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Abstract Background Numerous studies have been conducted to manage anemia in surgical patients through iron supplementation as an alternative to blood transfusion. However, patients with locally advanced rectal cancer have often been excluded from these studies, due to their standard treatment involving neoadjuvant chemoradiotherapy. This study aims to evaluate the impact of intravenous versus oral iron supplementation on iron deficiency anemia in patients with rectal cancer receiving preoperative chemoradiotherapy. Methods This open-label, single-center, parallel, superiority, randomized trial includes patients with primary rectal cancer who are candidates for preoperative chemoradiotherapy and have confirmed iron-deficiency anemia. A total of 94 patients will be randomly assigned in a 1:1 ratio to receive either intravenous or oral iron supplementation. Stratification factors include age (> 70 vs. ≤ 70 years) and baseline serum hemoglobin levels (7–10 g/dL vs. 10–13 g/dL). The primary endpoint is the percentage of patients achieving normalized hemoglobin levels from the start of treatment to the day of admission for surgery. Secondary endpoints include changes in serum hemoglobin from baseline to postoperatively, changes in iron assay parameters, time needed to hemoglobin normalization, volume of blood transfusions required, and incidence of postoperative complications. Discussion This study is the first randomized controlled trial investigating the effect of iron supplementation in iron-deficient patients with rectal cancer undergoing neoadjuvant chemoradiotherapy. This trial is expected to provide evidence for the benefits of administering iron supplementation in patients with rectal cancer undergoing neoadjuvant chemoradiotherapy. Trial registration Clinical Research Information Service (CRIS) of Republic of Korea, KCT0009260, Registered on March 21, 2024.

Abstract Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

Abstract Osteoarthritis (OA) is a progressive and irreversible degenerative joint disease that is characterized by cartilage destruction, osteophyte formation, subchondral bone remodeling, and synovitis. Despite affecting millions of patients, effective and safe disease-modifying osteoarthritis drugs are lacking. Here we reveal an unexpected role for the small molecule 5-aminosalicylic acid (5-ASA), which is used as an anti-inflammatory drug in ulcerative colitis. We show that 5-ASA competes with extracellular-matrix collagen-II to bind to osteoclast-associated receptor (OSCAR) on chondrocytes. Intra-articular 5-ASA injections ameliorate OA generated by surgery-induced medial-meniscus destabilization in male mice. Significantly, this effect is also observed when 5-ASA was administered well after OA onset. Moreover, mice with DMM-induced OA that are treated with 5-ASA at weeks 8–11 and sacrificed at week 12 have thicker cartilage than untreated mice that were sacrificed at week 8. Mechanistically, 5-ASA reverses OSCAR-mediated transcriptional repression of PPARγ in articular chondrocytes, thereby suppressing COX-2-related inflammation. It also improves chondrogenesis, strongly downregulates ECM catabolism, and promotes ECM anabolism. Our results suggest that 5-ASA could serve as a DMOAD.

Abstract Osteoarthritis (OA) is a degenerative joint disease. While it is classically characterized by articular cartilage destruction, OA affects all tissues in the joints and is thus also accompanied by local inflammation, subchondral bone changes, and persistent pain. However, our understanding of the underlying subchondral bone dynamics during OA progression is poor. Here, we demonstrate the contribution of immunoglobulin superfamily 11 (IgSF11) to OA subchondral bone remodeling by using a murine model. In particular, IgSF11 was quickly expressed by differentiating osteoclasts and upregulated in subchondral bone soon after destabilization-of-the-medial-meniscus (DMM)-induced OA. In mice, IgSF11 deficiency not only suppressed subchondral bone changes in OA but also blocked cartilage destruction. The IgSF11-expressing cells in OA subchondral bone were found to be involved in osteoclast maturation and bone resorption and colocalized with receptor-activator of nuclear-factor κ-B (RANK), the key osteoclast differentiation factor. Thus, our study shows that blocking early subchondral bone changes in OA can ameliorate articular cartilage destruction in OA.

Abstract Background The effect of fecal stream diversion on the gut microbiota is still uncertain. The present study was designed to assess the effect of fecal stream diversion on the composition of the gut microbiota in patients with colorectal cancer. We included patients undergoing left-sided colorectal cancer surgery with (ileostomy group) or without (control group) diverting ileostomy. Fecal samples were collected from 10 patients in each group before surgery (t 1 ) and after ileostomy repair in the ileostomy group and 6–12 months after the initial surgery in the control group (t 2 ). The fecal microbiota was assessed using 16S rRNA sequencing, and changes in the composition of the fecal microbiota were compared between the two groups. Results Alpha diversity analysis revealed that the complexity of fecal microbiota decreased between t 1 and t 2 only in the ileostomy group. Beta diversity analysis also showed dissimilarity between t 1 and t 2 only in the ileostomy group. The composition of the microbiota was similar between the two groups at t 1 . However, at t 2 , the ileostomy group had lower proportion of beneficial bacteria (Lachnospiraceae, 3.8% vs. 29.9%, p

Abstract Wafer map defect pattern classification is essential in semiconductor manufacturing processes for increasing production yield and quality by providing key root-cause information. However, manual diagnosis by field experts is difficult in large-scale production situations, and existing deep-learning frameworks require a large quantity of data for learning. To address this, we propose a novel rotation- and flip-invariant method based on the labeling rule that the wafer map defect pattern has no effect on the rotation and flip of labels, achieving class discriminant performance in scarce data situations. The method utilizes a convolutional neural network (CNN) backbone with a Radon transformation and kernel flip to achieve geometrical invariance. The Radon feature serves as a rotation-equivariant bridge for translation-invariant CNNs, while the kernel flip module enables the model to be flip-invariant. We validated our method through extensive qualitative and quantitative experiments. For qualitative analysis, we suggest a multi-branch layer-wise relevance propagation to properly explain the model decision. For quantitative analysis, the superiority of the proposed method was validated with an ablation study. In addition, we verified the generalization performance of the proposed method to rotation and flip invariants for out-of-distribution data using rotation and flip augmented test sets.

Abstract Background Minimally invasive surgery has become popular as a surgical approach for colorectal cancer because it has fewer complications related to the abdominal incision and perioperative complications. However, the incidence of incisional hernias in laparoscopic surgery has been reported to be similar to that in open surgery. We developed a new method, the non-muscle-cutting periumbilical transverse incision, for a small incision in laparoscopic colon cancer surgery. This study aims to evaluate the effectiveness of the non-muscle-cutting periumbilical transverse incision in comparison with the midline incision in reducing the incidence of an incisional hernia in patients undergoing laparoscopic colon cancer surgery. Methods This is an open-label, multi-centre, parallel, superiority, and randomised trial. Altogether, 174 patients will be allocated in a 1:1 ratio to either the midline incision or the non-muscle-cutting periumbilical transverse incision group, after stratifying by the location of the tumour (right- or left-sided). The primary outcome of this study is the incidence of incisional hernias (both symptomatic and radiologic hernias) at 12 months after surgery. The secondary outcomes include operative outcomes, 30-day postoperative complications, pathological results, and patient-reported outcomes (short form-12 health survey questionnaire and body image questionnaire). Both primary (intention-to-treat) and secondary (as-treated principles) analyses will be performed for all outcomes. The statistical significance level was set at p

Background Kidney organoids derived from human pluripotent stem cells (hPSCs) contain multilineage nephrogenic progenitor cells and can recapitulate the development of the kidney. Kidney organoids derived from hPSCs have the potential to be applied in regenerative medicine as well as renal disease modeling, drug screening, and nephrotoxicity testing. Despite biotechnological advances, individual differences in morphological and growth characteristics among kidney organoids need to be addressed before clinical and commercial application. In this study, we hypothesized that an automated noninvasive method based on deep learning of bright-field images of kidney organoids can predict their differentiation status. Methods Bright-field images of kidney organoids were collected on day 18 after differentiation. To train convolutional neural networks (CNNs), we utilized a transfer learning approach. CNNs were trained to predict the differentiation of kidney organoids on bright-field images based on the messenger RNA expression of renal tubular epithelial cells as well as podocytes. Results The best prediction model was DenseNet121 with a total Pearson correlation coefficient score of 0.783 on a test dataset. W classified the kidney organoids into two categories: organoids with above-average gene expression (Positive) and those with below-average gene expression (Negative). Comparing the best-performing CNN with human-based classifiers, the CNN algorithm had a receiver operating characteristic-area under the curve (AUC) score of 0.85, while the experts had an AUC score of 0.48. Conclusion These results confirmed our original hypothesis and demonstrated that our artificial intelligence algorithm can successfully recognize the differentiation status of kidney organoids.

Abstract Adult stem cell-based therapeutic approaches have great potential in regenerative medicine because of their immunoregulatory properties and multidifferentiation capacity. Nevertheless, the outcomes of stem cell‑based therapies to date have shown inconsistent efficacy owing to donor variation, thwarting the expectation of clinical effects. However, such donor dependency has been elucidated by biological consequences that current research could not predict. Here, we introduce cellular morphology-based prediction to determine the multipotency rate of human nasal turbinate stem cells (hNTSCs), aiming to predict the differentiation rate of keratocyte progenitors. We characterized the overall genes and morphologies of hNTSCs from five donors and compared stemness-related properties, including multipotency and specific lineages, using mRNA sequencing. It was demonstrated that transformation factors affecting the principal components were highly related to cell morphology. We then performed a convolutional neural network-based analysis, which enabled us to assess the multipotency level of each cell group based on their morphologies with 85.98% accuracy. Surprisingly, the trend in expression levels after ex vivo differentiation matched well with the deep learning prediction. These results suggest that AI‑assisted cellular behavioral prediction can be utilized to perform quantitative, non-invasive, single-cell, and multimarker characterizations of live stem cells for improved quality control in clinical cell therapies.

Abstract Background Although many efforts have been made to decrease the incidence of anastomotic leak (AL), it remains one of the most serious complications of rectal cancer surgery. Many previous studies have reported an association between the ligation level of the inferior mesenteric artery (IMA) (high or low) and the incidence of AL after rectal cancer surgery. However, we cannot draw a solid conclusion because of the low quality and heterogeneity of those studies. Therefore, this study aims to investigate the impact of the IMA ligation level on the occurrence of AL after minimally invasive anterior resection of rectal cancer. Methods/design Patients with primary rectal cancer without distant metastases will be included after screening. They will be randomly assigned (1:1) to receive high or low ligation of the IMA. The primary endpoint is AL incidence; secondary endpoints are quality of life; urinary, sexual, and defecatory functions; and 3-year disease-free survival. We hypothesized that the incidence rate of AL would be 15% and 5% in the high- and low-ligation groups, respectively. With a two-sided α of 0.05 and a power of 0.8, the sample size is calculated to be 314 patients (157 per group), considering a 10% dropout rate. Discussion Although many studies have compared the short- and long-term outcomes of high and low ligation of the IMA in rectal cancer surgery, it is still debatable. This trial aims to help draw a more solid conclusion regarding the association between the IMA ligation level and AL incidence after rectal cancer surgery. We also hope to contribute to standardizing the method of rectal cancer surgery in this trial. Trial registration Clinical Research Information Service KCT0003523. Registered on February 18, 2019

Abstract Boron neutron capture therapy (BNCT) has been attracting interest as a new radiation modality for cancer therapy because it can selectively destroy cancer cells while maintaining the healthy state of surrounding normal cells. Many experimental trials have demonstrated significant BNCT treatment efficacy using neutron beams from research reactors. However, nuclear reactor technology cannot be scaled to sites in hospitals delivering patient treatment. Therefore, compact accelerator-based neutron sources that could be installed in many hospitals are under development or have even been commissioned at many facilities around the world. In Korea, a radio-frequency (RF) linac-based BNCT (A-BNCT) facility is under development by DawonMedax (DM). It provides the highly efficient production of an epithermal neutron beam with an optimized neutron energy spectrum range of 0.1~10 keV. With a 2-mA 10-MeV proton beam from the accelerator, the irradiation port epithermal neutron flux is higher than 1 × 109 n/cm2⋅s. Comprehensive verification and validation of the system have been conducted with the measurement of both proton and neutron beam characteristics. Significant therapeutic effects from BNCT have been confirmed by DM in both in vitro and in vivo non-clinical trials. Further, during exposure to epithermal neutrons, all other unintended radiation is controlled to levels meeting International Atomic Energy Agency (IAEA) recommendations. Recently, the Korean FDA has accepted an investigational new drug (IND) and the first-in-human clinical trial of BNCT is now being prepared. This paper introduces the principles of BNCT and accelerator-based neutron sources for BNCT and reports the recent advances of DM A-BNCT facility which is the main part of this paper.

Since Toll-like receptors (TLRs) recognize the earliest signs of infection or cell damage, they play fundamental roles in innate immunity. This review summarizes the numerous studies on the expression of TLRs in patients with Coronavirus disease 2019 (COVID-19). We show that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can stimulate at least six of the ten TLRs in humans and that this can shape the severity of COVID-19. Specifically, TLR2, TLR4, and TLR9 appear to play pathogenic roles while TLR3, TLR7, and TLR8 may be protective. Most have mutations that could partly explain the susceptibility phenotypes of COVID-19. Further understanding the roles of TLRs in COVID-19 immunopathogenesis could reveal prognostic biomarkers and help drive the development of novel and effective therapeutics for COVID-19.

Osteoarthritis (OA) is the most common joint disease that causes local inflammation and pain, significantly reducing the quality of life and normal social activities of patients. Currently, there are no disease-modifying OA drugs (DMOADs) available, and treatment relies on pain relief agents or arthroplasty. To address this significant unmet medical need, we aimed to develop monoclonal antibodies that can block the osteoclast-associated receptor (OSCAR). Our recent study has revealed the importance of OSCAR in OA pathogenesis as a novel catabolic regulator that induces chondrocyte apoptosis and accelerates articular cartilage destruction. It was also shown that blocking OSCAR with a soluble OSCAR decoy receptor ameliorated OA in animal models. In this study, OSCAR-neutralizing monoclonal antibodies were isolated and optimized by phage display. These antibodies bind to and directly neutralize OSCAR, unlike the decoy receptor, which binds to the ubiquitously expressed collagen and may result in reduced efficacy or deleterious off-target effects. The DMOAD potential of the anti-OSCAR antibodies was assessed with in vitro cell-based assays and an in vivo OA model. The results demonstrated that the anti-OSCAR antibodies significantly reduced cartilage destruction and other OA signs, such as subchondral bone plate sclerosis and loss of hyaline cartilage. Hence, blocking OSCAR with a monoclonal antibody could be a promising treatment strategy for OA.

Abstract Background In women with autoimmune rheumatic disorders (ARD), pregnancy complications or postpartum events are more frequent compared to the general population. Transplacental autoantibodies or cytokines influence various fetal and neonatal outcomes. We compared the growth patterns of babies born to mothers with ARD versus healthy mothers to assess the long-term growth outcomes of children born to women with ARD. Methods This was a retrospective age-matched cohort analyses of babies born to mothers with ARD from the hospitals belonging to the Catholic University of Korea between 2010 and 2017. Demographic and autoimmune laboratory test data of the mothers and newborns were assessed. Neonatal growth was measured in terms of height and weight, measured at birth and follow-up examinations. Results We enrolled 142 infants from mothers with ARD and 149 infants from healthy mothers. There was no significant difference between mothers with ARD and healthy mothers in terms of delivery age, parity, abortion, and premature delivery history. The mothers with ARD were diagnosed with systemic lupus erythematosus (81%), Sjogren syndrome (6%), and other autoimmune phenomena (11%). The groups were significantly different in terms of neonatal characteristics such as prematurity, gestational age, birth weight, and height, but not in Apgar score and delivery type. For most neonates, autoimmune laboratory results were normalized within 1 year, except for anti-La/SSB antibody, which remained high in some. The height and weight for age z-score were lower than the normal age groups at birth but showed catch-up growth by 2 years of age. Conclusions Low birthweight and prematurity at birth for neonates born to mothers with ARD could be caught up by 2 years of age, and maternal ARD does not affect the growth of their offspring.

Purpose: Pre-operative evaluation identifying clinical-stage affects the decision regarding the extent of surgical resection in right colon cancer. This study was designed to predict a proper surgical resection through the prognosis of clinical Stage I right colon cancer. Patients and Methods: We included patients who were diagnosed with clinical and pathological Stage I right-sided colon cancer, including appendiceal, caecal, ascending, hepatic flexure and proximal transverse colon cancer, between August 2010 and December 2016 in two tertiary teaching hospitals. Patients who underwent open surgeries were excluded because laparoscopic surgery is the initial approach for colorectal cancer in our institutions. Results: Eighty patients with clinical Stage I and 104 patients with pathological Stage I were included in the study. The biopsy reports showed that the tumour size was larger in the clinical Stage I group than in the pathological Stage I group (3.4 vs. 2.3 cm, P < 0.001). Further, the clinical Stage I group had some pathological Stage III cases (positive lymph nodes, P = 0.023). The clinical Stage I group had a higher rate of distant metastases (P = 0.046) and a lower rate of overall (P = 0.031) and cancer-specific survival (P = 0.021) than the pathological Stage I group. Compared to pathological Stage II included in the period, some of the survival curves were located below the pathological Stage II, but there was no statistical difference. Conclusion: The study results show that even clinical Stage I cases, radical resection should be considered in accordance with T3 and T4 tumours.

Abstract The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID‐19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self‐dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc‐mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID‐19 in several countries, can effectively trap SARS‐CoV‐2 virus‐like particles in fresh human airway mucus. IN‐006, a reformulation of regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN‐006 resulted in 100‐fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN‐006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS‐CoV‐2 and other respiratory pathologies.

Abstract Photoacoustic computed tomography (PACT) has become a premier preclinical and clinical imaging modality. Although PACT's image quality can be dramatically improved with a large number of ultrasound (US) transducer elements and associated multiplexed data acquisition systems, the associated high system cost and/or slow temporal resolution are significant problems. Here, a deep learning‐based approach is demonstrated that qualitatively and quantitively diminishes the limited‐view artifacts that reduce image quality and improves the slow temporal resolution. This deep learning‐enhanced multiparametric dynamic volumetric PACT approach, called DL‐PACT, requires only a clustered subset of many US transducer elements on the conventional multiparametric PACT. Using DL‐PACT, high‐quality static structural and dynamic contrast‐enhanced whole‐body images as well as dynamic functional brain images of live animals and humans are successfully acquired, all in a relatively fast and cost‐effective manner. It is believed that the strategy can significantly advance the use of PACT technology for preclinical and clinical applications such as neurology, cardiology, pharmacology, endocrinology, and oncology.

Selenoproteins containing selenium have a variety of physiological functions including redox homeostasis and thyroid hormone metabolism. Here, the authors show that RANKL-dependent repression of selenoprotein W regulates cell fusion during osteoclast differentiation and bone remodelling in mice.

The development of waterborne polyurethane (WPU) has been stimulated as an alternative to solvent-based polyurethanes due to low-VOC alternatives and reduced exposure to solvents. However, their relatively low mechanical performance and degradation have presented challenges in their wide application. Here, we developed environmentally-friendly bio polyol-based WPU nanocomposite dispersions and films, and presented the optimal process conditions for their manufacture. Additionally, the condition was established without using harmful catalysts or ethyl methyl ketone (MEK) during the polymerization. Moreover, regenerated cellulose nanoparticles (RCNs) were employed as natural chain-extenders in order to improve the biodegradability and mechanical performances of the nanocomposite films. The RCNs have a lower crystallinity compared to cellulose nanocrystals (CNCs), allowing them to possess high toughness without interfering with the elastomeric properties of polyurethane. The prepared CWPU/RCNs nanocomposite films exhibited high toughness of 58.8 ± 3 kgf∙mm and elongation at break of 240 ± 20%. In addition, depending on the molar ratio of NCO/OH, the polyurethane particle size is variously controlled from 70 to 230 nm, enabling to fabricate their dispersions with various transmittances. We believe that our findings not only open a meaningful path toward green elastomers with biodegradability but provides the design concept for bio-elastomers in order to develop industrial elastomers with mechanical and thermal properties.

Purpose: The colon originates from the midgut and hindgut, with subsequent differentiation into the right and left colon. The embryology, clinical symptoms, incidence, molecular pathways, and oncologic outcomes differ between right and left colorectal cancers. However, the differences have not been fully accepted. Aim of the Study: This study compared short- and long-term outcomes between right and left colon cancers. Materials and Methods: This study included 966 patients who underwent laparoscopic resection with radical lymph node dissection for stage I, II, and III colon cancers between 2009 and 2014 at a tertiary teaching hospital. We excluded cases with fewer than 12 retrieved lymph nodes, emergency operations, synchronous or multiple cancers, and those located in the transverse colon and rectum. Results: The right colon group included 343 (35.5%) patients and the left colon group 623. Female patients had a high incidence of right colon cancer (p

Purpose This study aimed to evaluate the relationship between high-output stomas (HOSs), postoperative ileus (POI), and readmission after rectal cancer surgery with diverting ileostomy. Methods We included 302 patients with rectal cancer who underwent restorative resection with diverting ileostomy between January 2011 and December 2015. HOSs were defined as stomas with ≥ 2,000 mL/day output. We analyzed predictive factors for readmission of these patients. Results Forty-eight patients (15.9%) had HOSs during the hospital stay, and 41 patients (13.6%) experienced POI. HOSs were strongly associated with POI (45.8% vs. 7.5%, P < 0.001). The all-cause readmission rate was 16.9%, with 19 (6.3%) and 20 (6.6%) experiencing ileus and acute kidney injury, respectively. HOSs (27.1% vs. 15.0%, P = 0.040) and POI (34.1% vs. 14.2%, P = 0.002) were associated with all-cause readmission, and POI was associated with readmission with ileus (17.1% vs. 4.6%, P = 0.007). POI was an independent risk factor for all-cause readmission (adjusted odds ratio [OR], 2.640; 95% confidence interval [CI], 1.162 to 6.001; P = 0.020) and readmission with ileus (adjusted OR = 3.869; 95% CI 1.387 to 10.792; P = 0.010). Conclusion POI was associated with readmission, particularly for subsequent ileus, in patients with diverting ileostomy. We should make efforts to reduce POI, such as strong control of HOSs, to prevent readmission.

Abstract Background Very few studies have been conducted on the treatment strategy for enlarged paraaortic lymph nodes (PALNs) incidentally detected during surgery. The purpose of this study was to investigate the benefit of lymph node dissection in patients with incidentally detected enlarged PALNs. Methods We retrospectively reviewed patients with left colon and rectal cancer who underwent surgical resection with PALN dissection between January 2010 and December 2018. The predictive factors for pathologic PALN metastasis (PALNM) were analyzed, and survival analyses were conducted to identify prognostic factors. Results Among 263 patients included, 19 (7.2%) showed pathologic PALNM and 5 (26.33%) had enlarged PALNs incidentally detected during surgery. These 5 patients accounted for 2.2% of 227 patients who had no evidence of PALNM on preoperative radiologic examination. Radiologic PALNM (odds ratio [OR] 12.737, 95% confidence interval [CI] 3.472–46.723) and radiologic distant metastasis other than PALNM (OR = 4.090, 95% CI 1.011–16.539) were independent predictive factors for pathologic PALNM. Pathologic T4 stage (hazard ratio [HR] 2.196, 95% CI 1.063–4.538) and R2 resection (HR 4.643, 95% CI 2.046–10.534) were independent prognostic factors for overall survival (OS). In patients undergoing R0 resection, pathologic PALNM was not associated with 5-year OS (90% vs. 82.2%, p = 0.896). Conclusion Dissection of enlarged PALNs incidentally detected during colorectal surgery may benefit patients with favorable survival outcomes.

The vehicle suspension control unit serves as a critical component to the vehicle system, as it ensures the steering stability and sound ride quality of the vehicle. To effectively realize control strategies, it is essential to foreknowledge the road profile and the suspension system's internal state variables. While the mentioned variables are not practically measurable using commercial sensors, it is necessary to estimate the desired variables by utilizing observer systems. Conventional means have mainly employed model-based approaches, in which model uncertainties and high computational cost pose limitations for practical implementation. Herein, we propose a data-driven deep learning method as an alternative because no explicit physical modeling is required, and evaluation is computationally cheap. We first propose a novel encoder-decoder structured recurrent neural network model with a two-phase attention mechanism to estimate the unknown road profile and four state variables of the vehicle suspension system. Based on a simulated data set, we assess the proposed model's qualitative and quantitative results and demonstrate that our model can achieve highly accurate estimation results with fast computation time. Besides, we validate our black-box model's reliability by comparing its interpretation with the suspension system's actual physical characteristics. Furthermore, we compare the proposed model with existing baseline methods, and the results show that our proposed deep learning model significantly outperforms the baseline. Lastly, we experiment with our network's autoregressive capability and demonstrate the feasibility of estimating a sequence of future values, which has not been presented in previous works.

Gender inequality poses grave consequences for young women’s health and wellbeing. The aim of this study was to understand how gender influences the lives of young women living in urban slums of Lucknow, Uttar Pradesh, India using story circles as a research methodology. Narrative-based participatory methods like story circles (which involves sharing individual stories in a group circle on a given topic) can provide the nuance and detail needed to understand young people’s experiences, build trust between participants and researchers, and offer spaces to speak about culturally sensitive subjects. Six story circle sessions were conducted with 50 young women (aged 15–24) in Lucknow. Sessions were audio-recorded, transcribed, and coded. Transcriptions were analysed to identify the following salient themes, all of which act as mechanisms of gender inequality: mobility restrictions, rampant sexual harassment in the community, limited educational and work opportunities, and the utmost prioritization of marriage for young women.

Being born small for gestational age (SGA) has been strongly associated with mortality during the perinatal period and long-term risk of metabolic syndrome, including type 2 diabetes mellitus, hypertension, hyperlipidemia, and coronary heart disease. Insulin resistance is an important factor in the development of metabolic syndrome in SGA, with several proposed hypotheses. Here, we report two cases of non-obese adolescent patients with early onset type 2 diabetes who were born SGA. Of these, one experienced catch-up growth, while the other did not. Both had a high body fat percentage at the time of diagnosis of type 2 diabetes and were diagnosed with fatty liver and hyperlipidemia before adolescence, at the age of 7 years. Early interventions for SGA are needed for healthy catch-up growth to prevent metabolic diseases in the future.

Osteoarthritis (OA) is associated with cartilage disruption, but the underlying mechanisms remain unclear. Here, the authors show that expression of osteoclast-associated receptor (OSCAR) is associated with OA, that its genetic ablation or targeting with OSCAR-Fc fusion protein ameliorates OA in mice by decreasing chondrocyte apoptosis.

Abstract Background Current guidelines recommend the prescription of immune-enriched oral nutritional supplements for malnourished patients before major gastrointestinal surgery. However, the benefit of preoperative immunonutrition is still controversial. This randomized controlled trial aims to evaluate the effect of preoperative immunonutrition on the outcomes of surgery for colon cancer. Methods/design Patients with primary colon cancer will be included as study participants after screening. They will be randomly assigned (in a ratio of 1:1) to receive preoperative immunonutrition added to the normal diet (experimental arm) or consume normal diet alone (control arm). Patients in the experimental arm will receive oral supplementation (400 mL/day) with arginine and ω-3 fatty acids for 7 days before elective surgery. The primary endpoint is the rate of infectious complications, while the secondary endpoints are postoperative complication rate, change in body weight, length of hospital stay, and nature of fecal microbiome. The authors hypothesize that the rate of infectious complications would be 13% in the experimental arm and 30% in the control arm. With a two-sided alpha of 0.05 and a power of 0.8, the sample size is calculated as 176 patients (88 per arm). Discussion Although there have been many studies demonstrating significant benefits of preoperative immunonutrition, these were limited by a small sample size and potential publication bias. Despite the recommendation of immunonutrition before surgery in nutritional guidelines, its role in reduction of rate of infectious complications is still controversial. This trial is expected to provide evidence for the benefits of administration of preoperative immunonutrition in patients with colon cancer. Trial registration Clinical Research Information Service KCT0003770 . Registered on 15 April 2019.

Bone maintenance: regulating cells that break down bone A gene-controlling protein called Spi-C promotes the development of bone-processing cells called osteoclasts; details of the molecular mechanisms involved will aid understanding of Spi-C’s role in bone health and disease. Osteoclasts degrade bone during the normal process of bone remodeling, balanced by the activity of osteoblast cells that form new bone. Excessive osteoclast activity can cause the bone loss associated with various bone diseases including early-onset osteoporosis. Researchers in South Korea led by Soo Young Lee at Ewha Womans University and Na Kyung Lee at Soonchunhyang University, Asan, found that Spi-C promotes osteoclast development by activating genes that code for key proteins of a signaling pathway known to be crucial for bone health. Drugs that interfere with Spi-C activity may therefore offer a new approach for treating bone disease.

Bone diseases such as osteoporosis and periodontitis are induced by excessive osteoclastic activity, which is closely associated with inflammation. Benzydamine (BA) has been used as a cytokine-suppressive or non-steroidal anti-inflammatory drug that inhibits the production of pro-inflammatory cytokines or prostaglandins. However, its role in osteoclast differentiation and function remains unknown. Here, we explored the role of BA in regulating osteoclast differentiation and elucidated the underlying mechanism. BA inhibited osteoclast differentiation and strongly suppressed interleukin-1β (IL-1β) production. BA inhibited osteoclast formation and bone resorption when added to bone marrow-derived macrophages and differentiated osteoclasts, and the inhibitory effect was reversed by IL-1β treatment. The reporter assay and the inhibitor study of IL-1β transcription suggested that BA inhibited nuclear factor-κB and activator protein-1 by regulating IκB kinase, extracellular signal regulated kinase and P38, resulting in the down-regulation of IL-1β expression. BA also promoted osteoblast differentiation. Furthermore, BA protected lipopolysaccharide- and ovariectomy-induced bone loss in mice, suggesting therapeutic potential against inflammation-induced bone diseases and postmenopausal osteoporosis. Key words: Benzydamine, Osteoclast, Bone, Interleukin-1β, Nuclear factor-κB, Activator protein-1

Continuous casting is the procedure of the successive casting for solidification of the steel, which contains several cooling processes along the caster to coagulate the molten steel. It is such a rule of thumb that strand surface quality and casting productivity is highly dependent on temperature control. A finite-difference method is one of estimating temperature distribution, yet it hinders the process control efficiently. Song, et al. suggest a multimodal deep learning approach for prediction of the temperature. However, sequential and transient phenomena of solidifying steel are not considered, which makes it difficult to estimate the sequential heat-transfer characteristics in the whole process of the steel concretion. Herein, a deep learning model is proposed to predict the temperature distribution by taking into account both transient and steady-state characteristics. The proposed model addresses both spatial and sequential information by incorporating a convolutional neural network (CNN) and a recurrent neural network (RNN). Our quantitative and qualitative results show considerable predictive performance improvement against baseline models. Furthermore, the proposed model is applicable in a real-world steel-making industry by providing real-time temperature prediction, whilst retaining a lower computational cost.

In the era of the fourth industrial revolution (Industry 4.0) and the Internet of Things (IoT), real-time data is enormously collected and analyzed from mechanical equipment. By classifying and characterizing the measured signals, the fault condition of mechanical components could be identified. However, most current health monitoring techniques utilize time-consuming and labor-intensive feature engineering, i.e., feature extraction and selection, that are carried out by experts. This paper, on the contrary, deals with an automatic diagnosis method of machine monitoring using a convolutional neural network (CNN) with class activation maps (CAM). A class activation map enables us to discriminate the fault region in the images, thus allowing us to localize the fault precisely. The goal of the paper is to demonstrate how CNN and CAM could be employed to real-world vibration video to characterize the machine's status, representing normal or fault conditions. The performance of the proposed model is validated with a base-excited cantilever beam dataset and a water pump dataset. This paper presents a novel industrial application by developing a promising method for automatic machine condition-based monitoring.

Summary: Background: Among rectal cancer patients, some of good responders after neoadjuvant chemoradiotherapy (nCRT) are considered for non-operative treatments to avoid postoperative morbidities and permanent stoma. However, oncologic feasibility of non-operative treatment has not been fully understood. Methods: From 2008 to 2017, we retrospectively reviewed patient's records who had lower or mid rectal cancer and diagnosed to clinical complete response by magnetic resonance imaging after nCRT. Clinical differences and oncologic outcomes were compared among Radical surgery (RS), Local excision (LE) and Wait-and-see (WS) group. Results: Number of 129, 25, 15 patients included to RS, LE, WS groups. Local recurrence was frequent type of recurrence in both of LE and WS group (RS; 31.3%, LE; 80%, WS; 66.7%), and many patients in WS group omitted salvage treatment (RS; 75%, LE; 100%, WS; 33.3%). 5-years local-recurrence/disease-free survival rate (LRFS, DFS) between RS and LE were similar between each group, but WS showed significantly inferior outcomes than that of RS (LRFS; p = 0.001, DFS; p = 0.001). In multivariate analysis, WS protocol (OR; 7.163, 95% CI; 1.995–25.715) and cT4 stage (OR; 8.206, 95% CI; 1.596–42.198) were independent factors for LRFS. Conclusions: Wait-and-see group showed high rate of rejection of salvage treatments for recurrence, and poor oncologic outcomes. However, recent low-level evidences reported favorable outcome of WS protocol when salvage treatment was followed after recurrence. It seems that the application of WS protocol should be postponed until the results of randomized-controlled trials are available. Local excision seems to be good alternative option to radical surgery when salvage treatment is followed. Keywords: Rectal cancer, Complete response, Local excision, Wait-and-see

Bone disease: scaffolding protein essential for bone resorption The interaction between RACK1, a so-called scaffolding protein that can assemble components of a signaling pathway into complexes, and c-Src, an enzyme involved in the re-organization of the actin cytoskeleton, is crucial for bone resorption. Previous studies have implicated RACK1 in differentiation of osteoclasts, bone cells that resorb bone, but a study led by Soo Young Lee at Ewha Womans University, Seoul, South Korea, shows that it is also required for mature osteoclast function. Mutations in RACK1 or c-Src that prevented them from binding to each other impaired the bone resorption activity of osteoclasts seeded on bone slices. Osteoclasts bearing the mutated proteins were unable to form transient actin rings, cytoskeleton structures that are typically observed during bone resorption. These findings could lead to new targeted therapies against diseases characterized by bone loss such as osteoporosis.

Purpose The bowel frequency of patients who had undergone rectal resection might be difficult to distinguish from the diarrhea of Clostridium difficile infection (CDI). The change of bowel movement following rectal surgery has been a challenge for the diagnosis of CDI and scarce studies discussed this diagnostic difficulty. Methods From January 2004 to January 2018, a total of 8,327 patients in a single tertiary colorectal cancer center was evaluated for CDI, and their medical records were ret rospectively reviewed. Bowel frequency and treatment outcomes were compared between the rectal resection group (RG) and colectomy group (CG). Diagnostic time was defined as the time interval between first diarrhea (more than three times a day) and pathologic confirmation date of CDI. Results CDI incidence was 2.3% (17/752) vs. 0.41% (31/7,575) between RG and CG (P

Purpose The aim of this study was to assess oncological outcomes of postoperative radiotherapy plus chemotherapy (CRT) versus chemotherapy alone (CTx) in stage II or III upper rectal cancer patients who underwent curative surgery. Methods We retrospectively reviewed 263 consecutive patients with pathologic stage II or III upper rectal cancer who underwent primary curative resection with postoperative CRT or CTx from January 2008 to December 2014 at Chonnam National University Hwasun Hospital. Multivariate and propensity score matching analyses were used to reduce selection bias. Results Median follow-up was 48.1 months for the entire cohort and 53.5 months for the matched cohort. In subgroup analysis of the propensity score matched cohort, the 3-year local recurrence-free survival was 94.1% (95% confidence interval [CI], 87.8%–100%) in the CRT group and 90.1% (95% CI, 82.8%–97.9%) in the CTx group (P = 0.370). No significant difference in disease-free survival was observed according to treatment type. On multivariate analysis, circumferential resection margin involvement (hazard ratio [HR], 2.386; 95% CI, 1.190–7.599; P = 0.032), N stage (HR, 6.262; 95% CI, 1.843–21.278, P = 0.003), and T stage (HR, 5.896, 95% CI, 1.298–6.780, P = 0.021) were identified as independent risk factors for local recurrence of tumors of the upper rectum. Conclusion Omission of radiotherapy in an adjuvant treatment setting may not jeopardize oncologic outcomes in stages II and III upper rectal cancer.

Abstract Background In its RING domain, tumor necrosis factor receptor-associated factor 6 (TRAF6) has ubiquitin E3 ligase activity that facilitates the formation of lysine 63-linked polyubiquitin chains. This activity is required to activate nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and plays an important role in the IκB kinase (IKK) complex. Methods An in vitro ubiquitination assay was used to establish whether c-Cbl could promote TRAF6 ubiquitination. We assessed direct binding and performed fine mapping between c-Cbl and TRAF6 based on the results of an immunoprecipitation assay with cultured 293 T cells. The luciferase reporter assay was applied to establish if c-Cbl-mediated ubiquitination affected NF-κB activation after stimulus from various TRAF-mediated signals: tumor necrosis factor-α (TNF-α), receptor activator of NF-κB ligand (RANKL), and interleukin-1β (IL-1β). An in vivo ubiquitination assay was performed using endogenous immunoprecipitation of TRAF6 in bone marrow macrophages (BMMs) and osteoclasts. Results Here, we report on a form of TRAF6 ubiquitination that is mediated by c-Cbl, leading to the formation of lysine 48-linked polyubiquitin chains. The NF-κB activity induced by RANKL and IL-1β treatment is inhibited when c-Cbl is overexpressed, while the NF-κB activity induced by TNFα treatment is not. c-Cbl inhibits NF-κB activity mediated by TRAF6, but not by TRAF2. These findings show that c-Cbl ubiquitin ligase activity is essential for TRAF6 ubiquitination and negative regulation of NF-κB activity. Fine mapping revealed that the proline-rich domain of c-Cbl is critical for interaction with TRAF6. Stimulation with RANKL or interferon-γ (IFN-γ) caused c-Cbl to bind to polyubiquitinated TRAF6. Conclusions These findings indicate that the interaction of TRAF6 with c-Cbl causes lysine 48-linked polyubiquitination for both negative feedback regulation and signaling cross-talk between RANKL and IFN-γ.

Purpose Treatment after failure of circumferential resection margin (CRM) conversion after preoperative chemoradiotherapy (pCRT) for locally advanced rectal cancer (LARC) has not been evaluated well. We conducted a single‐center, retrospective analysis to fill this information gap. Methods From 2008 to 2016, we included 112 patients who had predictive CRM involvement on baseline magnetic resonance imaging (MRI) and who underwent surgery following pCRT for LARC. Baseline and posttreatment radiologic and clinical factors were analyzed. Results Of 493 patients with LARC, 112 had CRM involvement by baseline MRI (mrCRM). In 40 patients (35.7%), mrCRM involvement was converted as negative posttreatment CRM (ymrCRM−). Multivariate analysis showed the risk factors for persistent CRM involvement (ymrCRM+) after pCRT were extramural venous invasion (mrEMVI+) (P = 0.030) and lower tumor location (P = 0.007). In addition, persistent CRM involvement after pCRT was an independent risk factor for predicting pathologic CRM involvement. The Cox proportional hazard model showed baseline positive mrEMVI remained significant for disease-free survival (DFS) (P < 0.001). On posttreatment MRI, abdominoperineal resection (P = 0.031), intersphincteric resection (P = 0.006), and persistent CRM involvement (P = 0.001) remained significant for local recurrence-free survival. With regard to DFS, persistent CRM involvement (P = 0.048) and positive EMVI on posttreatment MRI (ymrEMVI) (P = 0.014) were significant. In the patient subgroup with persistent CRM involvement, 5-year DFS in patients with mrEMVI and ymrEMVI was 29.8% and 21.2%, respectively. Conclusion Patients who fail to convert to negative CRM have extremely poor oncologic outcomes. Lower tumor height and negative mrEMVI status were good responders to ymrCRM conversion. Our results suggest that these patients require a more intensive treatment modality.

Situs inversus is a rare hereditary disorder in which various anomalies have been reported with internal rotation abnormalities. This case involved an 85-year-old woman who had been diagnosed with transverse colon cancer and who underwent reduced-port laparoscopic surgery. All intra-abdominal organs were reversed left to right and right to left. The aberrant midcolic artery was identified during surgery. The total surgery time was 170 minutes, and the patient lost 20 mL of blood. The patient was discharged on the 8th postoperative day without complications.

Identifying phase information of high-entropy alloys (HEAs) can be helpful as it provides useful information such as anticipated mechanical properties. Recently, machine learning methods are attracting interest to predict phases of HEAs, which could reduce the effort for designing new HEAs. As research direction is in its infancy, there is still plenty of room to develop machine learning models to improve the prediction accuracy and further guide the design of HEAs. In this work, we employ deep learning-based methods regarding optimization, generation, and explanation, for enhancing the performance and identifying key design parameters for phase prediction of HEAs. We first establish regularized deep neural networks for predicting HEA phases and optimize hyper-parameters concerning model architecture, training, and regularization. To overcome data shortage of HEAs, we then focus on developing conditional generative adversarial network for generating additional HEA samples. We observe the augmentation from our generative model significantly improves model performance, achieving prediction accuracy of 93.17%. Lastly, we concentrate on understanding contributions of design parameters to identifying solid solution (SS) phase as an example. Our work delivers guidance not only for developing a reliable deep learning-based phase prediction model, but for explaining significant design parameters to assist design of novel HEAs.

Post-exposure prophylaxis (PEP) is highly effective in preventing disease progression of rabies when used in timely and appropriate manner. The key treatment for PEP is infiltration of rabies immune globulin (RIG) into lesion site after bite exposure, besides wound care and vaccination. Unfortunately, however, RIG is expensive and its supply is limited. Currently, several anti-rabies virus monoclonal antibody (mAb) products are under development as alternatives to RIG, and two recently received regulatory approval in India. In this study, fully human mAbs that recognize different rabies virus glycoprotein conformational antigenic site (II and III) were created from peripheral blood mononuclear cells of heathy vaccinated subjects. These mAbs neutralized a diverse range of lyssavirus types. As at least two anti-rabies virus mAbs are recommended for use in human PEP to ensure broad coverage against diverse lyssaviruses and to minimize possible escape variants, two most potent mAbs, NP-19-9 and 11B6, were selected to be used as cocktail treatment. These two mAbs were broadly reactive to different types of lyssaviruses isolates, and were shown to have no interference with each other. These results suggest that NP-19-9 and 11B6 are potent candidates to be used for PEP, suggesting further studies involving clinical studies in human.

Abstract Background An optimal therapy for the treatment of pneumonia caused by drug-resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis. Methods Systematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%. Results Twenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41–0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04–0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07–0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19–0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32–0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16–0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL. Conclusions This Bayesian network meta-analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order.

Abstract Toll-like receptor 2 (TLR2) mediates the innate immune response to bacterial lipopeptides and peptidoglycans by stimulating the production of inflammatory cytokines. However, the mechanisms by which TLR2 signaling regulates type I interferon (IFN)-β production are poorly understood. Here, we identified Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) as a negative regulator of TLR2-induced IFN-β production. Pharmacological inhibition or reduced expression of SHP2 potentiated TLR2 agonist-mediated IFN-β transcription and STAT1 activation, whereas overexpression of SHP2 impaired IFN-β transcription and STAT1 activation. SHP2 physically associated with the glycogen synthase kinase 3β (Gsk3β) in an agonist-dependent manner. Gsk3β positively regulates transcription of IFN-β following TLR2 stimulation by inhibiting the phosphorylation of SHP2. SHP2 inhibited the transcriptional activity of IRF-1 and IRF-8 at the IFN-β promoter. Remarkably, IRF-1 and IRF-8 are recruited to the IFN-β promoter in a SHP2 phosphatase activity-dependent manner. These findings provide insight into the mechanisms by which SHP2 and Gsk3β work together to modulate TLR2-mediated IFN-β production in macrophages.

Coleoptera is a group of insects that are most diverse among insect resources. Although used as indicator species and applied in developing new drugs, it is difficult to identify them quickly. Since the development of a method using mitochondrial DNA information for identification, studies have been conducted in Korea to swiftly and accurately identify species. The National Science Museum of Korea (NSMK) has been collecting and morphologically identifying domestic reference insects since 2013, and building a database of DNA barcodes with digital images. The NSMK completed construction of a database of digital images and DNA barcodes of 60 beetle species in the Korean National Research Information System. A total of 179 specimens and 60 species were used for the analysis, and the averages of intraspecific and interspecific variations were 0.70±0.45% and 26.34±6.01%, respectively, with variation rates ranging from 0% to 1.45% and 9.83% to 56.23%, respectively.

Contrast-induced acute kidney injury (CIAKI) is a leading cause of acute kidney injury following radiographic procedures. Intrarenal oxidative stress plays a critical role in CIAKI. Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidases (Noxs) are important sources of reactive oxygen species (ROS). Among the various types of Noxs, Nox4 is expressed predominantly in the kidney in rodents. Here, we evaluated the role of Nox4 and benefit of Nox4 inhibition on CIAKI using in vivo and in vitro models. HK-2 cells were treated with iohexol, with or without Nox4 knockdown, or the most specific Nox1/4 inhibitor (GKT137831). Effects of Nox4 inhibition on CIAKI mice were examined. Expression of Nox4 in HK-2 cells was significantly increased following iohexol exposure. Silencing of Nox4 rescued the production of ROS, downregulated pro-inflammatory markers (particularly phospho-p38) implicated in CIAKI, and reduced Bax and caspase 3/7 activity, which resulted in increased cellular survival in iohexol-treated HK-2 cells. Pretreatment with GKT137831 replicated these effects by decreasing levels of phospho-p38. In a CIAKI mouse model, even though the improvement of plasma blood urea nitrogen was unclear, pretreatment with GKT137831 resulted in preserved structure, reduced expression of 8-hydroxy-2'-deoxyguanosine (8OHdG) and kidney injury molecule-1 (KIM-1), and reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells. These results suggest Nox4 as a key source of reactive oxygen species responsible for CIAKI and provide a novel potential option for prevention of CIAKI.

Background. Although many surgical strategies have been used to reduce the anastomotic leak (AL) rate after laparoscopic rectal cancer surgery, limited data are available on the risk factors for AL and the effective strategy to reduce AL. Methods. The present study enrolled 736 consecutive patients who underwent laparoscopic resection without a diverting stoma for rectal adenocarcinoma. A nomogram was constructed to predict AL. Based on the nomogram, personalized risk was calculated and sequential surgical strategies were monitored using risk-adjusted cumulative sum (RA-CUSUM) analysis. Results. Among the 736 patients, clinical AL occurred in 65 patients (8.8%). Sex, an American Society of Anesthesiologists score, operation time, blood transfusion, and tumor location were identified as significant predictive factors for AL. Based on these factors, a nomogram was created to predict AL, with a concordance index (C-index) of 0.753 (95% confidence interval, 0.690–0.816). A calibration plot showed good statistical performance on internal validation (bias-corrected C-index of 0.742). The RA-CUSUM curve showed that extended splenic flexure mobilization (SFM) could be the most influential strategy to reduce AL. Conclusions. Our nomogram for predicting AL after laparoscopic rectal cancer surgery might be helpful to identify the individual risk of AL. Furthermore, extended SFM might be the most appropriate strategy for reducing AL.

Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.