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Abstract T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) exhibits unique, cell type- and context-dependent characteristics and functions. Here, we report that TIM-3 on myeloid cells plays essential roles in modulating lung inflammation. We found that myeloid cell-specific TIM-3 knock-in (FSF-TIM3/LysM-Cre+) mice have lower body weight and shorter lifespan than WT mice. Intriguingly, the lungs of FSF-TIM3/LysM-Cre+ mice display excessive inflammation and features of disease-associated pathology. We further revealed that galectin-3 levels are notably elevated in TIM-3-overexpressing lung-derived myeloid cells. Furthermore, both TIM-3 blockade and GB1107, a galectin-3 inhibitor, ameliorated lung inflammation in FSF-TIM3/LysM-Cre+/− mice. Using an LPS-induced lung inflammation model with myeloid cell-specific TIM-3 knock-out mice, we demonstrated the association of TIM-3 with both lung inflammation and galectin-3. Collectively, our findings suggest that myeloid TIM-3 is an important regulator in the lungs and that modulation of TIM-3 and galectin-3 could offer therapeutic benefits for inflammation-associated lung diseases.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Serotonin (5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system and as a paracrine, exocrine, or endocrine messenger in peripheral tissues. In this study, we hypothesized that inhibition of serotonin signaling using 5-HT receptor 2B (HTR2B) inhibitors could potentially impede the progression of CRC. We treated CT26 and COLO-205 cells with SB204741, an inhibitor of HTR2B, and evaluated CRC cell proliferation and migration. We then evaluated the effects of HTR2B inhibition in a xenograft mouse model of human colorectal cancer. We also evaluated the role of a novel inhibitor, GM-60186, using both in vitro and in vivo models. RNA sequencing analysis was performed to elucidate the underlying mechanism of the anti-tumor effects of pharmacological inhibition of HTR2B on CRC. In both CRC cell lines and xenograft mouse models, we show that pharmacological inhibition of HTR2B with SB204741 and GM-60186 significantly inhibits CRC cell proliferation and migration. HTR2B inhibition leads to the suppression of extracellular signal-regulated kinase (ERK) signaling, a critical pathway in CRC pathogenesis. Notably, transcriptomic analysis reveals distinct gene expression changes associated with HTR2B inhibition, providing insight into its therapeutic potential. In this study, we found that pharmacological inhibition of HTR2B suppressed CRC proliferation via ERK signaling. In addition, we proposed a novel HTR2B inhibitor for the treatment of CRC. This study highlights the potential role of HTR2B signaling in CRC. These inhibitors may contribute to new therapeutics for CRC treatment.

Objective Fall from height (FFH) is a major public health problem that can result in severe injury, disability, and death. This study investigated how the characteristics of jumpers and fallers differ. Methods This was a retrospective study of FFH patients enrolled in an Emergency Department-based Injury In-depth Surveillance (EDIIS) registry between 2011 and 2018. Depending on whether the injury was intentional, FFH patients who had fallen from a height of at least 1 m were divided into two groups: jumpers and fallers. Patient characteristics, organ damage, and death were compared between the two groups, and factors that significantly affected death were identified using multivariable logistic analysis. Results Among 39,419 patients, 1,982 (5.0%) were jumpers. Of the jumpers, 977 (49.3%) were male, while 30,643 (81.9%) of fallers were male. The jumper group had the highest number of individuals in their 20s, with the number decreasing as age increased. In contrast, the number of individuals in the faller group rose until reaching their 50s, after which it declined. More thoracoabdominal, spinal, and brain injuries were found in jumpers. The in-hospital mortality of jumpers and fallers was 832 (42.0%) and 1,268 (3.4%), respectively. Intentionality was a predictor of in-hospital mortality, along with sex, age, and fall height, with an odds ratio of 7.895 (95% confidence interval, 6.746–9.240). Conclusion Jumpers and fallers have different epidemiological characteristics, and jumpers experienced a higher degree of injury and mortality than fallers. Differentiated prevention and treatment strategies are needed for jumpers and fallers to reduce mortality in FFH patients.

Abstract Background High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection. Methods This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity. Discussion The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses. Trial registration ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Abstract Background Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). Methods A multicenter randomized phase II trial involving 364 patients with LARC (cT3–4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45–50.4 Gy in 25–28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2–5 weeks from the last cycle of chemotherapy in the experimental arm and 6–8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. Discussion This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. Trial registration This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

Abstract Background Bioelectric impedance analysis (BIA)-measured body composition and nutritional status have been used as prognostic indicators in various cancer cohorts. This study investigated whether BIA could provide information on prognosis in peritoneal carcinomatosis patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods We retrospectively analyzed the data of 99 patients with preoperative BIA data among those who underwent CRS and HIPEC. The association between BIA-derived parameters and intraoperative peritoneal cancer index (PCI) score was assessed. Predictive analysis for the occurrence of postoperative morbidities including major complications (Clavien–Dindo classification 3–4) and re-admission within 30 days after surgery as well as 1 year mortality was also performed. Results BIA-derived mineral (r = 0.224, p = 0.027), fat (r = − 0.202, p = 0.048), and total body water (TBW)/fat-free mass (FFM) (r = − 0.280, p = 0.005) showed significant associations with intraoperative PCI score. Lower TBW/FFM was an independent predictor of major postoperative complications (OR 0.047, 95% CI 0.003–0.749, p = 0.031) and re-admission (OR 0.094, 95% CI 0.014–0.657, p = 0.017) within 30 days after surgery. Higher fat mass was also independently associated with a higher risk of major postoperative complications (OR 1.120, 95% CI 1.006–1.248, p = 0.039) and re-admission (OR 1.123, 95% CI 1.024–1.230, p = 0.013). Intraoperative PCI score > 20 (OR 4.489, 95% CI 1.191–16.917, p = 0.027) and re-admission within 30 days after surgery (OR 5.269, 95% CI 1.288–21.547, p = 0.021) independently predicted postoperative 1-year mortality. Conclusions We demonstrate that preoperative BIA-derived TBW/FFM and fat mass were significantly correlated with metastatic extent, assessed by PCI score, in patients with peritoneal carcinomatosis. In addition, BIA-derived TBW/FFM and fat mass showed independent predictability for postoperative 30-day major complications and re-admission in patients undergoing CRS and HIPEC. Our findings suggest that assessment of BIA may improve discrete risk stratification in patients who are planned to receive CRS and HIPEC.

Exposure to particulate matter (PM), especially PM2.5, is known to exacerbate asthma, posing a significant public health risk. This study investigated the asthma-reducing effects of photobiomodulation (PBM) in a mice model mimicking allergic airway inflammation exacerbated by PM2.5 exposure. The mice received sensitization with ovalbumin (OVA) and were subsequently treated with PM2.5 at a dose of 0.1 mg/kg every 3 days, for 9 times over 3 weeks during the challenge. PBM, using a 610 nm wavelength LED, was applied at 1.7 mW/cm2 to the respiratory tract via direct skin contact for 20 min daily for 19 days. Results showed that PBM significantly reduced airway hyperresponsiveness, plasma immunoglobulin E (IgE) and OVA-specific IgE, airway inflammation, T-helper type 2 cytokine, histamine and tryptase in bronchoalveolar lavage fluid (BALF), and goblet cell hyperplasia in PM2.5-exposed asthmatic mice. Moreover, PBM alleviated subepithelial fibrosis by reducing collagen deposition, airway smooth muscle mass, and expression of fibrosis-related genes. It mitigated reactive oxygen species generation, oxidative stress, endoplasmic reticulum stress, apoptotic cell death, ferroptosis, and modulated autophagic signals in the asthmatic mice exposed to PM2.5. These findings suggest that PBM could be a promising intervention for PM2.5-induced respiratory complications in patients with allergic asthma.

Abstract Background Myosteatosis and systemic inflammation are well‐known prognostic factors in patients with colorectal cancer (CRC). The serum albumin level is a reflection of malnutrition and systemic inflammation, which in turn plays a key role in the development of myosteatosis. However, few studies have been conducted on these synergistic effects. This study aimed to examine the individual and synergistic effects of different prognostic markers related to skeletal muscle quality and serum albumin levels in patients with CRC. Methods This study enrolled patients with stage I–III CRC who underwent surgical resection between July 2006 and February 2014. Skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) were calculated using computed tomography at the L3 level obtained within 2 months prior to surgery. The albumin‐myosteatosis gauge (AMG) was defined as SMD × albumin. Patients were divided into sex‐specific quartiles (G1 to G4) according to the AMG, and analysis of variance for continuous variables and chi‐square test for categorical variables were used to compare variables among quartiles. Cox proportional hazard models were constructed and integrated receiver operating characteristic curve (iAUC) analysis was used to compare the prognostic performance of SMD, albumin and AMG. Results Among the 906 participants, the median (interquartile) age was 64 (55–72) years, and 365 (40.3%) were female. AMG was significantly correlated with the occurrence of complications, albumin level, SMI and SMD (all P

Purpose This study aimed to investigate the clinicopathologic features and survival in patients with both breast cancer (BrC) and colorectal cancer (CRC). Methods Between 1996 and 2019, patients who were diagnosed with both BrC and CRC were evaluated retrospectively. Patients with distant metastasis, palliative resection, and previous cancer histories except for BrCs or CRCs were excluded. Altogether, 105 patients were divided into the B=C group (n=21), B-first group (n=40), and C-first group (n=44) according to the definition of synchronous and metachronous cancers. The clinicopathologic features and overall survival were evaluated. Results TNM stages and histologic types were comparable among the 3 groups (P=0.434). The interval of diagnosis was 67.1±40.4 and 59.3±47.2 months in the B- and C-first groups, respectively. The incidence of adjuvant chemotherapy in the B-first group was 57.5%, which was higher than the B=C and C-first groups (P

Thermogenic adipocytes maintain body temperature in response to cold, but how this is tuned during cold and re-warming is unclear. Here, the authors show HIF2α inhibits beige adipocyte retention, regulating PKA catalysis to control dynamic adipocyte remodelling.

Elucidation of the interplay between viruses and host cells is crucial for taming viruses to benefit human health. Cancer therapy using adenovirus, called oncolytic virotherapy, is a promising treatment option but is not robust in all patients. In addition, inefficient replication of human adenovirus in mouse hampered the development of an in vivo model for preclinical evaluation of therapeutically engineered adenovirus. nc886 is a human non-coding RNA that suppresses Protein Kinase R (PKR), an antiviral protein. In this study, we have found that nc886 greatly promotes adenoviral gene expression and replication. Remarkably, the stimulatory effect of nc886 is not dependent on its function to inhibit PKR. Rather, nc886 facilitates the nuclear entry of adenovirus via modulating the kinesin pathway. nc886 is not conserved in mouse and, when xenogeneically expressed in mouse cells, promotes adenovirus replication. Our investigation has discovered a novel mechanism of how a host ncRNA plays a pro-adenoviral role. Given that nc886 expression is silenced in a subset of cancer cells, our study highlights that oncolytic virotherapy might be inefficient in those cells. Furthermore, our findings open future possibilities of harnessing nc886 to improve the efficacy of oncolytic adenovirus and to construct nc886-expressing transgenic mice as an animal model.

Background and aimsThis study compared the prognostic significance of various nutritional and inflammatory indicators such as neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio, prognostic nutritional index, and controlling nutritional status score. In addition, we aimed to establish a more accurate prognostic indicator.MethodsWe retrospectively evaluated 1112 patients with stage I–III colorectal cancer between January 2004 and April 2014. The controlling nutritional status scores were classified as low (0–1), intermediate (2–4), and high (5–12) scores. The cut-off values for prognostic nutritional index and inflammatory markers were calculated using the X-tile program. P-CONUT, a combination of prognostic nutritional index and the controlling nutritional status score, was suggested. The integrated areas under the curve were then compared.ResultsThe multivariable analysis showed that prognostic nutritional index was an independent prognostic factor for overall survival, whereas the controlling nutritional status score, neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio were not. The patients were divided into three P-CONUT groups as follows: G1, controlling nutritional status (0–4) and high prognostic nutritional index; G2, controlling nutritional status (0–4) and low prognostic nutritional index; and G3, controlling nutritional status (5–12) and low prognostic nutritional index. There were significant survival differences between the P-CONUT groups (5-year overall survival of G1, G2, and G3 were 91.7%, 81.2%, and 64.1%, respectively; p < 0.0001). The integrated areas under the curve of P-CONUT (0.610, CI: 0.578–0.642) was superior to those of the controlling nutritional status score alone (bootstrap integrated areas under the curve mean difference=0.050; 95% CI=0.022–0.079) and prognostic nutritional index alone (bootstrap integrated areas under the curve mean difference=0.012; 95% CI=0.001–0.025).ConclusionPrognostic effect of P-CONUT may be better than inflammatory markers such as neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio. Thus, it could be used as a reliable nutritional risk stratification tool in patients with colorectal cancer.

Abstract Background Although skeletal muscle index (SMI) and radiodensity (SMD) are well‐known prognostic factors, the clinical impact of the integrated measure, known as skeletal muscle gauge (SMG), has been limited in patients with colorectal cancer (CRC). Patients and Methods A total of 727 and 268 patients with CRC at two tertiary centers were included and allocated into the training and test sets, respectively. Preoperative slice computed tomography images of the third lumbar area were evaluated for SMI and SMD. SMG was calculated as SMI × SMD and expressed as an arbitrary unit (AU). The optimal cutoff SMG value was determined to maximize the overall survival (OS) difference between the groups with respect to sex in the training set. The multivariate Cox proportional hazard model evaluated the association of its clinical significance. Results With regard to SMG, 1640 and 1523 AU were identified as cutoff values for males and females, respectively. The patients with low SMG values showed significantly worse 5‐year OS than those with high SMG values in the two datasets (both p

Sphincter preservation and organ restoration during rectal cancer surgery avoids permanent stoma creation and diminishes psychosocial damages. However, decreased rectal volumes and sphincter dysfunction—including pelvic nerve damage—results in low anterior resection syndrome, as well as urinary and sexual dysfunction after rectal resection. Bowel habit changes such as fecal incontinence, fecal urgency, frequent bowel movements, clustered stools, and difficulties in bowel emptying can be treated using medications, pelvic floor rehabilitation, sacral neuromodulation, or neorectal reservoir reconstruction. Pelvic nerve damage resulting from superior and inferior hypogastric plexi during sphincter-preserving rectal cancer surgery can induce urologic and sexual dysfunctions. Preoperative voiding difficulty, perioperative blood loss, and autonomic nerve injury are considered independent risk factors for postoperative urinary dysfunction. Retrograde ejaculation and erectile dysfunction, female dyspareunia, and vaginal dryness are manifestations of sexual dysfunction resulting from autonomic nerve injury during rectal cancer surgery. Multifactorial causes for functional outcomes after sphincter- preserving surgeries are considered to improve patient’s quality of life with acceptable oncologic outcomes in the treatment of rectal cancer patients.

Abstract The purpose of this study was to investigate whether sex differences in visceral fat volume and glucose uptake measured by positron emission tomography/computed tomography (PET/CT) in abdominal visceral fat can stratify overall survival (OS) in patients with colorectal cancer (CRC). We retrospectively enrolled 293 patients diagnosed with CRC who underwent PET/CT before surgical resection. Fluorodeoxyglucose uptake of visceral adipose tissue (VAT-SUV) and subcutaneous adiposity tissue (SAT-SUV) were measured using PET/CT. The relative VAT (rVAT) was defined as the visceral fat volume normalized to the total volume of fat (VAT plus SAT). We defined sex-specific cutoff values for VAT-SUV, SAT-SUV, and rVAT. Univariate and multivariate analyses using Cox proportional hazard regression analysis were performed to identify the independent prognostic factors. The study population comprised 181 men and 112 women. The rVAT (0.40 vs. 0.29, p

Abstract Serum inflammatory markers are used in the prognostication of colorectal cancer (CRC); however, the corresponding role of positron emission tomography (PET)-derived inflammatory markers remains unclear. This study aimed to investigate the prognostic value of 18F-fluorodeoxyglucose (FDG) uptake in the bone marrow and spleen of patients with CRC and evaluate the relationship between FDG uptake estimates in these organs and serum inflammatory markers. In total, 411 patients who underwent preoperative FDG PET/computed tomography (CT) within 1 month of surgery were enrolled. The mean standardized uptake values of the bone marrow and spleen were normalized to the value of the liver, thereby generating bone marrow-to-liver uptake ratio (BLR) and spleen-to-liver uptake ratio (SLR) estimates. The value of BLR and SLR in predicting overall survival (OS) was assessed using the Cox proportional hazards model. The correlation between BLR or SLR and neutrophil-to-lymphocyte ratio (NLR) was evaluated. The predictive accuracy of BLR alone and in combination with SLR was compared using the integrated area under the receiver operating characteristic curves (iAUC). In the univariate analysis, BLR (> 1.06) and SLR (> 0.93) were significant predictors of OS. In the multivariate analysis, BLR was an independent predictor of OS (hazard ratio = 5.279; p

Abstract Background This study aimed to examine the characteristics of older adults patients who suffered a head injury after a ground-level fall in comparison to non-head injury patients as well as the factors associated with severity in those with head injury only. Methods Patients were classified into two groups, the head injury group and the non-head injury group. The characteristics were compared and factors associated with head injury were evaluated. Factors relating to severe injury in the head injury group were also investigated. Results The head injury group comprised 42 % of a study subjects. Male sex; fall time of 18:00–23:59; fall location of medical facility, transportation area, and public or commercial facility; fall in an outdoor area; fall during daily activity; alcohol ingestion; fall from stairs; non-slippery floor conditions; concrete flooring; sloped flooring; and presence of obstacles on the floor were risk factors for head injury in the older adults after a ground-level fall. Male sex and age over 70 years; fall time of 00:00–05:59; fall in a residential facility; fall in an indoor area; fall during daily activity; fall from stairs; non-slippery floor conditions; and presence of obstacles on the floor were factors associated with severe injury in the head injury group. Conclusions Male sex with advanced age, indoor fall, and the presence of obstacles on the floor were risk factors for severe injury in the head injury group in older adults individuals who suffered a ground-level fall. It is necessary to develop appropriate ground-level fall prevention programs by evaluating the individual and environmental characteristics of older adults patients.

BackgroundThis study aimed to evaluate the prognostic significance of preoperative, postoperative, and trajectory changes in carcinoembryonic antigen (CEA) levels in patients with colorectal cancer (CRC).MethodsThis retrospective study included patients who underwent surgical resection for nonmetastatic CRC. The optimal cutoff values of preoperative CEA (CEA-pre), early postoperative CEA (CEA-post), and CEA level change (CEA-delta) were determined to maximize the differences in overall survival (OS) among groups. The patients were divided into three groups according to CEA-trend: normal, low CEA-pre; normalized, high CEA-pre/low CEA-post; elevated, high CEA-pre/high CEA-post. The integrated area under the curve (iAUC) was used to compare the discriminatory power of all variables.ResultsA total of 1019 patients diagnosed with stage I–III CRC were enrolled. The optimal cutoff values of CEA level were determined as 2.3 ng/mL for CEA-pre, 2.3 ng/mL for CEA-post, and -0.93 ng/mL for CEA-delta. Although subgroup dichotomization showed that CEA-pre, CEA-post, CEA-delta, and CEA-trend were all associated with OS in univariate analysis, CEA-trend was the only independent prognostic factor in multivariate analysis. The iAUC of CEA-trend was superior to that of CEA-pre, CEA-post, and CEA-delta. Compared with the normal group, the normalized group showed worse OS (p=.0007) in stage II patients but similar OS (p=.067) in stage III patients.ConclusionThe optimal cutoff value of CEA level in the preoperative and postoperative periods was determined to be 2.3 ng/mL, and the combination of CEA-pre and CEA-post showed better prognostic stratification. However, its prognostic significance may differ depending on the CRC stage.

Renal ischemia reperfusion (IR) injury is a major cause of acute kidney injury (AKI) that is often complicated by multiple organ failure of the liver and intestine. The mineralocorticoid receptor (MR) is activated in patients with renal failure associated with glomerular and tubular damage. We thus investigated whether canrenoic acid (CA), a mineralocorticoid receptor (MR) antagonist, protects against AKI-induced hepatic and intestinal injury, suggesting the underlying mechanisms. Mice were divided into five groups: sham mice, mice subjected to renal IR, and mice pretreated with canrenoic acid (CA; 1 or 10 mg/kg) 30 min prior to renal IR. At 24 h after renal IR, the levels of plasma creatinine, alanine aminotransferase and aldosterone were measured, and structural changes and inflammatory responses of the kidney, liver, and intestine were analyzed. We found that CA treatment reduced plasma creatinine levels, tubular cell death and oxidative stress induced by renal IR. CA treatment also decreased renal neutrophil infiltration and inflammatory cytokine expression and inhibited the release of high-mobility group box 1 induced by renal IR. Consistently, CA treatment reduced renal IR-induced plasma alanine transaminase, hepatocellular injury and neutrophil infiltration, and inflammatory cytokine expression. CA treatment also decreased small intestinal cell death, neutrophil infiltration and inflammatory cytokine expression induced by renal IR. Taken together, we conclude that MR antagonism by CA treatment protects against multiple organ failure in the liver and intestine after renal IR.

Abstract Background This study aimed to evaluate the clinical outcomes of concurrent liver resection with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in colorectal cancer patients with synchronous liver and peritoneal metastases. Methods Patients with colorectal liver and peritoneal metastasis who underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy with concurrent liver surgery between September 2014 and July 2018 were included. Perioperative outcomes, overall survival, and progression-free survival were analyzed retrospectively. Results In total, 22 patients were included. The median peritoneal cancer index was 13 (range, 0–26), and the median number of liver metastases was 3 (range, 1–13). The mean total operative time was 11.4 ± 2.6 h. Minor postoperative complications (Clavien-Dindo grade I–II) were reported in 10 patients (45.5%), and major postoperative complications (grade III–V) were reported in five patients (22.7%), including one mortality patient. The median overall survival since diagnosis with metastasis was 27.4 months. The median overall survival since surgical intervention and the progression-free survival were 16.7 months and 7.1 months, respectively. Conclusions This short-term follow-up study showed that, in an experienced center, combined resection with hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases was feasible and safe with acceptable oncologic outcomes.

G-749 is an FLT3 kinase inhibitor that was originally developed as a treatment for acute myeloid leukemia. Some FLT3 kinase inhibitors are dual kinase inhibitors that inhibit the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase family and are used to treat solid cancers such as non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). AXL promotes metastasis, suppression of immune response, and drug resistance in NSCLC and TNBC. G-749, a potential TAM receptor tyrosine kinase inhibitor, and its derivative SKI-G-801, effectively inhibits the phosphorylation of AXL at nanomolar concentration (IC50 = 20 nM). This study aimed to investigate the anticancer effects of G-749 targeting the TAM receptor tyrosine kinase in colon cancer. Here, we demonstrate the potential of G-749 to effectively inhibit tumorigenesis by degrading TYRO3 via regulated intramembrane proteolysis both in vitro and in vivo. In addition, we demonstrated that G-749 inhibits the signaling pathway associated with cell proliferation in colon cancer cell lines HCT15 and SW620, as well as tumor xenograft mouse models. We propose G-749 as a new therapeutic agent for the treatment of colon cancer caused by abnormal TYRO3 expression or activity.

Homocysteine (Hcy), a homologue of cysteine, is biosynthesized during methionine metabolism. Elevated plasma Hcy is associated with glomerular injury and considered as a risk factor for renal dysfunction, predicting incident chronic kidney disease. Hcy promotes oxidative stress, inflammation, and endothelial dysfunction. Acute kidney injury (AKI) is defined as a sudden decline in renal function and is important clinically due to the high mortality rate in AKI patients with multiple organs failure, including the brain. However, the cytotoxic role of Hcy on the brain following AKI is not directly shown. In this study, C57BL/6 mice were subjected to renal ischemia reperfusion (IR), one of the causes of AKI, and treated with vehicle or Hcy (0.2 mg/kg) to analyse the brain inflammation. IR mice showed a significant induction in plasma creatinine and Hcy levels, associated with tubular injury and neutrophil infiltration, and upregulation of pro-inflammatory cytokines and tubular apoptosis. Hcy treatment aggravated these renal damage and dysfunction by regulating cyclooxygenase-2 (COX-2), inhibitor of κB phosphorylation, and heme oxygenase-1. Consistently, Hcy treatment significantly increased expression of pro-inflammatory cytokines, glial fibrillary acidic protein, and COX-2 in the prefrontal cortex of IR mice. We conclude that Hcy treatment aggravated the renal dysfunction and enhanced IR-induced inflammatory cytokines and astrocyte activation in the brain. We propose that lowering plasma Hcy levels may attenuate neurological dysfunction found in patients with AKI.

Acute kidney injury (AKI) is an inflammatory sequence. It can lead to distant organ injury, including damage to the central nervous system (CNS), mediated by increased circulating cytokines and other inflammatory mediators. It can also lead to increased blood–brain barrier (BBB) permeability. However, the effect of AKI on the inflammatory response of the brain has not yet been investigated. Therefore, we observed the effect of AKI on BBB permeability, microglia and astrocyte activation, and neuronal toxicity in the brain. The striatum and ventral midbrain, known to control overall movement, secrete the neurotransmitter dopamine. The activation of microglia and astrocytes present in this area causes neuro-degenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The activation of astrocytes and microglia in the hippocampus and cerebral cortex, which are responsible for important functions, including memory, learning, concentration, and language, can trigger nerve cell apoptosis. The activation of astrocytes and microglia at this site is also involved in the inflammatory response associated with the accumulation of beta-amyloid. In the situation of kidney ischemia reperfusion (IR)-induced AKI, activation of microglia and astrocytes were observed in the striatum, ventral midbrain, hippocampus, and cortex. However, neuronal cell death was not observed until 48 h.

Objective: Diabetic nephropathy (DN) is one of the most common complications of diabetes and a critical risk factor for developing end-stage renal disease. Activation of purinergic receptors, including P2Y2R has been associated with the pathogenesis of renal diseases, such as polycystic kidney and glomerulonephritis. However, the role of P2Y2R and its precise mechanisms in DN remain unknown. We hypothesised that P2Y2R deficiency may play a protective role in DN by modulating the autophagy signalling pathway. Methods: We used a mouse model of DN by combining a treatment of high-fat diet and streptozotocin after unilateral nephrectomy in wild-type or P2Y2R knockout mice. We measured renal functional parameter in plasma, examined renal histology, and analysed expression of autophagy regulatory proteins. Results: Hyperglycaemia and ATP release were induced in wild type-DN mice and positively correlated with renal dysfunction. Conversely, P2Y2R knockout markedly attenuates albuminuria, podocyte loss, development of glomerulopathy, renal tubular injury, apoptosis and interstitial fibrosis induced by DN. These protective effects were associated with inhibition of AKT-mediated FOXO3a (forkhead box O3a) phosphorylation and induction of FOXO3a-induced autophagy gene transcription. Furthermore, inhibitory phosphorylation of ULK-1 was decreased, and the downstream Beclin-1 autophagy signalling was activated in P2Y2R deficiency. Increased SIRT-1 (sirtuin-1) and FOXO3a expression in P2Y2R deficiency also enhanced autophagy response, thereby ameliorating renal dysfunction in DN. Conclusions: P2Y2R contributes to the pathogenesis of DN by impairing autophagy and serves as a therapeutic target for treating DN.

Breast cancer: A protein link for treatment? The role of disrupted activity of the protein BRCA1 in the progression of breast cancer has been clarified, suggesting that targeting another protein with which it interacts could offer a new route to treatment. Mutations of BRCA1 are known to predispose women to both breast and ovarian cancers. Researchers led by Sang Soo Kim (National Cancer Center, South Korea) and Rui-Hong Wang (University of Macau, China) studied the interaction with a protein called cyclin B1 that controls cell growth and division. They found that, in mitosis, BRCA1 interacts with and stabilizes cyclin B1, explaining why the loss of BRCA1 can disrupt the G2/M cell cycle control and accumulate the genetic instability. Treatment of Brca1-mutant mammary tumors with vinblastine, which alters cyclin B1 level, significantly reduced tumor progression with reduction of survival and induction of apoptosis.

Summary: Background/Objective: Infliximab is regarded as an effective therapeutic to treat Crohn's disease. This study aimed to assess the efficacy of infliximab combined with surgery and to analyze clinical manifestations according to fistula subtypes in patients with fistulizing perianal Crohn's disease. Methods: From April 2013 to December 2015, 47 patients with perianal Crohn's disease in two hospitals of South Korea (Goo Hospital, Gangnam Severance Hospital) were evaluated retrospectively. Patients were categorized into two groups as simple fistula (n = 20) and complex fistula group (n = 27). All patients received 5 mg/kg of infliximab intravenously at 0, 2, and 6 weeks after surgical treatments. Then every eight weeks, the responders continued to receive 5 mg/kg infliximab for maintenance therapy. Results: Complete response of induction therapy was 72.3%, and partial response was 27.7%. After maintenance therapy, complete response was 97.9% and partial response was 2.1%. There was no patient without a response to infliximab in this study. The median time to the first fistula closure was 6.00 ± 8.00 weeks. Infliximab was used on average 2.13 ± 0.71 times until the first fistula closure. The rate of recurrence was 8.5% and adverse events were 4.2%. In comparison with clinical manifestations between simple and complex fistula groups, there was no significant difference except for the coexistence of perianal abscess. Conclusions: Combined surgical and infliximab therapy was efficacious to treat fistulizing perianal Crohn's disease with rapid treatment response and favorable clinical outcomes. It is expected that this top-down strategy with combining surgeries can overcome previous limitations in treating perianal Crohn's disease. Keywords: Crohn's disease, Infliximab, Perianal fistula, Biologics

Summary of Event: A 2 cm-sized colonic perforation occurred during diagnostic colonoscopy. Endoscopic closure was performed immediately using detachable snare and conservative management with intravenous antibiotics was followed for several days. However, abdominal computed tomography showed huge abscess and its connection to the sigmoid colon. The patient underwent segmental colectomy, which revealed the incomplete closure of perforated lesion with severe serosal fibrotic change. Teaching Point: Endoscopic treatment of large-sized colonic perforations should be undertaken with caution since the possibility of incomplete closure is high. For large-sized colonic perforations, early surgical treatment should be preferentially considered over endoscopic treatment.

Abstract Background Persistent Müllerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism in dogs, is an abnormal sexual phenotype in males that is characterized by the existence of a hypoplastic oviduct, uterus, and cranial part of the vagina. Dogs suffering from PMDS are often accompanied by cryptorchidism. To date, it has been mainly found in the Miniature Schnauzer breed. Case presentation In this report, two cases of PMDS with a malignant testicular tumor originating from cryptorchidism in breeds other than the Miniature Schnauzer breed are described. The patients were a seven-year-old male Maltese dog and a 17-year-old male mixed-breed dog weighing 3.8 kg. They also exhibited an enlarged prostate with or without abscess and an elevated serum estradiol level and were surgically treated to remove the testicular tumor and Müllerian duct derivatives. Conclusions It is recommended that PMDS should be differentially diagnosed by ultrasonography and that orchiectomy be performed at an early age in patients suspected to have cryptorchidism to prevent the ectopic testes from becoming tumorous.

PURPOSE:This study investigated the significance of change in neutrophil-to-lymphocyte ratio (NLR) during preoperative chemoradiotherapy (preop-CRT) in patients with non-metastatic rectal cancer using a propensity score matching method (PSM). METHODS:Patients who underwent surgery after completion of preop-CRT for non-metastatic rectal cancers from Jan 2004 to Dec 2013 were retrospectively enrolled. NLRs were obtained before commencement of CRT (pre-NLR) and between completion of CRT and surgery (post-NLR). Using Cox regression hazards models, the association of NLRs with survival after PSM was examined. RESULTS:A total of 131 patients were grouped as follows: group A, pre-NLR < 3 & post-NLR < 3 (n = 47); group B, pre-NLR < 3 & post-NLR ≥ 3 (n = 45); group C, pre-NLR ≥ 3 & post-NLR < 3 (n = 5); group D, pre-NLR ≥ 3 & post-NLR ≥ 3 (n = 34). There was no difference in disease-free survival (DFS) or overall survival (OS) rate according to group. When dichotomized into group A versus groups B-D, DFS was higher in group A (84.7%) than groups B-D (67.5%, p = 0.021). After PSM (n = 94), multivariable analysis identified persistent lower NLR as an independent favorable prognosticator of DFS (HR 0.37, 95% CI 0.15-0.92, p = 0.033). CONCLUSIONS:Persistent non-inflammatory state measured by NLR may be an indicator of decreased risk of recurrence in patients with locally advanced rectal cancer treated with preop-CRT.

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid β-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.

Diabetic nephropathy (DN) is a common pathological feature in patients with diabetes and the leading cause of end-stage renal disease. Although several pharmacological agents have been developed, the management of DN remains challenging. Geniposide, a natural compound has been reported for anti-inflammatory and anti-diabetic effects; however, its role in DN remains poorly understood. This study investigated the protective effects of geniposide on DN and its underlying mechanisms. We used a C57BL/6 mouse model of DN in combination with a high-fat diet and streptozotocin after unilateral nephrectomy and treated with geniposide by oral gavage for 5 weeks. Geniposide effectively improves DN-induced renal structural and functional abnormalities by reducing albuminuria, podocyte loss, glomerular and tubular injury, renal inflammation and interstitial fibrosis. These changes induced by geniposide were associated with an increase of AMPK activity to enhance ULK1-mediated autophagy response and a decrease of AKT activity to block oxidative stress, inflammation and fibrosis in diabetic kidney. In addition, geniposide increased the activities of PKA and GSK3β, possibly modulating AMPK and AKT pathways, efficiently improving renal dysfunction and ameliorating the progression of DN. Conclusively, geniposide enhances ULK1-mediated autophagy and reduces oxidative stress, inflammation and fibrosis, suggesting geniposide as a promising treatment for DN.

Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886′s role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings.

The prognostic impact of the combination of the modified Glasgow prognostic score (mGPS) and C-reactive protein/albumin ratio (CAR) in colorectal cancer (CRC) is unclear. We aimed to investigate the clinical usefulness of this combination as a predictor of survival in CRC patients. We retrospectively evaluated 769 CRC patients who had undergone surgery between January 2006 and March 2014. The CAR and mGPS within 1 month postoperation were examined. The integrated area under the curve (iAUC) was compared among mGPS, CAR, and the combined classification (CC). The optimal CAR cut-off for discriminating overall survival was 0.14. Based on this cut-off, the mGPS 0 group was divided into the mGPS 0 with low CAR and the mGPS 0 with high CAR groups, whereas all mGPS 1 and 2 patients were classified into the high CAR group. CC was an independent prognostic factor, and its iAUC value (0.587, 95% CI 0.553–0.624) was superior to those of the mGPS (0.544, 95% CI 0.516–0.576) (bootstrap iAUC mean difference = 0.043; 95% CI = 0.015–0.072) and CAR (0.578, 95% CI 0.545–0.613) (bootstrap iAUC mean difference = 0.009; 95% CI = 0.002–0.017), respectively. In conclusion, the combination of mGPS and CAR has a synergistic effect and has a higher prognostic accuracy than mGPS or CAR alone in patients with CRC.

Glutathione (GSH) is an endogenous antioxidant found in plants, animals, fungi, and some microorganisms that protects cells by neutralizing hydrogen peroxide. Honokiol, an active ingredient of Magnolia officinalis, is known for antioxidant, anti-inflammatory, and anti-bacterial properties. We investigated the protective mechanism of honokiol through regulating cellular GSH in renal proximal tubules against acute kidney injury (AKI). First, we measured cellular GSH levels and correlated them with the expression of GSH biosynthetic enzymes after honokiol treatment in human kidney-2 (HK-2) cells. Second, we used pharmacological inhibitors or siRNA-mediated gene silencing approach to determine the signaling pathway induced by honokiol. Third, the protective effect of honokiol via de novo GSH biosynthesis was investigated in renal ischemia-reperfusion (IR) mice. Honokiol significantly increased cellular GSH levels by upregulating the subunits of glutamate-cysteine ligase (Gcl)—Gclc and Gclm. These increases were mediated by activation of nuclear factor erythroid 2-related factor 2, via PI3K/Akt and protein kinase C signaling. Consistently, honokiol treatment reduced the plasma creatinine, tubular cell death, neutrophil infiltration and lipid peroxidation in IR mice and the effect was correlated with upregulation of Gclc and Gclm. Conclusively, honokiol may benefit to patients with AKI by increasing antioxidant GSH via transcriptional activation of the biosynthetic enzymes.

Endotoxin-induced acute liver injury is mediated by an excessive inflammatory response, hepatocellular oxidative stress, and apoptosis. Traditional medicinal plants have been used to treat various disorders. Platycodon grandifloras (PG) has been shown to be beneficial in relieving cough and asthma and to have anti-tumor, anti-inflammatory, anti-diabetic activities. The pharmacological action of PG is mainly due to saponins, flavonoids, phenolic, and other compounds. However, raw PG exhibits some side effects at high doses. Here, we extracted raw PG with varying fermentation methods and examined its anti-inflammatory effect and associated signaling kinases in Raw264.7 cells. Then, we investigated the effect of fermented black PG (FBPG) on endotoxin-induced liver injury. Mice were administered FBPG orally at 1 h before the lipopolysaccharide and D-galactosamine (LPS/GalN) injection and sacrificed after 5 h. Black PG (BPG) and FBPG showed a significant reduction in pro-inflammatory cytokines and extracellular nitric oxide (NO); p-38 and ERK signaling was involved in reducing inducible NO synthase in Raw264.7 cells. Consistently, FBPG attenuates LPS/GalN-induced liver injury; plasma ALT and AST, hepatic necrosis, pro-inflammatory cytokines, apoptosis, and lipid peroxidation were all reduced. In conclusion, PG extracts, particularly FBPG, play anti-inflammatory, antioxidant, and anti-apoptotic roles, alleviating endotoxin-induced acute liver injury. Processing raw PG into FBPG extract may be clinically useful by improving the pharmacologically active ingredients and reducing the required dosage.

Colorectal cancer with peritoneal metastasis has a poor prognosis because of inadequate responses to systemic chemotherapy. Cytoreductive surgery followed by intraperitoneal (IP) chemotherapy using oxaliplatin has attracted attention; however, the short half-life of oxaliplatin and its rapid clearance from the peritoneal cavity limit its clinical application. Here, a multivesicular liposomal (MVL) depot of oxaliplatin was prepared for IP administration, with an expected prolonged effect. After optimization, a combination of phospholipids, cholesterol, and triolein was used based on its ability to produce MVL depots of monomodal size distribution (1–20 µm; span 1.99) with high entrapment efficiency (EE) (92.16% ± 2.17%). An initial burst release followed by a long lag phase of drug release was observed for the MVL depots system in vitro. An in vivo pharmacokinetic study mimicking the early postoperative IP chemotherapy regimen in rats showed significantly improved bioavailability, and the mean residence time of oxaliplatin after IP administration revealed that slow and continuous erosion of the MVL particles yielded a sustained drug release. Thus, oxaliplatin-loaded MVL depots presented in this study have potential for use in the treatment of colorectal cancer.

Pit viper venom commonly causes venom-induced consumptive coagulopathy (VICC), which can be complicated by life-threatening hemorrhage. VICC has a complex pathophysiology affecting multiple steps of the coagulation pathway. Early detection of VICC is challenging because conventional blood tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are unreliable for early-stage monitoring of VICC progress. As the effects on the coagulation cascade may differ, even in the same species, the traditional coagulation pathways cannot fully explain the mechanisms involved in VICC or may be too slow to have any clinical utility. Antivenom should be promptly administered to neutralize the lethal toxins, although its efficacy remains controversial. Transfusion, including fresh frozen plasma, cryoprecipitate, and specific clotting factors, has also been performed in patients with bleeding. The effectiveness of viscoelastic monitoring in the treatment of VICC remains poorly understood. The development of VICC can be clarified using thromboelastography (TEG), which shows the procoagulant and anticoagulant effects of snake venom. Therefore, we believe that TEG may be able to be used to guide hemostatic resuscitation in victims of VICC. Here, we aim to discuss the advantages of TEG by comparing it with traditional coagulation tests and propose potential treatment options for VICC.

Environmental and genetic factors exert important influences on lifespan and neoplastic transformation. We have previously shown that spontaneous tumors form frequently in mice homozygous for a full-length Brca1 deletion. In general, mutations of BRCA1 are closely associated with induction of breast and ovarian cancers but are also known to contribute to the incidence of other cancers at a low frequency. Female Brca1-mutant mice (Brca1co/coMMTV-cre) were generated by crossing Brca1 conditional knockout mice and MMTV-cre mice, and the occurrence of lacrimal gland abnormalities and tumors was followed until mice reached 18 months of age. Lacrimal gland tumors, which occur at a very low frequency in the human population (1 per 1,000,000 per year), were detected in 7 cases of Brca1co/coMMTV-cre mice (2.75%) older than 9 months of age. None of seven mice exhibited any abnormality in the mammary gland including neoplasia, suggesting lacrimal gland tumor is spontaneously and independently formed. These tumors, which were detected in seven mutant mice that displayed exophthalmoses, were malignant, originated from epithelial cells, and were identified as acinic cell carcinoma by pathological analysis. Further analysis revealed that tumorigenesis was accompanied by the accumulation of cyclin D1 and decreased expression of the cellular oncogenes, c-Myc, c-Jun, and c-Raf. Tumors also exhibited rearrangement of cytoskeletal proteins, including β-catenin, keratin 5, and vimentin, depending on tumor progression. These results suggest that BRCA1 is involved in genetic stability of the lacrimal gland, providing new insight into genomic instability in organism maintenance and tumorigenesis of the lacrimal gland.

BackgroundAnastomotic leakage can be classified by free and contained leakage according to clinical manifestations. The risk factors and their comparison between these leakage subtypes are uncertain. This study aims to evaluate anastomotic leakage patterns and to compare clinical features between free and contained leakages after low anterior resection for rectal cancer.Materials and methodsBetween January 2005 and December 2012, a total of 2035 consecutive patients who underwent low anterior resection for primary rectal cancer were evaluated retrospectively at two-tertiary referral centers. The primary end points of this study were to assess detailed clinical features among leakage subtypes. The secondary end point was to compare risk factors between free and contained leakages.ResultsPatients were subdivided into a no leakage group (n = 1890), free leakage group (n = 73), and contained leakage group (n = 72). Free leakage occurred more frequently in laparoscopic and robotic surgeries than open surgery (p = 0.015). On the other hand, contained leakage was developed in a higher rate of patients who received preoperative chemoradiotherapy (pConclusionsContained leakage in rectal cancer surgery showed different clinical manifestations and risk factors compared to free leakage. It is necessary to pay more attention to patients with particular risk factors for anastomotic leakage subtypes.

BackgroundNeck and shoulder pain is fairly common among adolescents in Korea and results in significant health problem. The aims of this prospective study was to identify the effects of education, in terms of recognition of this issue and posture correction, on prevalence and severity of neck and shoulder pain in Korean adolescents.MethodsA prospective, observational cohort design was used. The 912 students from two academic high schools in the city of Seoul were eligible for the current study and 887 completed this study. After a baseline cross-sectional survey, students listened to a lecture about cervical health, focusing on good posture, habits, and stretching exercises to protect the spine, and were encouraged by their teachers to keep the appropriate position. And follow-ups were conducted 3 months later, to evaluate the effect of education.ResultsThe prevalence of neck and shoulder pain was decreased 19.5% (from 82.5 to 66.4%). The baseline mean usual and worst numeric rating scale were 19.9/100 (95% CI, 18.1-21.7) and 31.2/100 (95% CI, 28.7-33.2), respectively. On the follow-up survey, the mean usual and worst numeric rating scale were decreased significantly by 24.1 and 21.7%, respectively, compared with baseline (P < 0.01). Of the 570 students reporting neck and shoulder pain, 16.4% responded that they had experienced improvement during the 3 months.ConclusionsEducation; recognition of this issue and posture correction, for cervical health appeared to be effective in decreasing the prevalence and severity of neck and shoulder pain at a 3 month follow-up.

Background/Aims: Ginseng regulates gastrointestinal (GI) motor activity but the underlying components and molecular mechanisms are unknown. We investigated the effect of gintonin, a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, on the pacemaker activity of the interstitial cells of Cajal (ICC) in murine small intestine and GI motility. Materials and Methods: Enzymatic digestion was used to dissociate ICC from mouse small intestines. The whole-cell patch-clamp configuration was used to record pacemaker potentials and currents from cultured ICC in the absence or presence of gintonin. In vivo effects of gintonin on gastrointestinal (GI) motility were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal and streptozotocin (STZ)-induced diabetic mice. Results: We investigated the effects of gintonin on pacemaker potentials and currents in cultured ICC from mouse small intestine. Gintonin caused membrane depolarization in current clamp mode but this action was blocked by Ki16425, an LPA1/3 receptor antagonist, and by the addition of GDPβS, a GTP-binding protein inhibitor, into the ICC. To study the gintonin signaling pathway, we examined the effects of U-73122, an active PLC inhibitor, and chelerythrine and calphostin, which inhibit PKC. All inhibitors blocked gintonin actions on pacemaker potentials, but not completely. Gintonin-mediated depolarization was lower in Ca2+-free than in Ca2+-containing external solutions and was blocked by thapsigargin. We found that, in ICC, gintonin also activated Ca2+-activated Cl- channels (TMEM16A, ANO1), but not TRPM7 channels. In vivo, gintonin (10-100 mg/kg, p.o.) not only significantly increased the ITR in normal mice but also ameliorated STZ-induced diabetic GI motility retardation in a dose-dependent manner. Conclusions: Gintonin-mediated membrane depolarization of pacemaker activity and ANO1 activation are coupled to the stimulation of GI contractility through LPA1/3 receptor signaling pathways in cultured murine ICC. Gintonin might be a ingredient responsible for ginseng-mediated GI tract modulations, and could be a novel candidate for development as a prokinetic agent that may prevent or alleviate GI motility dysfunctions in human patients.

Colorectal cancer (CRC) is one of the most malignant and fatal cancers worldwide. Although cytoreductive surgery combined with chemotherapy is considered a promising therapy, peritoneal adhesion causes further complications after surgery. In this study, oxaliplatin-loaded Poly-(d,l-lactide-co-glycolide) (PLGA) microparticles were prepared using a double emulsion method and loaded into hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based cross-linked (HC) hydrogels. From characterization and evaluation study PLGA microparticles showed smaller particle size with higher entrapment efficiency, approximately 1100.4 ± 257.7 nm and 77.9 ± 2.8%, respectively. In addition, microparticle-loaded hydrogels showed more sustained drug release compared to the unloaded microparticles. Moreover, in an in vivo pharmacokinetic study after intraperitoneal administration in rats, a significant improvement in the bioavailability and the mean residence time of the microparticle-loaded hydrogels was observed. In HC21 hydrogels, AUC0−48h, Cmax, and Tmax were 16012.12 ± 188.75 ng·h/mL, 528.75 ± 144.50 ng/mL, and 1.5 h, respectively. Furthermore, experimental observation revealed that the hydrogel samples effectively protected injured tissues from peritoneal adhesion. Therefore, the results of the current pharmacokinetic study together with our previous report of the in vivo anti-adhesion efficacy of HC hydrogels demonstrated that the PLGA microparticle-loaded hydrogels offer novel therapeutic strategy for CRC treatment.

Colorectal cancer (CRC) is among the leading causes of cancer deaths and can be caused by environmental factors as well as genetic factors. Therefore, we developed a prediction model of CRC using genetic risk scores (GRS) and evaluated the effects of conventional risk factors, including family history of CRC, in combination with GRS on the risk of CRC in Koreans. This study included 187 cases (men, 133; women, 54) and 976 controls (men, 554; women, 422). GRS were calculated with most significantly associated single-nucleotide polymorphism with CRC through a genomewide association study. The area under the curve (AUC) increased by 0.5% to 5.2% when either counted or weighted GRS was added to a prediction model consisting of age alone (AUC 0.687 for men, 0.598 for women) or age and family history of CRC (AUC 0.692 for men, 0.603 for women) for both men and women. Furthermore, the risk of CRC significantly increased for individuals with a family history of CRC in the highest quartile of GRS when compared to subjects without a family history of CRC in the lowest quartile of GRS (counted GRS odds ratio [OR], 47.9; 95% confidence interval [CI], 4.9 to 471.8 for men; OR, 22.3; 95% CI, 1.4 to 344.2 for women) (weighted GRS OR, 35.9; 95% CI, 5.9 to 218.2 for men; OR, 18.1, 95% CI, 3.7 to 88.1 for women). Our findings suggest that in Koreans, especially in Korean men, GRS improve the prediction of CRC when considered in conjunction with age and family history of CRC.

Tumor necrosis factor-?#6184;TNF-?#6752;is a major proinflammatory cytokine involved in the pathophysiology of juvenile rheumatoid arthritis. Etanercept is an effective inhibitor of TNF-?#6177;nd has shown a beneficial effect in patients with JRA. However, the most important cause of concern related to etanercept administration is infection. We report a case of encephalitis in a JRA patient receiving long-term treatment with etanercept. The patient was a 4-year-old boy with refractory JRA, and he received etanercept subcutaneously at a dose of 0.4 mg kg-1 day-1 twice a week for 14 months, along with non-steroidal anti-inflammatory drugs, methotrexate, oral steroids, and sulfasalazine. The patient presented with sudden fever, headache, vomiting, a generalized tonic seizure, and changes in mental status. We suspected a central nervous system infection, and simultaneously administered antibiotics, an antiviral agent, and steroids. After 2 days of hospitalization, his mental function returned to normal, and he showed no further seizure-like movements. Brain magnetic resonance imaging scan of the patient showed a multifocal cortical lesion on both sides of the temporoparietooccipital lobe, which indicated encephalitis. Although we were unable to identify the causative organism of encephalitis, we think that the encephalitis may be attributed to infection, and the use of etanercept may have increased the risk of severe infection. Therefore, etanercept was discontinued and the patient recovered shortly after. To the best of our knowledge, this is the first case of encephalitis in a juvenile rheumatoid arthritis patient treated with etanercept.

PurposeMedical professionals' practices and knowledge regarding cancer pain management have often been cited as inadequate. This study aimed to evaluate knowledge, practices and perceived barriers regarding cancer pain management among physicians and nurses in Korea.MethodsA nationwide questionnaire survey was administered to physicians and nurses involved in the care of cancer patients. Questionnaire items covered pain assessment and documentation practices, knowledge regarding cancer pain management, the perceived barriers to cancer pain control, and processes perceived as the major causes of delay in opioid administration.ResultsA total of 333 questionnaires (149 physicians and 284 nurses) were analyzed. Nurses performed pain assessment and documentation more regularly than physicians did. Although physicians had better knowledge of pain management than did nurses, both groups lacked knowledge regarding the side effects and pharmacology of opioids. Physicians working in the palliative care ward and nurses who had received pain management education obtained higher scores on knowledge. Physicians perceived patients' reluctance to take opioids as a barrier to pain control, more so than did nurses, while nurses perceived patients' tendency to under-report of pain as a barrier, more so than did physicians. Physicians and nurses held different perceptions regarding major cause of delay during opioid administration.ConclusionsThere were differences between physicians and nurses in knowledge and practices for cancer pain management. An effective educational strategy for cancer pain management is needed in order to improve medical professionals' knowledge and clinical practices.

Whereas it has been assumed that genetically modified tissues or cells derived from somatic cell nuclear transfer (SCNT) should be accepted by a host of the same species, their immune compatibility has not been extensively explored. To identify acceptance of SCNT-derived cells or tissues, skin grafts were performed between cloned dogs that were identical except for their mitochondrial DNA (mtDNA) haplotypes and foreign gene. We showed here that differences in mtDNA haplotypes and genetic modification did not elicit immune responses in these dogs: 1) skin tissues from genetically-modified cloned dogs were successfully transplanted into genetically-modified cloned dogs with different mtDNA haplotype under three successive grafts over 63 days; and 2) non-transgenic cloned tissues were accepted into transgenic cloned syngeneic recipients with different mtDNA haplotypes and vice versa under two successive grafts over 63 days. In addition, expression of the inserted gene was maintained, being functional without eliciting graft rejection. In conclusion, these results show that transplanting genetically-modified tissues into normal, syngeneic or genetically-modified recipient dogs with different mtDNA haplotypes do not elicit skin graft rejection or affect expression of the inserted gene. Therefore, therapeutically valuable tissue derived from SCNT with genetic modification might be used safely in clinical applications for patients with diseased tissues.

The nuclear DNA binding protein high mobility group box 1 (HMGB1) has recently been suggested to act as a late mediator of septic shock. The effect of ((S)-6,7-dihydroxy-1-(4-hydroxynaphthylmethyl)-1,2,3,4-tetrahydroisoquinoline alkaloid, also known as THI-56, in an experimental model of sepsis was investigated. THI-56 exhibited potent anti-inflammatory properties in response to LPS in RAW 264.7 cells. In particular, THI-56 significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the release of HMGB1 in activated macrophages. THI-56 activated NE-F2-regulated factor 2 (Nrf-2)/heme oxygenase 1 (HO-1). The specific knockdown of the HO-1 gene by HO-1 siRNA significantly reversed the inhibitory effects of THI-56 on iNOS expression and HMGB1 release in LPS-stimulated macrophages. Importantly, THI-56 administration protected animals from death induced by either a lethal dose of LPS or cecal ligation and puncture (CLP). Furthermore, the ALT, AST, BUN, creatinine, and HMGB1 levels in the blood were significantly increased in CLP-induced septic mice, and the administration of THI-56 reduced these levels in a concentration-dependent and zinc protoporphyrin IX (ZnPPIX)-sensitive manner. In addition, the administration of THI-56 significantly ameliorated not only lung damage but also macrophage infiltration in the livers of CLP-induced septic mice, and these effects were also abrogated in the presence of ZnPPIX. Thus, we conclude that THI-56 significantly attenuates the proinflammatory response induced by LPS and reduces organ damage in a CLP-induced sepsis model through the upregulation of Nrf-2/HO-1.