A machine learning-based quantitative model (LogBB_Pred) to predict the blood-brain barrier permeability (logBB value) of drug compounds.

MOTIVATION: Efficient assessment of the blood-brain barrier (BBB) penetration ability of a drug compound is one of the major hurdles in central nervous system drug discovery since experimental methods are costly and time-consuming. To advance and elevate the success rate of neurotherapeutic drug discovery, it is essential to develop an accurate computational quantitative model to determine the absolute logBB value (a logarithmic ratio of the concentration of a drug in the brain to its concentration in the blood) of a drug candidate. RESULTS: Here, we developed a quantitative model (LogBB_Pred) capable of predicting a logBB value of a query compound. The model achieved an R2 of 0.61 on an independent test dataset and outperformed other publicly available quantitative models. When compared with the available qualitative (classification) models that only classified whether a compound is BBB-permeable or not, our model achieved the same accuracy (0.85) with the best qualitative model and far-outperformed other qualitative models (accuracies between 0.64 and 0.70). For further evaluation, our model, quantitative models, and the qualitative models were evaluated on a real-world central nervous system drug screening library. Our model showed an accuracy of 0.97 while the other models showed an accuracy in the range of 0.29-0.83. Consequently, our model can accurately classify BBB-permeable compounds as well as predict the absolute logBB values of drug candidates. AVAILABILITY AND IMPLEMENTATION: Web server is freely available on the web at http://ssbio.cau.ac.kr/software/logbb_pred/. The data used in this study are available to download at http://ssbio.cau.ac.kr/software/logbb_pred/dataset.zip.

A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3ß), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Prediction of intradialytic hypotension using pre-dialysis features-a deep learning-based artificial intelligence model.

BACKGROUND: Intradialytic hypotension (IDH) is a serious complication of hemodialysis (HD) that is associated with increased risks of cardiovascular morbidity and mortality. However, its accurate prediction remains a clinical challenge. The aim of this study was to develop a deep learning-based artificial intelligence (AI) model to predict IDH using pre-dialysis features. METHODS: Data from 2007 patients with 943 220 HD sessions at seven university hospitals were used. The performance of the deep learning model was compared with three machine learning models (logistic regression, random forest and XGBoost). RESULTS: IDH occurred in 5.39% of all studied HD sessions. A lower pre-dialysis blood pressure (BP), and a higher ultrafiltration (UF) target rate and interdialytic weight gain in IDH sessions compared with non-IDH sessions, and the occurrence of IDH in previous sessions was more frequent among IDH sessions compared with non-IDH sessions. Matthews correlation coefficient and macro-averaged F1 score were used to evaluate both positive and negative prediction performances. Both values were similar in logistic regression, random forest, XGBoost and deep learning models, developed with data from a single session. When combining data from the previous three sessions, the prediction performance of the deep learning model improved and became superior to that of other models. The common top-ranked features for IDH prediction were mean systolic BP (SBP) during the previous session, UF target rate, pre-dialysis SBP, and IDH experience during the previous session. CONCLUSIONS: Our AI model predicts IDH accurately, suggesting it as a reliable tool for HD treatment.

Comparison of the Pharmacokinetics of CT-P13 Between Crohn's Disease and Ulcerative Colitis.

BACKGROUND: We aimed to compare trough infliximab levels and the development of antidrug antibody (ADA) for 1 year between Crohn's disease (CD) and ulcerative colitis (UC) patients who were biologic-naive, and to evaluate their impact on clinical outcomes. METHODS: This was a prospective, multicenter, observational study. Biologic-naive patients with moderate to severe CD or UC who started CT-P13, an infliximab biosimilar, therapy were enrolled. Trough drug and ADA levels were measured periodically for 1 year after CT-P13 initiation. RESULTS: A total of 267 patients who received CT-P13 treatment were included (CD 168, UC 99). The rates of clinical remission (72% vs. 32.3%, P <0.001) at week 54 were significantly higher in CD than in UC. The median trough drug level (µg/mL) was significantly higher in CD than in UC up to week 14 (week 2, 18.7 vs. 14.7, P <0.001; week 6, 12.5 vs. 8.6, P <0.001; week 14, 3.4 vs. 2.5, P =0.001). The median ADA level (AU/mL) was significantly lower in CD than in UC at week 2 (6.3 vs. 6.5, P =0.046), week 30 (7.9 vs. 11.8, P =0.007), and week 54 (9.3 vs. 12.3, P =0.032). Development of ADA at week 2 [adjusted odds ratio (aOR)=0.15, P =0.026], initial C-reactive protein level (aOR=0.87, P =0.032), and CD over UC (aOR=1.92, P <0.001) were independent predictors of clinical remission at week 54. CONCLUSION: Infliximab shows more favorable pharmacokinetics, including high drug trough and low ADA levels, in CD than in UC, which might result in better clinical outcomes for 1-year infliximab treatment in CD patients.

Effectiveness and safety of adalimumab in patients with intestinal Behçet's disease: a real-world prospective observational study in South Korea.

BACKGROUND: Intestinal Behçet's disease (BD) is characterized by typical gastrointestinal ulcers in patients with BD followed by complications such as bleeding, perforation and fistula. Biologic agents are currently under active investigation to delay the disease course. Various data regarding infliximab are available, but there is relatively lack of data regarding adalimumab. METHODS: This was a multicenter, real-world prospective observational study to evaluate the effectiveness and safety of adalimumab in intestinal BD. The primary endpoint was disease activity at each follow up, including disease activity index for intestinal Behçet's disease (DAIBD), serum C-reactive protein (CRP) level, and endoscopic findings. The secondary endpoint was the incidence of adverse drug reactions (ADRs). RESULTS: A total of 58 patients were enrolled and 8 of them were excluded. Adverse events were reported in 72.0% of patients with 122 events. ADRs were reported in 24.0% with 28 events. For adverse events, arthralgia was most commonly reported (13.1%: 16/122) and only one experienced critical adverse event (0.82%, 1/122: death due to stroke). On multivariable regression analysis, a longer disease duration was significantly associated with decreased ADRs [Odds ratio 0.976 (0.953-0.999, 95% CI); p = 0.042]. Clinical response rates as assessed by DAIBD were 90.9% at Week 12 and 89.7% at Week 56, respectively. The mean serum CRP level at baseline was significantly decreased after 12 weeks (3.91 ± 4.93 to 1.26 ± 2.03 mg/dL; p = 0.0002). CONCLUSION: Adalimumab was found to be safe and effective in Korean patients with intestinal BD. A longer disease duration was significantly associated with decreased ADRs.

Efficacy and safety of one-step knife compared to conventional insulated-tip knife for endoscopic submucosal dissection: a preliminary study with prospective data collection and retrospective review.

BACKGROUND: Endoscopic submucosal dissection (ESD) is not as tiresome as gastrectomy, but it is a time-consuming procedure. One-step knife (OSK) is a novel knife that combines a knife for ESD and an injection needle into one sheath. In this study, we aimed to compare the insulated tip type of OSK and conventional knife (CK) in terms of procedure time and complication rate. METHODS: Medical records of patients with ESD using CK between February and September 2020 were retrospectively reviewed. Subsequently, data from patients who underwent ESD using OSK by September 2021 were prospectively collected. Total procedure time, procedure time by location and complication rate in the OSK and CK group were compared. RESULTS: In the study period, a total of 203 patients (OSK, 102 patients; CK, 101 patients) were analyzed. On multivariate analysis, using CK, body location, resection size ≥ 40 mm, and submucosal fibrosis were associated with longer procedure time. The total procedure time was statistically significantly reduced in the OSK group (median 11 vs. 17 min, p < 0.01). The procedure time for each location was more reduced in the body (median 14 vs. 19 min p < 0.01) than the antrum (median 10 vs. 14 min, p = 0.01) in the OSK group. There was no significant difference in post-ESD bleeding and perforation in the two groups (3.9 vs. 3.9%, p = 0.99 and 1.0 vs. 2.0%, p = 0.56). CONCLUSIONS: OSK significantly reduced the total procedure time of ESD. OSK could be an effective and safe knife for gastric ESD, especially for body lesions.

Clinical outcomes and risk factors associated with poor prognosis after endoscopic resection of 10-20 mm rectal neuroendocrine tumors: a multicenter, retrospective study of 10-year experience.

BACKGROUND: The efficacy of endoscopic resection for of 10-20 mm rectal neuroendocrine tumor (NET) remains controversial. We aimed to evaluate the clinical outcomes and risk factors associated with poor prognosis after endoscopic resection of 10-20 mm rectal NET and to determine the optimal treatment. METHODS: Patients who underwent endoscopic resection for rectal NET in four tertiary hospitals were enrolled, and data on with the clinical outcomes and risk factors related to poor prognosis were retrospectively analyzed. RESULTS: A total of 105 patients who underwent endoscopic submucosal resection (ESD; n = 65, 61.9%), modified endoscopic mucosal resection (mEMR; n = 31, 29.5%), and conventional EMR (cEMR; n = 9, 8.6%) were enrolled. The mean follow-up period was 41.2 ± 21.9 months. In the morphologic findings, the mean diameter was 11.6 mm (range 10-19); the shape was sessile (50.5%) and mixed type (49.5%), and surface depression was observed in 41.9% of patients. In the histologic findings, 87.6% of patients had G1 and 12.4% G2 tumor grade, and 3.8% of patients had lymphovascular invasion. The overall en bloc and histologically complete (R0) resections were 99.1% and 76.2%, respectively. cEMR was a less-frequently developed R0 resection. In the univariate and multivariate analyses for R0 resection, only surface depression was significantly associated. Regional or distant organs metastasis during follow-up developed in three patients (2.9%) and was significantly associated with female sex, redness, G2 tumor grade, and non-ESD methods. CONCLUSION: Patients who underwent endoscopic resection of 10-20 mm rectal NET had good prognosis; therefore, endoscopic resection can be considered as the first-line treatment, particularly for 10-14 mm rectal NET. However, the risk factors, such as female sex, redness, G2 tumor grade and non-ESD methods, were associated with regional or distant metastases during follow-up. Therefore, patients with these risk factors should be carefully monitored.

Preventive effect of peptides derived from fermented milk on chronic stress-induced brain damage and intestinal dysfunction in mice.

This study investigated the preventive effects of peptides derived from milk fermented with the probiotic strain Lactobacillus gasseri 505 (505) against stress-related brain damage and anxiety-like behavior. The peptides MKPWIQPKTKVIPYVRYL (Pep14) and VYQHQKAMKPWIQPKTKVIPYVRYL (Pep21), which exhibit high antioxidant and anti-inflammatory activities, were administered to stressed mice. The results showed that the stress mechanism in the gut-brain axis was regulated by pretreatment with both peptides, leading to inhibition of neurodevelopment and neuroinflammation through the hypothalamic-pituitary-adrenal (HPA) axis, based on the expression of related mRNA and proteins. The expression of colonic inflammation-related mRNA and proteins was also reduced. Moreover, anxiety-like behavior was significantly reduced in mice treated with Pep14 and Pep21. These results indicate that the bioactive peptides Pep14 and Pep21, derived from milk fermented with 505, may prevent stress-induced brain damage and anxiety-like behavior via regulation of the HPA axis.

Comparison of biannual and annual endoscopic gastric cancer surveillance after endoscopic resection.

BACKGROUND: Patients who received endoscopic resection (ER) for early gastric cancer (EGC) or high-grade dysplasia (HGD) are at high risk for the subsequent development of metachronous gastric cancer (MGC). This study aims to compare the detection rate and stage of MGC between biannual and annual endoscopic surveillance after ER of EGC or HGD. METHODS: From September 2009 to August 2019, 859 patients who underwent ER for the treatment of EGC or HGD were analyzed, retrospectively. Patients received endoscopic surveillance twice a year (high-intensity group) or annually (low-intensity group) for 3 years. RESULTS: A total of 521 patients were enrolled in this study (267 patients in the high-intensity group and 254 patients in the low-intensity group). During a mean follow-up of 5.3 ± 1.6 years, MGCs were found in 27 patients (16.9%) in the high-intensity group and 18 patients (7.1%) in the low-intensity group (P = 0.219). In patients with moderate to severe atrophy (Kimura-Takemoto grade C3 ~ O3), detection rates of MGC during 3 years from were 8.4% (16/191) and 2.2% (4/186), respectively (P = 0.007). Forty-four patients who received treatment for MGC, including endoscopic or surgical resection, were stage IA. Only one patient in the low-intensity group was diagnosed as stage IIIA advanced gastric cancer. CONCLUSIONS: There was no significant difference in the detection rate of MGC between biannual and annual endoscopic surveillance after ER of EGC or HGD. However, biannual surveillance showed a higher detection rate during the first 3 years, especially for patients with moderate to severe gastric atrophy.

Optimal ICG dosage of preoperative colonoscopic tattooing for fluorescence-guided laparoscopic colorectal surgery.

BACKGROUND: Indocyanine green (ICG) is a multifunctional dye used in tumor localization, tissue perfusion, and lymph node (LN) mapping during fluorescence-guided laparoscopic colorectal surgery. PURPOSE: This study aimed to establish the optimal protocol for preoperative endoscopic submucosal ICG injection to perform fluorescence lymph node mapping (FLNM), along with undisturbed fluorescent tumor localization and ICG angiography during a single surgery. METHODS: Colorectal cancer patients (n = 192) were enrolled from May 2017 to December 2019. Colonoscopic submucosal ICG injection was performed 12 to 18 h before surgery. ICG injection protocols were modified based on the total injected ICG (mg) and tattooing site number. The concentrations of ICG were gradually decreased from the standard dose (2.5 mg/ml) to the minimum dose (0.2 mg/ml). Successful FLNM (FLNM-s) was defined as distinct fluorescent LNs observed under NIR camera. The patient's age, sex, body mass index (BMI), stage, cancer location, obstruction, and laboratory findings were compared between the FLNM-s and failed FLNM (FLNM-f) groups to identify clinical and pathological factors that affect FLNM. RESULTS: In the ICG dose section of 0.5 to 1 mg, the success rate was highest within all functions including FLNM, fluorescent tumor localization, and ICG angiography. FLNM-s was related to ICG dose (0.5-1 mg), multiple submucosal injections, location of cancer, camera light source, and lower BMI. In the multivariate analysis, camera light source, non-obesity, and multiple injections were independent factors for FLNM-s). The mean total number of harvested LNs was significantly higher in the FLNM-s group than that in the FLNM-f group (p < 0.001). The number of metastatic lymph nodes was comparable between the two groups (p = 0.859). CONCLUSIONS: Preoperative, endoscopic submucosal ICG injection with dose range 0.5 to 1 mg would be optimal protocol for multifunctional ICG applications during fluorescence-guided laparoscopic colorectal surgery.

Endoscopic visualization of graft status in patients with pancreas transplantation.

BACKGROUND: Enteric drainage into the recipient duodenum in pancreas transplantation (PT) can identify the graft duodenum by endoscopy. This study aimed to identify the characteristic endoscopic findings associated with graft failure or acute rejection in patients with PT. METHODS: We reviewed the medical records of patients who underwent PT with duodenoduodenostomy (DD) between January 2015 and August 2019. During this period, there were 44 PTs with DD in 42 patients; 122 endoscopies were performed and analyzed. RESULTS: Overall, pancreatic graft survival was 82% at a mean follow-up of 27 months (range 6-55 months). There were 8 graft failures and 10 acute rejections. In all 8 graft failures, a deep ulcer covered with fibrinous exudates of the graft duodenum was confirmed on endoscopy. Diffuse erythema inside the graft duodenum was observed in 8 of 10 acute rejections. The factors associated with acute rejection were elevated serum lipase level (OR 8.5, p = 0.02) and diffuse erythema inside the graft duodenum on endoscopy (OR 20.5, p < 0.01) in multivariate analysis. CONCLUSIONS: In PT with DD patients, graft failure can be visualized by endoscopy, and diffuse erythema inside the graft duodenum may be a finding of acute rejection.

Long-term outcomes and surveillance timing of patients with large non-pedunculated colorectal polyps with histologically incomplete resection in endoscopic resection.

BACKGROUND: Histologically incomplete resection of large colorectal polyps is frequently encountered; however, the long-term outcomes or surveillance timing is not well known. We evaluated the incidence rate and time of recurrence of these cases during a long-term follow-up. METHODS: We performed a retrospective analysis of patients who underwent endoscopic resection for large (≥10 mm in size) non-pedunculated colorectal polyps at a tertiary academic hospital. Patients who had positive or indeterminate lateral margin in the histology and underwent completed surveillance colonoscopy first at 3-12 months and finally at ≥2 years after initial resection were included. RESULTS: Of 169 polyps (148 patients), 37 (21.9%) and 132 (78.1%) polyps had positive and indeterminate lateral margins, respectively. The median time intervals of the first and last surveillance from the initial resection were 6 (3-12) and 48 (24-114) months, respectively. The recurrence rate was 9.5% (16/169) during follow-up, and the mean time to recurrence was 31.9 months. Thirteen (81.3%) polyps recurred after ≥12 months. Most (14/16, 87.5%) recurrent polyps were benign, and 2 cases had advanced cancer. The only factor that was significantly associated with recurrence in the univariate and multivariate analyses was ≥3 piecemeal resections (odds ratio in the multivariate analysis, 16.92; 95% CI, 1.19-241.81; p = 0.037). CONCLUSION: During the long-term follow-up, the only factor that was significantly associated with recurrence was ≥3 piecemeal resections, and most recurrences occurred after ≥12 months. Thus, a histologically incomplete resection with ≤2 piecemeal resections and no findings of suspected submucosal cancer may be considered as complete resection, and these patients may undergo first surveillance colonoscopy after 1-2 years.

Analysis of phototoxin taste closely correlates nucleophilicity to type 1 phototoxicity.

Pigments often inflict tissue-damaging and proaging toxicity on light illumination by generating free radicals and reactive oxygen species (ROS). However, the molecular mechanism by which organisms sense phototoxic pigments is unknown. Here, we discover that Transient Receptor Potential Ankyrin 1-A isoform [TRPA1(A)], previously shown to serve as a receptor for free radicals and ROS induced by photochemical reactions, enables Drosophila melanogaster to aphotically sense phototoxic pigments for feeding deterrence. Thus, TRPA1(A) detects both cause (phototoxins) and effect (free radicals and ROS) of photochemical reactions. A group of pigment molecules not only activates TRPA1(A) in darkness but also generates free radicals on light illumination. Such aphotic detection of phototoxins harboring the type 1 (radical-generating) photochemical potential requires the nucleophile-sensing ability of TRPA1. In addition, agTRPA1(A) from malaria-transmitting mosquitoes Anopheles gambiae heterologously produces larger current responses to phototoxins than Drosophila TRPA1(A), similar to their disparate nucleophile responsiveness. Along with TRPA1(A)-stimulating capabilities, type 1 phototoxins exhibit relatively strong photo-absorbance and low energy gaps between the highest occupied molecular orbital and the lowest unoccupied molecular orbital. However, TRPA1(A) activation is more highly concordant to type 1 phototoxicity than are those photochemical parameters. Collectively, nucleophile sensitivity of TRPA1(A) allows flies to taste potential phototoxins for feeding deterrence, preventing postingestive photo-injury. Conversely, pigments need to bear high nucleophilicity (electron-donating propensity) to act as type 1 phototoxins, which is consistent with the fact that transferring photoexcited electrons from phototoxins to other molecules causes free radicals. Thus, identification of a sensory mechanism in Drosophila reveals a property fundamental to type 1 phototoxins.

Absent or impaired rectoanal inhibitory reflex as a diagnostic factor for high-grade (grade III-V) rectal prolapse: a retrospective study.

BACKGROUND: Clinically diagnosing high-grade (III-V) rectal prolapse might be difficult, and the prolapse can often be overlooked. Even though defecography is the significant diagnostic tool for rectal prolapse, it is noticed that rectoanal inhibitory reflex (RAIR) can be associated with rectal prolapse. This study investigated whether RAIR can be used as a diagnostic factor for rectal prolapse. METHODS: In this retrospective study, we evaluated 107 patients who underwent both anorectal manometry and defecography between July 2012 and December 2019. Rectal prolapse was classified in accordance with the Oxford Rectal Prolapse Grading System. Patients in the high-grade (III-V) rectal prolapse (high-grade group, n = 30), and patients with no rectal prolapse or low-grade (I, II) rectal prolapse (low-grade group, n = 77) were analyzed. Clinical variables, including symptoms such as fecal incontinence, feeling of prolapse, and history were collected. Symptoms were assessed using yes/no surveys answered by the patients. The manometric results were also evaluated. RESULTS: Frequencies of fecal incontinence (p = 0.002) and feeling of prolapse (p < 0.001) were significantly higher in the high-grade group. The maximum resting (77.5 vs. 96 mmHg, p = 0.011) and squeezing (128.7 vs. 165 mmHg, p = 0.010) anal pressures were significantly lower in the high-grade group. The frequency of absent or impaired RAIR was significantly higher in the high-grade group (19 cases, 63% vs. 20 cases, 26%, p < 0.001). In a multivariate analysis, the feeling of prolapse (odds ratio [OR], 23.88; 95% confidence interval [CI], 4.43-128.78; p < 0.001) and absent or impaired RAIR (OR, 5.36; 95% CI, 1.91-15.04, p = 0.001) were independent factors of high-grade (III-V) rectal prolapse. In addition, the percentage of the absent or impaired RAIR significantly increased with grading increase of rectal prolapse (p < 0.001). The sensitivity of absent or impaired RAIR as a predictor of high-grade prolapse was 63.3% and specificity 74.0%. CONCLUSIONS: Absent or impaired RAIR was a meaningful diagnostic factor of high-grade (III-V) rectal prolapse. Furthermore, the absent or impaired reflex had a positive linear trend according to the increase of rectal prolapse grading.

Transurethral prostate surgery as a preventive method against progression of chronic kidney disease in patients with urodynamically proven bladder outlet obstruction.

OBJECTIVE: The present study was aimed to investigate (1) whether urodynamic factors are responsible for kidney damage in patients with bladder outlet obstruction (BOO) and (2) whether transurethral prostate surgery for BOO can alleviate the damage to the kidneys. METHODS: This prospective observational study involved men aged 50-80 years. Prostate size and urodynamic test were performed during screening period. Laboratory tests to measure the glomerular filtration rate, the urinary protein to creatinine ratio and dipstick urinalysis were performed before and 6 months after the transurethral prostate surgery. RESULTS: Sixty-seven patients completed the laboratory study among a hundred enrolled patients with urodynamically proven BOO. Among the urodynamic parameters, only low bladder compliance (lower than 60 mL/cmH2O) was associated with clinically significant proteinuria (p < 0.001). Transurethral prostate surgery significantly improved proteinuria (p = 0.007), especially in patients with low bladder compliance (p = 0.004), and subsequently decreased the risk grade of CKD progression (p < 0.001). CONCLUSIONS: Low bladder compliance in patients with BOO may be a risk factor for kidney damage. Transurethral prostate surgery to relieve BOO could be a preventive method against CKD progression in patients with low bladder compliance.

Factors associated with conversion to snare resection during gastric endoscopic submucosal dissection.

BACKGROUND AND AIMS: Although gastric endoscopic submucosal dissection (ESD) achieves a higher en-bloc resection rate compared to that with endoscopic mucosal resection (EMR) for gastric epithelial tumors, the higher complication rate and the longer procedure time are obstacles for its widespread use. Rescue EMR may be a valuable treatment option during difficult ESD procedures. We have aimed to identify the clinical outcomes and associated factors of rescue EMR during ESD. PATIENTS AND METHODS: The medical records of patients who underwent ESD between January 2009 and February 2016 were reviewed. The clinical outcomes of rescue EMR during ESD and associated factors with rescue EMR were evaluated. RESULTS: A total of 1778 gastric epithelial lesions were enrolled. ESD without using a snare and rescue EMR were performed in 94.5% and 5.5% of patients, respectively. Lesion locations of mid-third [odd ratio (OR 4.470)], upper-third (OR 1.997), and submucosal fibrosis (OR 1.906) were the significant associated factors with rescue EMR. The en-bloc resection rate and complete resection rate of rescue EMR were lower than that of ESD (98.4% vs. 93.8% and 96.2% vs. 83.5%, respectively). Local recurrence rate was higher after rescue EMR than that after ESD (4.1% vs. 1.2%). Procedure-related complications and procedure time were not significantly different between the two groups. CONCLUSIONS: In a difficult ESD procedure, rescue EMR may be an alternative treatment option, especially for lesions located at the mid-to-upper third of the stomach, without increasing either the procedure time or the rate of complications.

Clinical outcomes of endoscopic submucosal dissection for lesions on the proximal location between remnant and entire stomach.

BACKGROUND: Tumors located on the proximal stomach are associated with a longer procedure time and lower en-block resection of endoscopic submucosal dissection (ESD). Additionally, it is more difficult to perform ESD for lesions after distal gastrectomy because of the narrow inner space. We aimed to evaluate the therapeutic outcomes of ESD for lesions on the remnant stomach compared with those on the upper third of the entire stomach. METHODS: A total of 135 patients with a neoplasm located on the proximal stomach who received ESD between Aug 2008 and Dec 2016 were enrolled. We retrospectively reviewed en-bloc resection rate, complete resection rate, and complication rate according to whether distal gastrectomy was performed. Clinical outcomes were compared among the 1:2 propensity-matched groups. RESULTS: Between the remnant stomach and entire stomach, the en-bloc [92% (23/25) and 92.0% (46/50), respectively; P = 1.000] and complete resection [84% (21/25) and 88.0 (44/50), respectively; P = 0.723] rates were not significantly different. In patients with lesions that indicated ESD, there was no significant difference in en-bloc and complete resection rates. In a multivariable analysis, submucosal fibrosis [odds ratio (OR) 5.9, 95% confidence interval (CI) 1.1-30.7] and submucosa invasive cancer (OR 10.1, 95% CI 1.4-74.3) were independent risk factors for incomplete resection. CONCLUSIONS: ESD is a feasible therapeutic option for lesions located on the proximal stomach regardless the operation history of distal gastrectomy. However, the complete resection rate decreases for lesions with submucosal fibrosis or the submucosa invasion.

Autophagy in FOXD1 stroma-derived cells regulates renal fibrosis through TGF-ß and NLRP3 inflammasome pathway.

Renal fibrosis is the final common pathway of various renal injuries and it leads to chronic kidney disease. Recent studies reported that FOXD1-lineage pericyte plays a critical role in tubulointerstitial fibrosis (TIF). However the regulatory mechanisms remain unclear. Autophagy is a cellular process of degradation of damaged cytoplasmic components that regulates cell death and proliferation. To investigate the role of autophagy in FOXD1-lineage pericytes on renal TIF, we generated the FOXD1-lineage stromal cell-specific Atg7 deletion (Atg7△FOXD1) mice. FOXD1-lineage stromal cell-specific Atg7 deletion enhanced renal TIF through Smad-dependent transforming growth factor (TGF)-ß signaling after unilateral ureteral obstruction (UUO). FOXD1-lineage stromal cell-specific Atg7 deletion increased the accumulation of interstitial myofibroblasts and enhanced the differentiation of pericytes into myofibroblasts after UUO. Peritubular capillary rarefaction was accelerated in Atg7△FOXD1 mice after UUO. Atg7△FOXD1 mice increased the accumulation of SQSTM1/p62-positive aggregates in the obstructed kidney and resulted in increased expression of NLRP3 inflammasome, interleukin (IL) 1-ß and caspase-1 signaling pathway, which enhanced apoptosis of interstitial cells after UUO. In summary, our data showed that autophagy in FOXD1-lineage stromal cells plays a protective role in renal TIF through regulating the Smad4 dependent TGF-ß an NLRP3 inflammasome signaling pathway.

Efficacy of preoperative colonoscopic tattooing with indocyanine green on lymph node harvest and factors associated with inadequate lymph node harvest in colorectal cancer.

Objective: Adequate lymph node harvest (LNH) in colorectal cancer is closely related to survival. This study aimed to evaluate the effect of preoperative colonoscopic tattooing (PCT) with indocyanine green (ICG) on adequate LNH in colorectal cancer. Materials and methods: A total of 1079 patients who underwent surgical resection for colorectal cancer were divided into two groups: a tattooing group and a non-tattooing group. The patients were retrospectively analyzed for the number and adequacy of LNH according to tumor locations and stages. Univariate and multivariate analysis for factors associated with adequate LNH were done. Results: There was no significant difference between the two groups in the number and adequacy of LNH according to tumor locations. However, T1 colorectal cancer in the tattooing group had significantly higher adequate LNH (91.6% vs 82.1%, OR 2.370, p = .048) and T1 and N0 rectal cancer in the tattooing group also had higher adequate LNH although there was no statistical significance (100% vs 82.4%, OR 12.088, p = .095; 96.9% vs 84.8%, OR 5.570, p = .099) when compared to the non-tattooing group. Male sex and T1 stage were significantly associated with inadequate LNH in multivariate analysis (OR 0.556 (95% CI 0.340-0.909), p = .019; OR 0.555 (95% CI 0.339-0.910), p = .019, respectively). Conclusion: PCT with ICG did not improve adequate LNH in colorectal cancer but effectively improved adequate LNH in early colorectal cancer. Male sex and early cancer were risk factors for inadequate LNH in colorectal cancer, so PCT is needed for adequate LNH in these patients.

Clinical outcomes of iatrogenic upper gastrointestinal endoscopic perforation: a 10-year study.

BACKGROUND: Upper gastrointestinal endoscopic examination is a relatively safe procedure; however, all endoscopic procedures are invasive and are associated with a risk of iatrogenic perforation. To evaluate clinical outcomes of iatrogenic upper gastrointestinal endoscopic perforation. Factors associated with surgical management or mortality were analyzed. METHODS: Between November 2008 and November 2018, the medical records of 149,792 upper gastrointestinal endoscopic procedures were evaluated. The mechanisms of perforations were categorized as electrocoagulation-induced or blunt trauma-induced injuries. The incidence and clinical outcomes of iatrogenic perforations based on the types of procedures performed were evaluated. RESULTS: Iatrogenic endoscopic perforations occurred in 28 cases (0.019%). Iatrogenic perforation-related mortality occurred in 3 patients. The iatrogenic perforation rate based on the types of procedures performed was as follows: diagnostic endoscopy = 0.002%, duodenal endoscopic mucosal resection = 0.9%, esophageal endoscopic submucosal dissection = 10.7%, gastric endoscopic submucosal dissection = 0.2%, endoscopic self-expandable metal stent insertion for malignant esophageal obstruction = 0.1%, duodenoscope-induced injury = 0.02%, endoscopic sphincterotomy = 0.08%, and ampullectomy = 6.8%. All electrocoagulation-induced perforations (n = 21) were managed successfully (15 cases of endoscopic closure, 5 cases treated conservatively, and 1 case treated surgically). Three patients died among those with blunt trauma-induced perforations (n = 7). The factors associated with surgical management or mortality were old age, poor performance status (Eastern Cooperative Oncology Group score ≥ 1), advanced malignancy, and blunt trauma. CONCLUSIONS: Most cases of electrocoagulation-induced iatrogenic perforations can be treated using endoscopic clips. If endoscopic closure fails for blunt trauma-induced perforations, prompt surgical management is mandatory.