly attenuated angiogenic activity in endothelial cells by reducing the expression and secretion of IGF1 and VEGF. ELF3 silencing attenuated angiogenesis and tumorigenesis in ex vivo and xenograft mouse models. Consequently, ELF3 plays an important role in the induction of angiogenesis and tumorigenesis in EOC as a transcription factor of IGF1. A detailed understanding of the biological mechanism of ELF3 may both improve current antiangiogenic therapies and have anticancer effects for EOC.

SFRP4 and CDX1 Are Predictive Genes for Extragastric Recurrence of Early Gastric Cancer after Curative Resection.

Extragastric recurrence of early gastric cancer (EGC) after curative resection is rare, but prognosis has been poor in previous reports. Recently, single patient classifier (SPC) genes, such as secreted frizzled-related protein 4 (SFRP4) and caudal-type homeobox 1 (CDX1), were associated with prognosis and chemotherapy response in stage II-III gastric cancer. The aim of our study is, therefore, to elucidate predictive factors for extragastric recurrence of EGC after curative resection, including with the expression of SPC genes. We retrospectively reviewed electronic medical records of 1974 patients who underwent endoscopic or surgical curative resection for EGC. We analyzed clinicopathological characteristics to determine predictive factors for extragastric recurrence. Total RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue and amplified by real-time reverse transcription polymerase chain reaction to evaluate expression of SPC genes. Overall incidences of extragastric recurrence were 0.9%. In multivariate analysis, submucosal invasion (odds ratio [OR] = 6.351, p = 0.032) and N3 staging (OR = 171.512, p = 0.012) were independent predictive factors for extragastric recurrence. Mean expression of SFRP4 in extragastric recurrence (-2.8 ± 1.3) was significantly higher than in the control group (-4.3 ± 1.6) (p = 0.047). Moreover, mean expression of CDX1 in extragastric recurrence (-4.6 ± 2.0) was significantly lower than in the control group (-2.4 ± 1.8) (p = 0.025). Submucosal invasion and metastasis of more than seven lymph nodes were independent predictive factors for extragastric recurrence. In addition, SFRP4 and CDX1 may be novel predictive markers for extragastric recurrence of EGC after curative resection.

Superior therapeutic activity of TGF-ß-induced extracellular vesicles against interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by incapacitating pelvic pain. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are considered key mediators of the paracrine action of MSCs and show better biological activities than the parent MSCs, especially in the bladder tissue, which may be unfavorable for MSC survival. Here, we produced MSC-EVs using advanced three-dimensional (a3D) culture with exogenous transforming growth factor-ß3 (TGF-ß3) (T-a3D-EVs). Treatment with T-a3D-EVs led to significantly enhanced wound healing and anti-inflammatory capacities. Moreover, submucosal layer injection of T-a3D-EVs in chronic IC/BPS animal model resulted in restoration of bladder function, superior anti-inflammatory activity, and recovery of damaged urothelium compared to MSCs. Interestingly, we detected increased TGF-ß1 level in T-a3D-EVs, which might be involved in the anti-inflammatory activity of these EVs. Taken together, we demonstrate the excellent immune-modulatory and regenerative abilities of T-a3D-EVs as observed by recovery from urothelial denudation and dysfunction, which could be a promising therapeutic strategy for IC/BPS.

Association between triglyceride-glucose index and gastric carcinogenesis: a health checkup cohort study.

BACKGROUND: We aimed to investigate the association between the triglyceride-glucose (TyG) index and gastric carcinogenesis, including precancerous conditions such as dysplasia, atrophic gastritis, and intestinal metaplasia. METHODS: Patients who received an upper endoscopic assessment at a medical center were included. The enrolled patients were divided into four categories according to their TyG index quartile (Q). To evaluate the relationship between increase of TyG index and gastric cancer, we analyzed the patients who received a health checkup twice. Moreover, receiver-operating characteristic curve analysis was used to establish cut-off value of the TyG index for gastric cancer. RESULTS: Of 127,564 enrolled patients, 43,525 (34.1%) and 186 (0.1%) were diagnosed with precancerous conditions and gastric cancer, respectively. The odds ratios (ORs) of precancerous conditions given TyG index progressively increased across quartiles: using Q1 as the reference: Q2 (OR = 1.403, P < 0.001), Q3 (OR = 1.646, P < 0.001), and Q4 (OR = 1.656, P < 0.001). The ORs of gastric cancer also increased according to the quartiles: Q2 (OR = 1.619, P = 0.045), Q3 (OR = 2.180, P = 0.004), and Q4 (OR = 2.363, P = 0.001). Moreover, the increase in TyG index between baseline and follow-up tests was more significant in gastric cancer group than in control group (P = 0.001). The optimal cut-off value for predicting gastric cancer was 9.73. CONCLUSIONS: The TyG index may be a novel predictive biomarker for gastric carcinogenesis. Notably, increase in the TyG index is significantly associated with gastric cancer.

Peri-operative Inflammatory Marker as a Predictive Factor for Prolonged Post-operative Ileus After Gastrectomy for Gastric Cancer.

BACKGROUND/AIMS: Although prolonged post-operative ileus (PPOI) is an important factor for the prolonged length of post-operative hospital stay, there is still a lack of effective predictive and therapeutic methods for PPOI. Previous studies reported that increased inflammatory markers, such as C-reactive protein (CRP) level and neutrophil to lymphocyte ratio (NLR), are associated with malignancies. The aim of our study is to elucidate the association between peri-operative inflammatory markers and PPOI after gastrectomy for gastric cancer. METHODS: We enrolled patients who received gastrectomy for gastric cancer from June 2013 to January 2016 at a single tertiary referral center in Seoul, Korea. We evaluated peri-operative inflammatory markers, including CRP level, NLR, and platelet to lymphocyte ratio (PLR) of enrolled patients. We compared these data between control group and PPOI group. RESULTS: A total of 390 subjects were enrolled in this study, and 132 patients (33.8%) showed PPOI. In univariate analysis, preoperative CRP level and NLR, post-operative day (POD) 1 CRP level, NLR, and PLR, and POD3 CRP level, NLR, and PLR were significantly associated with PPOI. In multivariate analysis, preoperative NLR (P = 0.014), POD1 NLR (P = 0.019), POD3 CRP (P = 0.004), and POD3 NLR (P = 0.008) were independent risk factors for PPOI. CONCLUSIONS: Peri-operative inflammatory markers, such as CRP level and NLR, are useful predictive factors for PPOI who received gastrectomy for gastric cancer. Moreover, prophylactic antibiotics and anti-inflammatory drugs can be preventive and therapeutic agents for PPOI.

Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model.

BACKGROUND/AIMS: The aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI. METHODS: An experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeability, we measured leukocyte count and expression of calprotectin, claudin-1, claudin-2, and mast cell tryptase. We compared control, POI, and drug groups (mosapride [0.3 mg/kg and 1 mg/kg, orally], glutamine [500 mg/kg, orally], or ketotifen [1 mg/kg, orally] with regard to these parameters. RESULTS: Increased permeability after surgery significantly decreased after administration of mosapride, glutamine, or ketotifen. Leukocyte counts increased in the POI group and decreased significantly after administration of mosapride (0.3 mg/kg) in the ileum, and mosapride (0.3 mg/kg and 1 mg/kg), glutamine, or ketotifen in the proximal colon. Increased expression of calprotectin after surgery decreased after administration of mosapride (0.3 mg/kg), glutamine, or ketotifen in the ileum and proximal colon, and mosapride (1 mg/kg) in the ileum. The expression of claudin-1 decreased significantly and that of claudin-2 increased after operation. After administration of glutamine, the expression of both proteins was restored. Finally, mast cell tryptase levels increased in the POI group and decreased significantly after administration of ketotifen. CONCLUSIONS: The alteration in intestinal permeability is one of the factors involved in the pathogenesis of POI. We repositioned 3 drugs (mosapride, glutamine, and ketotifen) as novel therapeutic agents for POI.

Specialized endothelial tip cells guide neuroretina vascularization and blood-retina-barrier formation.

Endothelial tip cells guiding tissue vascularization are primary targets for angiogenic therapies. Whether tip cells require differential signals to develop their complex branching patterns remained unknown. Here, we show that diving tip cells invading the mouse neuroretina (D-tip cells) are distinct from tip cells guiding the superficial retinal vascular plexus (S-tip cells). D-tip cells have a unique transcriptional signature, including high TGF-ß signaling, and they begin to acquire blood-retina barrier properties. Endothelial deletion of TGF-ß receptor I (Alk5) inhibits D-tip cell identity acquisition and deep vascular plexus formation. Loss of endothelial ALK5, but not of the canonical SMAD effectors, leads to aberrant contractile pericyte differentiation and hemorrhagic vascular malformations. Oxygen-induced retinopathy vasculature exhibits S-like tip cells, and Alk5 deletion impedes retina revascularization. Our data reveal stage-specific tip cell heterogeneity as a requirement for retinal vascular development and suggest that non-canonical-TGF-ß signaling could improve retinal revascularization and neural function in ischemic retinopathy.

Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. METHODS: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. RESULTS: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1-deficient mice. CONCLUSIONS: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.

The antioxidant dieckol reduces damage of oxidative stress-exposed porcine oocytes and enhances subsequent parthenotes embryo development.

This study investigated the effect of the antioxidant dieckol, a component of Ecklonia cava, on maturation and developmental competence of porcine oocytes exposed to oxidative stress in vitro. Oocytes were matured in in vitro maturation (IVM) medium containing various concentrations of dieckol. The blastocyst formation rate was highest in the 0.5 µM dieckol-treated (0.5 DEK) group. The reactive oxygen species level was decreased, and the level of glutathione and expression of antioxidant genes (NFE2L, SOD1, and SOD2) at metaphase II were increased in the 0.5 DEK group. Abnormal spindle organization and chromosome misalignment were prevented in the 0.5 DEK group. Expression of maternal markers (CCNB1 and MOS) and activity of p44/42 mitogen-activated protein kinase were increased in the 0.5 DEK group. After parthenogenetic activation, the total number of cells per blastocyst was increased and the percentage of apoptotic cells was decreased in the 0.5 DEK group. Expression of development-related genes (CX45, CDX2, POU5F1, and NANOG), antiapoptotic genes (BCL2L1 and BIRC5), and a proapoptotic gene (CASP3) were altered in the 0.5 DEK group. These results indicate that the antioxidant dieckol improves IVM and subsequent development of porcine oocytes and can be used to improve the quality of oocytes under peroxidation experimental conditions.

Prognostic Significance of Interim Response Evaluation during Definitive Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

The study aimed to investigate the clinical significance of interim response evaluation during definitive chemoradiotherapy (dCRT) in predicting overall treatment response and survival of patients with locally advanced esophageal squamous cell carcinoma (LAESCC). We reviewed 194 consecutive patients treated with dCRT for biopsy-confirmed LAESCC. A total of 51 patients met the inclusion criteria. Interim response was assessed by defining a region of interest in initial and adaptive computed tomography (CT) images and subsequently examined against the overall treatment response assessed three months after dCRT, treatment failure pattern, overall survival (OS), and progression-free survival (PFS) estimates. Reductions in both the area and maximal diameter of the primary lesion (p < 0.001; p < 0.001, respectively) and those of the metastatic lymph nodes (LN) (p = 0.002; p < 0.001, respectively) in interim analysis were significantly higher among patients who achieved complete response (CR) than among those who did not. OS was significantly longer among patients who showed ≥30% interim reduction in the area and maximal diameter of the primary lesion and among those who showed such reduction in both the primary lesion and LN. PFS was significantly longer in the patients with ≥30% interim reduction in the area of the primary lesion. In addition, the proportion of cases with locoregional failure began decreasing at interim response of 20% or higher, while the proportion of cases with outfield failure followed the opposite pattern, increasing at interim response of 20% or higher. Among patients treated with dCRT for LAESCC, interim response assessed using adaptive CT images correlated with overall CR and OS rates. The evaluation of tumor burden reduction during dCRT may help predict patient prognosis.