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Abstract Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Objective:. We explored the oncological impact of tumor deposits (TDs) on colon cancer and proposed optimal modifications to the current staging system. Background:. In the existing American Joint Committee on Cancer colon cancer staging system, TDs are incorporated into the N category as N1c. When lymph node metastases (LNMs) are present, their number is considered to determine nodal stages, such as N1a/b or N2a/b, regardless of TDs. Methods:. 4212 patients with primary colon cancer who underwent surgical resection in the Seoul Colorectal Group (2010–2020) and 93,057 patients from the Surveillance, Epidemiology, and End Results*Stat database (2000–2017) were included in this study. Patients were classified according to the number of metastatic lymph nodes (LNs) (0/1–3/≥4) and the presence of TDs. Results:. TDs were significantly associated with left colon cancer, a higher T category, and vascular/perineural invasion. Patients with TDs had higher recurrence rates (23.1 vs 7.5%, P < 0.001). The TD-positive patients had notably worse overall survival (OS) and recurrence-free survival rates. The survival outcomes of TD-positive patients without LNM were inferior to those of TD-negative patients with LN1–3 (5-year OS: 78.9 vs 87.8%, P = 0.04). The survival outcomes of TD-positive patients with LN1–3 were similar to those of TD-negative patients with LN ≥4 (5-year OS: 87.0 vs 77.1%, P = 0.11). Survival outcomes obtained using the Surveillance, Epidemiology, and End Results *Stat database yielded consistent results. Conclusions:. TDs were associated with poor prognostic factors and had a significant impact on survival outcomes. The incorporation of tumor deposits into nodal classifications beyond the current N1c criteria may improve the staging system and more accurately reflect the recurrence and survival rates among patients with colon cancer. TD-positive in N1a or N1b could be categorized as N2.

Purpose The use of an ostomy for urination and defecation leads to reduced quality of life. Although many ostomy management strategies are needed, such strategies are often implemented by patients. Thus, there is a need for a home health care service platform that can be used in ostomy patient management. Methods We developed an ostomy patient management platform by identifying the needs of patients and medical staff through the Chronic Care Ostomy Self-Management Training Program in the United States and from studies conducted in Korea. Results The platform encompassed physical management, psychological management, maintenance of social function, spiritual stability, and home medical care. These components were implemented through monitoring, self-care guidance, and a community platform. For the monitoring function, patients entered their health status in a mobile application (app); the medical staff at the affiliated hospital then monitored the stoma status through a web interface. Conclusion Our platform allows medical staff to monitor ostomy patients through a web interface and help such patients to fully manage their ostomy at home using an app. We expect that the continued development of patient-oriented functions in our app will allow ostomy patients to experience quality-of-life improvements.

Abstract Background Parameters obtained from two‐dimensional (2D) cross‐sectional images have been used to determine body composition. However, data from three‐dimensional (3D) volumetric body images reflect real body composition more accurately and may be better predictors of patient outcomes in cancer. This study aimed to assess the 3D parameters and determine the best predictive factors for patient prognosis. Methods Patients who underwent surgery for colorectal cancer (CRC) between 2010 and 2016 were included in this study. Preoperative computed tomography images were analysed using an automatic segmentation program. Body composition parameters for muscle, muscle adiposity, subcutaneous fat (SF) and abdominal visceral fat (AVF) were assessed using 2D images at the third lumbar (L3) level and 3D images of the abdominal waist (L1–L5). The cut‐off points for each parameter were determined using X‐tile software. A Cox proportional hazards regression model was used to identify the association between the parameters and the treatment outcomes, and the relative influence of each parameter was compared using a gradient boosting model. Results Overall, 499 patients were included in the study. At a median follow‐up of 59 months, higher 3D parameters of the abdominal muscles and SF from the abdominal waist were found to be associated with longer overall survival (OS) and disease‐free survival (all P

Background: Although non-steroidal anti-inflammatory drugs (NSAIDs) are useful options for multimodal opioid-sparing analgesia, their effect on anastomotic leakage (AL) after colorectal surgery remains unclear. We aimed to investigate the association between early postoperative NSAID use and AL occurrence in patients who underwent colorectal cancer surgery at a high-volume tertiary care center. Methods: This retrospective observational study included all adult patients who underwent elective colorectal cancer resection surgery during 2011–2021 at a tertiary teaching hospital. Based on NSAID use within five postoperative days, patients were classified into either NSAID or no NSAID groups. We performed multivariable logistic regression analysis for the primary outcome, AL, within the first 30 postoperative days, before and after propensity score analysis using stabilized inverse probability of treatment weighting (sIPTW). Results: Among the 7928 patients analyzed, 0.6% experienced AL after surgery. The occurrence rates of AL were 1.7% (12/714) and 0.5% (37/7214) in the NSAID and no NSAID groups, respectively. Multivariable logistic regression analysis revealed that early postoperative NSAID use was significantly associated with AL [odds ratio (OR), 3.41; 95% confidence interval (CI), 1.76–6.60; P

Abstract Background The gut–brain axis (GBA) in Parkinson's disease (PD) has only been investigated in limited mice models despite dysbiosis of the gut microbiota being considered one of the major treatment targets for neurodegenerative disease. Therefore, this study examined the compositional changes of fecal microbiota in novel transgenic (Tg) mice overexpressing human α-synuclein (hαSyn) proteins under the neuron-specific enolase (NSE) to analyze the potential as GBA model. Results The expression level of the αSyn proteins was significantly higher in the substantia nigra and striatum of NSE-hαSyn Tg mice than the Non-Tg mice, while those of tyrosine hydroxylase (TH) were decreased in the same group. In addition, a decrease of 72.7% in the fall times and a 3.8-fold increase in the fall number was detected in NSE-hαSyn Tg mice. The villus thickness and crypt length on the histological structure of the gastrointestinal (GI) tract decreased in NSE-hαSyn Tg mice. Furthermore, the NSE-hαSyn Tg mice exhibited a significant increase in 11 genera, including Scatolibacter, Clostridium, Feifania, Lachnoclostridium, and Acetatifactor population, and a decrease in only two genera in Ligilactobacillus and Sangeribacter population during enhancement of microbiota richness and diversity. Conclusions The motor coordination and balance dysfunction of NSE-hαSyn Tg mice may be associated with compositional changes in gut microbiota. In addition, these mice have potential as a GBA model.

In mammals, nitric oxide (NO) is generated either by the nitric oxide synthase (NOS) enzymes from arginine or by the reduction of nitrate to nitrite by tissue xanthine oxidoreductase (XOR) and the microbiome and further reducing nitrite to NO by XOR or several heme proteins. Previously, we reported that skeletal muscle acts as a large nitrate reservoir in mammals, and this nitrate reservoir is systemically, as well as locally, used to generate nitrite and NO. Here, we report identifying two additional nitrate storage organs—bone and skin. We used bolus of ingested 15N-labeled nitrate to trace its short-term fluxes and distribution among organs. At baseline conditions, the nitrate concentration in femur bone samples was 96 ± 63 nmol/g, scalp skin 56 ± 22 nmol/g, with gluteus muscle at 57 ± 39 nmol/g. In comparison, plasma and liver contained 34 ± 19 nmol/g and 15 ± 5 nmol/g of nitrate, respectively. Three hours after 15N-nitrate ingestion, its concentration significantly increased in all organs, exceeding the baseline levels in plasma, skin, bone, skeletal muscle, and in liver 5-, 2.4-, 2.4-, 2.1-, and 2-fold, respectively. As expected, nitrate reduction into nitrite was highest in liver but also substantial in skin and skeletal muscle, followed by the distribution of 15N-labeled nitrite. We believe that these results underline the major roles played by skeletal muscle, skin, and bone, the three largest organs in mammals, in maintaining NO homeostasis, especially via the nitrate–nitrite–NO pathway.

Abstract Background Clinical diabetic traits have been reported to be associated with increased colorectal cancer (CRC) risk in observational studies. Using the Mendelian randomization (MR) analysis method, we examined the causal association between glycemic traits, such as fasting glucose (FG), fasting insulin (FI), and glycosylated hemoglobin A1c (HbA1c), and survival in a cohort of CRC patients. Methods We conducted a two‐sample MR analysis among a cohort of patients with locally advanced CRC at Seoul National University Hospital. Single‐nucleotide polymorphisms robustly associated (p

Abstract Background For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. Methods This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2–4 weeks in the TNT group and 6–10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. Discussion The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. Trial registration Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

Abstract Purpose To address the limited utility of the interferon (IFN)-γ release assay (IGRA) caused by its variability and inconsistency. Methods This retrospective cohort study was based on data obtained between 2011 and 2019. QuantiFERON-TB Gold-In-Tube was used to measure IFN-γ levels in nil, tuberculosis (TB) antigen, and mitogen tubes. Results Of 9,378 cases, 431 had active TB. The non-TB group comprised 1,513 IGRA-positive, 7,202 IGRA-negative, and 232 IGRA-indeterminate cases. Nil-tube IFN-γ levels were significantly higher in the active TB group (median = 0.18 IU/mL; interquartile range: 0.09–0.45 IU/mL) than in the IGRA-positive non-TB (0.11 IU/mL; 0.06–0.23 IU/mL) and IGRA-negative non-TB (0.09 IU/mL; 0.05–0.15 IU/mL) groups (P < 0.0001). From receiver operating characteristic analysis, TB antigen tube IFN-γ levels had higher diagnostic utility for active TB than TB antigen minus nil values. In a logistic regression analysis, active TB was the main driver of higher nil values. In the active TB group, after reclassifying the results based on a TB antigen tube IFN-γ level of 0.48 IU/mL, 14/36 cases with negative results and 15/19 cases with indeterminate results became positive, while 1/376 cases with positive results became negative. Overall, the sensitivity for detecting active TB improved from 87.2 to 93.7%. Conclusion The results of our comprehensive assessment can aid in IGRA interpretation. Since nil values are governed by TB infection rather than reflecting background noise, TB antigen tube IFN-γ levels should be used without subtracting nil values. Despite indeterminate results, TB antigen tube IFN-γ levels can be informative.

Abstract Background Computational drug repurposing is crucial for identifying candidate therapeutic medications to address the urgent need for developing treatments for newly emerging infectious diseases. The recent COVID-19 pandemic has taught us the importance of rapidly discovering candidate drugs and providing them to medical and pharmaceutical experts for further investigation. Network-based approaches can provide repurposable drugs quickly by leveraging comprehensive relationships among biological components. However, in a case of newly emerging disease, applying a repurposing methods with only pre-existing knowledge networks may prove inadequate due to the insufficiency of information flow caused by the novel nature of the disease. Methods We proposed a network-based complementary linkage method for drug repurposing to solve the lack of incoming new disease-specific information in knowledge networks. We simulate our method under the controlled repurposing scenario that we faced in the early stage of the COVID-19 pandemic. First, the disease-gene-drug multi-layered network was constructed as the backbone network by fusing comprehensive knowledge database. Then, complementary information for COVID-19, containing data on 18 comorbid diseases and 17 relevant proteins, was collected from publications or preprint servers as of May 2020. We estimated connections between the novel COVID-19 node and the backbone network to construct a complemented network. Network-based drug scoring for COVID-19 was performed by applying graph-based semi-supervised learning, and the resulting scores were used to validate prioritized drugs for population-scale electronic health records-based medication analyses. Results The backbone networks consisted of 591 diseases, 26,681 proteins, and 2,173 drug nodes based on pre-pandemic knowledge. After incorporating the 35 entities comprised of complemented information into the backbone network, drug scoring screened top 30 potential repurposable drugs for COVID-19. The prioritized drugs were subsequently analyzed in electronic health records obtained from patients in the Penn Medicine COVID-19 Registry as of October 2021 and 8 of these were found to be statistically associated with a COVID-19 phenotype. Conclusion We found that 8 of the 30 drugs identified by graph-based scoring on complemented networks as potential candidates for COVID-19 repurposing were additionally supported by real-world patient data in follow-up analyses. These results show that our network-based complementary linkage method and drug scoring algorithm are promising strategies for identifying candidate repurposable drugs when new emerging disease outbreaks.

Abstract This study aimed to assess the likely association of gut microbiome with low anterior resection syndrome (LARS) symptoms. Postoperative stool samples from patients with minor or major LARS after sphincter-preserving surgery (SPS) for rectal cancer were collected and analyzed using 16S ribosomal RNA sequencing method. The symptom patterns of LARS were classified into two groups (PC1LARS, PC2LARS) using principal component analysis. The dichotomized sum of questionnaire items (sub1LARS, sub2LARS) was used to group patients according to the main symptoms. According to microbial diversity, enterotype, and taxa, PC1LARS and sub1LARS were associated with frequency-dominant LARS symptoms and patients, while PC2LARS and sub2LARS were grouped as incontinence-dominant LARS symptoms and patients. Butyricicoccus levels decreased while overall LARS scores increased. The α-diversity richness index Chao1 showed a significantly negative correlation in sub1LARS and a positive correlation in sub2LARS. In sub1LARS, the severe group showed a lower Prevotellaceae enterotype and higher Bacteroidaceae enterotype than the mild group. Subdoligranulum and Flavonifractor showed a negative and a positive correlation with PC1LARS, respectively, while showing a negative relationship with PC2LARS. Lactobacillus and Bifidobacterium were negatively correlated to PC1LARS. Frequency-dominant LARS had decreased diversity of gut microbiome and showed lower levels of lactic acid-producing bacteria.

Background/Aims Although anti-hepatitis C virus (HCV) assay is widely used to screen for HCV infection, it has a high false-positive (FP) rate in low-risk populations. We investigated the accuracy of anti-HCV signal-to-cutoff (S/CO) ratio to distinguish true-positive (TP) from FP HCV infection. Methods We retrospectively analyzed 77,571 patients with anti-HCV results. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of anti-HCV S/CO ratio in anti-HCV positive patients. Results Overall, 1,126 patients tested anti-HCV positive; 34.7% of patients were FP based on HCV RNA and/or recombinant immunoblot assay (RIBA) results. The age and sex-adjusted anti-HCV prevalence was 1.22%. We identified significant differences in serum aspartate transaminase and alanine transaminase levels, anti-HCV S/CO ratio, and RIBA results between groups (viremia vs. non-viremia, TP vs. FP). Using ROC curves, the optimal cutoff values of anti-HCV S/CO ratio for HCV viremia and TP were 8 and 5, respectively. The area under the ROC curve, sensitivity, specificity, positive and negative predictive values were 0.970 (95% CI, 0.959–0.982, p < 0.001), 99.7%, 87.5%, 87.4%, and 99.7%, respectively, for predicting HCV viremia at an anti-HCV S/CO ratio of 8 and 0.987 (95% CI, 0.980–0.994, p < 0.001), 95.3%, 94.7%, 97.1%, and 91.4%, respectively, for TP HCV infection at an anti-HCV S/CO ratio of 5. No patients with HCV viremia had an anti-HCV S/CO ratio below 5. Conclusions The anti-HCV S/CO ratio is highly accurate for discriminating TP from FP HCV infection and should be considered when diagnosing HCV infections.

Purpose This retrospective study aimed to determine the number of times the ultrasound-guided attenuation parameter (UGAP) should be measured during the evaluation of hepatic steatosis. Methods Patients with suspected nonalcoholic fatty liver disease who underwent two UGAP repetition protocols (six-repetition [UGAP_6] and 12-repetition [UGAP_12]) and measurement of the controlled attenuation parameter (CAP) using transient elastography between October 2020 and June 2021 were enrolled. The mean attenuation coefficient (AC), interquartile range (IQR)/median, and coefficient of variance (CV) of the two repetition protocols were compared using the paired t test. Moreover, the diagnostic performances of UGAP_6 and UGAP_12 were compared using the area under the receiver operating characteristic (AUROC) curve, considering the CAP value as a reference standard. Results The study included 160 patients (100 men; mean age, 50.9 years). There were no significant differences between UGAP_6 and UGAP_12 (0.731±0.116 dB/cm/MHz vs. 0.734±0.113 dB/cm/MHz, P=0.156) and mean CV (7.6±0.3% vs. 8.0±0.3%, P=0.062). However, the mean IQR/median of UGAP_6 was significantly lower than that of UGAP_12 (8.9%±6.0% vs. 9.8%±5.2%, P=0.012). In diagnosing the hepatic steatosis stage, UGAP_6 and UGAP_12 yielded comparable AUROCs (≥S1, 0.908 vs. 0.897, P=0.466; ≥S2, 0.883 vs. 0.897, P=0.126; S3, 0.832 vs. 0.834, P=0.799). Conclusion UGAP had high diagnostic performance in diagnosing hepatic steatosis, regardless of the number of repetitions (six repetitions vs. 12 repetitions), with maintained reliability. Therefore, six UGAP measurements seem sufficient for evaluating hepatic steatosis using UGAP.

Abstract The reduction pathway of nitrate (NO3 −) and nitrite (NO2 −) to nitric oxide (NO) contributes to regulating many physiological processes. To examine the rate and extent of dietary nitrate absorption and its reduction to nitrite, we supplemented rat diets with Na15NO3-containing water (1 g/L) and collected plasma, urine and several tissue samples. We found that plasma and urine showed 8.8- and 11.7-fold increases respectively in total nitrate concentrations in 1-day supplementation group compared to control. In tissue samples—gluteus, liver and eyes—we found 1.7-, 2.4- and 4.2-fold increases respectively in 1-day supplementation group. These increases remained similar in 3-day supplementation group. LC–MS/MS analysis showed that the augmented nitrate concentrations were primarily from the exogenously provided 15N-nitrate. Overall nitrite concentrations and percent of 15N-nitrite were also greatly increased in all samples after nitrate supplementation; eye homogenates showed larger increases compared to gluteus and liver. Moreover, genes related to nitrate transport and reduction (Sialin, CLC and XOR) were upregulated after nitrate supplementation for 3 days in muscle (Sialin 2.3-, CLC1 1.3-, CLC3 2.1-, XOR 2.4-fold) and eye (XOR 1.7-fold) homogenates. These results demonstrate that dietary nitrate is quickly absorbed into circulation and tissues, and it can be reduced to nitrite in tissues (and likely to NO) suggesting that nitrate-enriched diets can be an efficient intervention to enhance nitrite and NO bioavailability.

Nitrate (NO3−) obtained from the diet is converted to nitrite (NO2−) and subsequently to nitric oxide (NO) within the body. Previously, we showed that porcine eye components contain substantial amounts of nitrate and nitrite that are similar to those in blood. Notably, cornea and sclera exhibited the capability to reduce nitrate to nitrite. To gain deeper insights into nitrate metabolism in porcine eyes, our current study involved feeding pigs either NaCl or Na15NO3 and assessing the levels of total and 15N-labeled NO3−/NO2− in various ocular tissues. Three hours after Na15NO3 ingestion, a marked increase in 15NO3− and 15NO2− was observed in all parts of the eye; in particular, the aqueous and vitreous humor showed a high 15NO3− enrichment (77.5 and 74.5%, respectively), similar to that of plasma (77.1%) and showed an even higher 15NO2− enrichment (39.9 and 35.3%, respectively) than that of plasma (19.8%). The total amounts of NO3− and NO2− exhibited patterns consistent with those observed in 15N analysis. Next, to investigate whether nitrate or nitrite accumulate proportionally after multiple nitrate treatments, we measured nitrate and nitrite contents after supplementing pigs with Na15NO3 for five consecutive days. In both 15N-labeled and total nitrate and nitrite analysis, we did not observe further accumulation of these ions after multiple treatments, compared to a single treatment. These findings suggest that dietary nitrate supplementation exerts a significant influence on nitrate and nitrite levels and potentially NO levels in the eye and opens up the possibility for the therapeutic use of dietary nitrate/nitrite to enhance or restore NO levels in ocular tissues.

Abstract Background Differences in the composition and diversity of the gut microbial communities among individuals are influenced by environmental factors. However, there is limited research on factors affecting microbiome variation in colorectal cancer patients, who display lower inter-individual variations than that of healthy individuals. In this study, we examined the association between modifiable factors and the microbiome variation in colorectal cancer patients. Methods A total of 331 colorectal cancer patients who underwent resection surgery at the Department of Surgery, Seoul National University Hospital between October 2017 and August 2019 were included. Fecal samples from colorectal cancer patients were collected prior to the surgery. Variations in the gut microbiome among patients with different lifestyles and metabolic diseases were examined through the network analysis of inter-connected microbial abundance, the assessment of the Anna Karenina principle effect for microbial stochasticity, and the identification of the enriched bacteria using linear discrimination analysis effect size. Associations of dietary diversity with microbiome variation were investigated using the Procrustes analysis. Results We found stronger network connectivity of microbial communities in non-smokers, non-drinkers, obese individuals, hypertensive subjects, and individuals without diabetes than in their counterparts. The Anna Karenina principle effect was found for history of smoking, alcohol consumption, and diabetes (with significantly greater intra-sample similarity index), whereas obesity and hypertension showed the anti-Anna Karenina principle effect (with significantly lower intra-sample similarity index). We found certain bacterial taxa to be significantly enriched in patients of different categories of lifestyles and metabolic diseases using linear discrimination analysis. Diversity of food and nutrient intake did not shape the microbial diversity between individuals (pProcrustes>0.05). Conclusions Our findings suggested an immune dysregulation and a reduced ability of the host and its microbiome in regulating the community composition. History of smoking, alcohol consumption, and diabetes were shown to affect partial individuals in shifting new microbial communities, whereas obesity and history of hypertension appeared to affect majority of individuals and shifted to drastic reductions in microbial compositions. Understanding the contribution of modifiable factors to microbial stochasticity may provide insights into how the microbiome regulates effects of these factors on the health outcomes of colorectal cancer patients.

Background: Rapid detection of the causative agents is essential for determining the appropriate treatment for patients with lower respiratory tract infections. We evaluated the performance of the Biofire FilmArray pneumonia panel (FA-PE; BioFire Diagnostics, USA) in the identification of bacterial pathogens and antibiotic resistance genes in endotracheal aspirate specimens. Methods: A total of 43 non-duplicated endotracheal aspirates were included in this study. The performance of the FA-PE was assessed using the routine culture method as the reference standard. Results: The FA-PE demonstrated 92.9% sensitivity and 79.3% specificity for the identification of 15 bacterial targets compared to routine bacterial culture. Four antimicrobial resistance genes in 43 specimens were detected by the FA-PE. The most frequently detected resistance genes were mecA/C and SCCmec in three specimens, followed by CTX-M in one specimen. Conclusion: The FA-PE offers a rapid diagnostic method for lower respiratory tract infections. It may be useful at the early stage of pneumonia, before routine culture and antimicrobial susceptibility results are available.

Abstract Background A significant proportion of colorectal cancer (CRC) patients suffer from early recurrence and progression after surgical treatment. Although the gut microbiota is considered as a key player in the initiation and progression of CRC, most prospective studies have been focused on a particular pathobionts such as Fusobacterium nucleatum. Here, we aimed to identify novel prognostic bacteria for CRC by examining the preoperative gut microbiota through 16S ribosomal RNA gene sequencing. Results We collected stool samples from 333 patients with primary CRC within 2 weeks before surgery and followed up the patients for a median of 27.6 months for progression and 43.6 months for survival. The sequence and prognosis data were assessed using the log-rank test and multivariate Cox proportional hazard analysis. The gut microbiota was associated with the clinical outcomes of CRC patients (P progress = 0.011, P decease = 0.007). In particular, the high abundance of Prevotella, a representative genus of human enterotypes, indicated lower risks of CRC progression (P = 0.026) and decease (P = 0.0056), while the occurrence of Alistipes assigned to Bacteroides sp., Pyramidobacter piscolens, Dialister invisus, and Fusobacterium nucleatum indicated a high risk of progression. A microbiota-derived hazard score considering the five prognostic bacteria accurately predicted CRC progression in 1000 random subsamples; it outperformed widely accepted clinical biomarkers such as carcinoembryonic antigen and lymphatic invasion, after adjustment for the clinicopathological stage (adjusted HR 2.07 [95% CI, 1.61–2.64], P = 7.8e−9, C-index = 0.78). PICRUSt2 suggested that microbial pathways pertaining to thiamine salvage and L-histidine degradation underlie the different prognoses. Conclusions The enterotypical genus Prevotella was demonstrated to be useful in improving CRC prognosis, and combined with the four pathobionts, our hazard score based on the gut microbiota should provide an important asset in predicting medical outcomes for CRC patients. Video Abstract

Abstract Background Previous studies showed that gestational diabetes mellitus (GDM) can be a risk factor for subsequent atherosclerotic cardiovascular disease. However, there is a paucity of information regarding diverse cardiovascular outcomes in elderly women after GDM. In the current study, we examined whether women with a history of GDM have an increased risk for long-term overall cardiovascular outcomes. Methods Among the UK participants, we included 219,330 women aged 40 to 69 years who reported at least one live birth. The new incidence of diverse cardiovascular outcomes was compared according to GDM history by multivariable Cox proportional hazard models. In addition, causal mediation analysis was performed to examine the contribution of well-known risk factors to observed risk. Results After enrollment, 13,094 women (6.0%) developed new overall cardiovascular outcomes. Women with GDM history had an increased risk for overall cardiovascular outcomes [adjusted HR (aHR) 1.36 (95% CI 1.18–1.55)], including coronary artery disease [aHR 1.31 (1.08–1.59)], myocardial infarction [aHR 1.65 (1.27–2.15)], ischemic stroke [aHR 1.68 (1.18–2.39)], peripheral artery disease [aHR 1.69 (1.14–2.51)], heart failure [aHR 1.41 (1.06–1.87)], mitral regurgitation [aHR 2.25 (1.51–3.34)], and atrial fibrillation/flutter [aHR 1.47 (1.18–1.84)], after adjustment for age, race, BMI, smoking, early menopause, hysterectomy, prevalent disease, and medication. In mediation analysis, overt diabetes explained 23%, hypertension explained 11%, and dyslipidemia explained 10% of the association between GDM and overall cardiovascular outcome. Conclusions GDM was associated with more diverse cardiovascular outcomes than previously considered, and conventional risk factors such as diabetes, hypertension, and dyslipidemia partially contributed to this relationship.

Abstract Background Tumor budding is associated with lymph node (LN) metastasis in submucosal colorectal cancer (CRC). However, the rate of LN metastasis associated with the number of tumor buds is unknown. Here, we determined the optimal tumor budding cut-off number and developed a composite scoring system (CSS) for estimating LN metastasis of submucosal CRC. Methods In total, 395 patients with histologically confirmed T1N0–2M0 CRC were evaluated. The clinicopathological characteristics were subjected to univariate and multivariate analyses. The Akaike information criterion (AIC) values of the multivariate models were evaluated to identify the optimal cut-off number. A CSS for LN metastasis was developed using independent risk factors. Results The prevalence of LN metastasis was 13.2%. Histological differentiation, lymphatic or venous invasion, and tumor budding were associated with LN metastasis in univariate analyses. In multivariate models adjusted for histological differentiation and lymphatic or venous invasion, the AIC value was lowest for five tumor buds. Unfavorable differentiation (odds ratio [OR], 8.16; 95% confidence interval [CI], 1.80–36.89), lymphatic or venous invasion (OR, 5.91; 95% CI, 2.91–11.97), and five or more tumor buds (OR, 3.01; 95% CI, 1.21–7.69) were independent risk factors. In a CSS using these three risk factors, the rates of LN metastasis were 5.6%, 15.5%, 31.0%, and 52.4% for total composite scores of 0, 1, 2, and ≥ 3, respectively. Conclusions For the estimation of LN metastasis in submucosal CRC, the optimal tumor budding cut-off number was five. Our CSS can be utilized to estimate LN metastasis.

Quasars are bright and unobscured active galactic nuclei (AGN) thought to be powered by the accretion of matter around supermassive black holes at the centers of galaxies. The temporal variability of a quasar’s brightness contains valuable information about its physical properties. The UV/optical variability is thought to be a stochastic process, often represented as a damped random walk described by a stochastic differential equation (SDE). Upcoming wide-field telescopes such as the Rubin Observatory Legacy Survey of Space and Time (LSST) are expected to observe tens of millions of AGN in multiple filters over a ten year period, so there is a need for efficient and automated modeling techniques that can handle the large volume of data. Latent SDEs are machine learning models well suited for modeling quasar variability, as they can explicitly capture the underlying stochastic dynamics. In this work, we adapt latent SDEs to jointly reconstruct multivariate quasar light curves and infer their physical properties such as the black hole mass, inclination angle, and temperature slope. Our model is trained on realistic simulations of LSST ten year quasar light curves, and we demonstrate its ability to reconstruct quasar light curves even in the presence of long seasonal gaps and irregular sampling across different bands, outperforming a multioutput Gaussian process regression baseline. Our method has the potential to provide a deeper understanding of the physical properties of quasars and is applicable to a wide range of other multivariate time series with missing data and irregular sampling.

Unintended genetic modifications that occur during the differentiation and proliferation of human induced pluripotent stem cells (hiPSCs) can lead to tumorigenicity. This is a crucial concern in the development of stem cell-based therapies to ensure the safety and efficacy of the final product. Moreover, conventional genetic stability testing methods are limited by low sensitivity, which is an issue that remains unsolved. In this study, we assessed the genetic stability of hiPSCs and hiPSC-derived cardiomyocytes using various testing methods, including karyotyping, CytoScanHD chip analysis, whole-exome sequencing, and targeted sequencing. Two specific genetic mutations in KMT2C and BCOR were selected from the 17 gene variants identified by whole-exome and targeted sequencing methods, which were validated using droplet digital PCR. The applicability of this approach to stem cell-based therapeutic products was further demonstrated with associated validation according to the International Council for Harmonisation (ICH) guidelines, including specificity, precision, robustness, and limit of detection. Our droplet digital PCR results showed high sensitivity and accuracy for quantitatively detecting gene mutations, whereas conventional qPCR could not avoid false positives. In conclusion, droplet digital PCR is a highly sensitive and precise method for assessing the expression of mutations with tumorigenic potential for the development of stem cell-based therapeutics.

The therapeutic potential of directly reprogrammed neural stem cells (iNSCs) for neurodegenerative diseases relies on reducing the innate tumorigenicity of pluripotent stem cells. However, the heterogeneity within iNSCs is a major hurdle in quality control prior to clinical applications. Herein, we generated iNSCs from human fibroblasts, by transfecting transcription factors using Sendai virus particles, and characterized the expression of iNSC markers. Using immunostaining and quantitative real time –polymerase chain reaction (RT –qPCR), no differences were observed between colonies of iNSCs and iNSC-derived neurons. Unexpectedly, patch-clamp analysis of iNSC-derived neurons revealed distinctive action potential firing even within the same batch product. We performed single-cell RNA sequencing in fibroblasts, iNSCs, and iNSC-derived neurons to dissect their functional heterogeneity and identify cell fate regulators during direct reprogramming followed by neuronal differentiation. Pseudotime trajectory analysis revealed distinct cell types depending on their gene expression profiles. Differential gene expression analysis showed distinct NEUROG1, PEG3, and STMN2 expression patterns in iNSCs and iNSC-derived neurons. Taken together, we recommend performing a predictable functional assessment with appropriate surrogate markers to ensure the quality control of iNSCs and their differentiated neurons, particularly before cell banking for regenerative cell therapy.

Background: The European Foundation for the Study of Chronic Liver Failure (EF-CLIF) consortium suggested that the clinical courses after acute decompensation (AD) stratify the long-term prognosis: stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre acute-on-chronic liver failure (pre ACLF), and ACLF. However, previous studies included patients with a history of previous AD and had limitations associated with identifying the clinical factors related to prognosis after the first AD. Method: The prospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort included cirrhotic patients who were hospitalised with first AD between July 2015 and August 2018. We analysed the factors associated with readmission after the first AD and compared the characteristics and prognosis among each subgroup to evaluate the risk factors for the occurrence of pre ACLF after AD. Result: A total of 746 cirrhotic patients who were hospitalised with first AD were enrolled. The subgroups consisted of SDC (n = 565), UDC (n = 29), pre ACLF (n = 28), and ACLF (n = 124). Of note, pre ACLF showed a poorer prognosis than ACLF. The risk factors associated with readmission within 3 months of first AD were non-variceal gastrointestinal (GI) bleeding, hepatic encephalopathy (HE), and high MELD score. Viral aetiology was associated with the occurrence of pre ACLF compared with alcohol aetiology regardless of baseline liver function status. Conclusion: Cirrhotic patients with first AD who present as non-variceal GI bleeding and HE can easily relapse. Interestingly, the occurrence of AD with organ failure within 3 months of first AD (pre ACLF) has worse prognosis compared with the occurrence of organ failure at first AD (ACLF). In particular, cirrhotic patients with viral hepatitis with/without alcohol consumption showed poor prognosis compared to other aetiologies. Therefore, patients with ACLF after AD within 3 months should be treated more carefully and definitive treatment through LT should be considered.

Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (ROS). The primary ROS responsible for inducing diclofenac-related hepatocellular toxicity and the principal antioxidant that mitigates these ROS remain unknown. Peroxiredoxin III (PrxIII) is the most abundant and potent H2O2-eliminating enzyme in the mitochondria of mammalian cells. Here, we investigated the role of mitochondrial H2O2 and the protective function of PrxIII in diclofenac-induced mitochondrial dysfunction and apoptosis in hepatocytes. Mitochondrial H2O2 levels were differentiated from other types of ROS using a fluorescent H2O2 indicator. Upon diclofenac treatment, PrxIII-knockdown HepG2 human hepatoma cells showed higher levels of mitochondrial H2O2 than PrxIII-expressing controls. PrxIII-depleted cells exhibited higher mitochondrial dysfunction as measured by a lower oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, and caspase activation, and were more sensitive to apoptosis. Ectopic expression of mitochondrially targeted catalase in PrxIII-knockdown HepG2 cells or in primary hepatocytes derived from PrxIII-knockout mice suppressed the diclofenac-induced accumulation of mitochondrial H2O2 and decreased apoptosis. Thus, we demonstrated that mitochondrial H2O2 is a key mediator of diclofenac-induced hepatocellular damage driven by mitochondrial dysfunction and apoptosis. We showed that PrxIII loss results in the critical accumulation of mitochondrial H2O2 and increases the harmful effects of diclofenac. PrxIII or other antioxidants targeting mitochondrial H2O2 could be explored as potential therapeutic agents to protect against the hepatotoxicity associated with NSAID use.

Highly porous layered double hydroxide (LDH) and its calcined mixed metal oxide (MMO) were obtained by utilizing egg white (EW) as a biogenic porous template. The LDH was prepared through coprecipitation under the existence of a beaten EW meringue, and the corresponding MMO was obtained by calcining LDH at 500 °C. According to X-ray diffraction, the crystal structure of LDH and MMO was well-developed with or without EW. In contrast, the crystallinity analyses and microscopic investigations clearly showed differences in the particle orientation in the presence of EW; the protein arrangement in the EW foam induced the ordered orientation of LDH platelets along proteins, resulting in well-developed inter-particle pores. As a result, the distinctive particle arrangement in EW-templated samples compared with non-templated ones showed dramatically enhanced specific surface area and porosity. The nitrogen adsorption–desorption isotherm exhibited that the high specific surface area was attributed to the homogeneous nanopores in EW-templated LDH and MMO, which originated from the sacrificial role of the EW.

Abstract Multifocal colorectal cancer (CRC) comprises both clonally independent primary tumors caused by inherited predisposition and clonally related tumors mainly due to intraluminal spreading along an intact basement membrane. The distinction between these multifocal CRCs is essential because therapeutic strategies vary according to the clonal association of multiple tumor masses. Here, we report one unique case of synchronous intestinal cancer (SIC) with tumors occurring along the entire bowel tract, including the small intestine. We established six patient-derived organoids (PDOs), and patient-derived cell lines (PDCs) from each site of the SIC, which were subjected to extensive genomic, transcriptomic, and epigenomic sequencing. We also estimated the drug responses of each multifocal SIC to 25 clinically relevant therapeutic compounds to validate how the clinically actionable alternations between SICs were associated with drug sensitivity. Our data demonstrated distinct clonal associations across different organs, which were consistently supported by multi-omics analysis, as well as the accordant responses to various therapeutic compounds. Our results indicated the imminent drawback of a single tumor-based diagnosis of multifocal CRC and suggested the necessity of an in-depth molecular analysis of all tumor regions to avoid unexpected resistance to the currently available targeted therapies.

Hyperechoic lesions of the breast encompass a wide range of conditions that are occasionally encountered during breast ultrasonography. Although typical hyperechoic lesions with a distinct fat component on imaging are well known, some hyperechoic lesions are diagnosed as unexpected pathology, making the radiology-pathology correlation difficult. Therefore, understanding the pathology of these lesions and how it correlates with imaging findings can help radiologists accurately diagnose and properly manage a range of related conditions. This article presents a pictorial review of unexpected hyperechoic benign and malignant breast lesions, with a focus on the pathological conditions that give rise to the hyperechoic pattern.

Moored floating platforms have great potential in ocean engineering applications because a mooring system is necessary to keep the platform in station, which is directly related to the operational efficiency and safety of the platform. This paper briefly introduces the technical and operational details of an optical sensor for measuring the tension of mooring lines of a moored platform in waves. In order to check the performance of optical sensors, an experiment with a moored floating platform in waves is carried out in the wave tank at Changwon National University. The experiment is performed in regular waves and irregular waves with a semi-submersible and triangle platform. The performance of the optical sensor is confirmed by comparing the results of the tension of the mooring lines by the optical sensor and tension gauges. The maximum tension of the mooring lines is estimated to investigate the mooring dynamics due to the effect of the wave direction and wavelength in the regular waves. The significant value of the tension of mooring lines in various wave directions is estimated in the case of irregular waves. The results show that the optical sensor is effective in measuring the tension of the mooring lines.

Abstract Background The effects of diet on the interaction between microbes and host health have been widely studied. However, its effects on the gut microbiota of patients with colorectal cancer (CRC) have not been elucidated. This study aimed to investigate the association between diet and the overall diversity and different taxa levels of the gut microbiota in CRC patients via the nutrition-wide association approach. Methods This hospital-based study utilized data of 115 CRC patients who underwent CRC surgery in Department of Surgery, Seoul National University Hospital. Spearman correlation analyses were conducted for 216 dietary features and three alpha-diversity indices, Firmicutes/Bacteroidetes ratio, and relative abundance of 439 gut microbial taxonomy. To identify main enterotypes of the gut microbiota, we performed the principal coordinate analysis based on the β-diversity index. Finally, we performed linear regression to examine the association between dietary intake and main microbiome features, and linear discriminant analysis effect size (LEfSe) to identify bacterial taxa phylogenetically enriched in the low and high diet consumption groups. Results Several bacteria were enriched in patients with higher consumption of mature pumpkin/pumpkin juice (ρ, 0.31 to 0.41) but lower intake of eggs (ρ, -0.32 to -0.26). We observed negative correlations between Bacteroides fragilis abundance and intake of pork (belly), beef soup with vegetables, animal fat, and fatty acids (ρ, -0.34 to -0.27); an inverse correlation was also observed between Clostridium symbiosum abundance and intake of some fatty acids, amines, and amino acids (ρ, -0.30 to -0.24). Furthermore, high intake of seaweed was associated with a 6% (95% CI, 2% to 11%) and 7% (95% CI, 2% to 11%) lower abundance of Rikenellaceae and Alistipes, respectively, whereas overall beverage consumption was associated with an 10% (95% CI, 2% to 18%) higher abundance of Bacteroidetes, Bacteroidia, and Bacteroidales, compared to that in the low intake group. LEfSe analysis identified phylogenetically enriched taxa associated with the intake of sugars and sweets, legumes, mushrooms, eggs, oils and fats, plant fat, carbohydrates, and monounsaturated fatty acids. Conclusions Our data elucidates the diet-microbe interactions in CRC patients. Additional research is needed to understand the significance of these results in CRC prognosis.

Abstract We aimed to compare the short- and long-term outcomes of simultaneous laparoscopic, hybrid, and open resection for colorectal cancer and synchronous liver metastases. We retrospectively analyzed the data of 647 patients with simultaneous resection of colorectal cancer and liver metastases between January 2006 and December 2018 at three tertiary referral hospitals. Patient’s baseline characteristics, perioperative outcomes, pathological examination results, liver-specific recurrence rate and survivals were compared between the propensity score-matched groups. Forty-two and 81 patients were selected for the laparoscopic vs. hybrid groups, and 48 and 136 patients for laparoscopic vs. open groups, respectively. The laparoscopic group had fewer wound complications (2.1 vs. 13.2%; p = 0.028) than the open group, and a shorter postoperative hospital stay than the hybrid and open groups (8 vs. 11 days, p

A 46-year-old male with alcoholic liver cirrhosis underwent a transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites. On the 9th day after the procedure, he presented with melena and decreasing hemoglobin levels. Hemobilia due to fistula formation between the right intrahepatic bile duct and right hepatic artery was suspected on computed tomography. Angiography revealed a fistula of the small branches of the hepatic segmental arteries, and right intrahepatic bile duct was confirmed; embolization was successfully performed with a coil for the eighth segmental hepatic artery, a glue-lipiodol mixture for the fifth segmental hepatic artery, and gelfoam slurry for the right anterior hepatic artery. However, 2 days after embolization, the patient died owing to aggravated disseminated intravascular coagulopathy. When gastrointestinal bleeding occurs after TIPS, careful evaluation is immediately required, and hemobilia should be considered.

A cardiopulmonary exercise test (CPET) is essential for lung resection. However, performing a CPET can be challenging. This study aimed to develop a machine learning model to estimate maximal oxygen consumption (VO2max) using data collected through a patch-type single-lead electrocardiogram (ECG) monitoring device in candidates for lung resection. This prospective, single-center study included 42 patients who underwent a CPET at a tertiary teaching hospital from October 2021 to July 2022. During the CPET, a single-lead ECG monitoring device was applied to all patients, and the results obtained from the machine-learning algorithm using the information extracted from the ECG patch were compared with the CPET results. According to the Bland–Altman plot of measured and estimated VO2max, the VO2max values obtained from the machine learning model and the FRIEND equation showed lower differences from the reference value (bias: −0.33 mL·kg−1·min−1, bias: 0.30 mL·kg−1·min−1, respectively). In subgroup analysis, the developed model demonstrated greater consistency when applied to different maximal stage levels and sexes. In conclusion, our model provides a closer estimation of VO2max values measured using a CPET than existing equations. This model may be a promising tool for estimating VO2max and assessing cardiopulmonary reserve in lung resection candidates when a CPET is not feasible.

Discontinuing mechanical ventilation remains challenging. We developed a machine learning model to predict weaning outcomes using only continuous monitoring parameters obtained from ventilators during spontaneous breathing trials (SBTs). Patients who received mechanical ventilation in the medical intensive care unit at a tertiary university hospital from 2019–2021 were included in this study. During the SBTs, three waveforms and 25 numerical data were collected as input variables. The proposed convolutional neural network (CNN)-based weaning prediction model extracts features from input data with diverse lengths. Among 138 enrolled patients, 35 (25.4%) experienced weaning failure. The dataset was randomly divided into training and test sets (8:2 ratio). The area under the receiver operating characteristic curve for weaning success by the prediction model was 0.912 (95% confidence interval [CI], 0.795–1.000), with an area under the precision-recall curve of 0.767 (95% CI, 0.434–0.983). Furthermore, we used gradient-weighted class activation mapping technology to provide visual explanations of the model’s prediction, highlighting influential features. This tool can assist medical staff by providing intuitive information regarding readiness for extubation without requiring any additional data collection other than SBT data. The proposed predictive model can assist clinicians in making ventilator weaning decisions in real time, thereby improving patient outcomes.

It is important to make a differential diagnosis between inflammatory diseases of the bowel with similar clinical and endoscopic features. The profiling of immune cells could be helpful for accurately diagnosing inflammatory bowel diseases. We compared immune marker expression between Crohn’s disease (CD), intestinal Behcet’s disease (BD), and intestinal tuberculosis (TB) and evaluated the usefulness of immune profiling in differentiating between these diseases. Biopsy specimens were acquired around ulcerations on the terminal ileum or cecum from five patients with each disease. Panel 1 included multiplex immunohistochemistry staining for CD8, CD4, Foxp3, CD20, programmed death-1, and granzyme B. CD56, CD68, CD163, CD11c, and HLA-DR were analyzed in panel 2. The differences in cytotoxic T cells (CD8+CD4−Fopx3−CD20−), helper T cells (CD8−CD4+Fopx3−CD20−), and regulatory T cells (CD8−CD4+Fopx3+CD20−) were also not significant. However, M1 macrophage (CD68+CD163−HLA−DR−) cell densities were significantly higher in intestinal BD than in other diseases. The expression level of dendritic cells (CD56−CD68−CD163−CD11c+HLA-DR+) was highest in intestinal TB and lowest in intestinal BD. The expression of immune cells, including M1 macrophages and dendritic cells, was different between CD, intestinal BD, and intestinal TB. Immune profiling can be helpful for establishing differential diagnoses of inflammatory bowel diseases.

Metal oxides (MOs) having Mg and Al with Mg/Al ratios of 1, 2, 3, and 4 were synthesized via calcination of the layered double hydroxides (LDH). The X-ray diffraction analysis revealed that all the MO consisted of periclase (MgO) crystallite with comparable crystallinity regardless of the metal ratio. According to the 27Al magic-angle spinning nuclear magnetic resonance, the phase transformation from LDH to MO upon calcination facilitated the evolution of the Al3+ ions with unsaturated coordination at the surface of MO. The specific surface area values of MOs were not significantly different from each other, ranging between 100 and 200 m2/g, suggesting that the metal ratio did not strongly influence the porous structure of MO. The temperature-dependent desorption of ammonia demonstrated that the Lewis acidity of the Al-rich MOs was the largest with an Mg/Al ratio of 1, attributed to the efficient exposure of the surface-active site Al3+-O2− pairs. The acidity of heterogenous Al-rich MOs significantly increased with the exposed tetrahedral Al site on the surface and dramatically diminished when the molar ratio (Mg/Al) was over two.

In recent decades, tissue engineering advances have led to more skin substitutes becoming available. Acellular dermal matrix, initially developed for use in the treatment of full-thickness burns, is made by removing the cellular components from the dermis collected from donated bodies or animals. This class of scaffold is used to replace skin and soft tissue deficiencies in a variety of fields, including breast reconstruction, abdominal wall reconstruction, and burn treatment. Herein, we provide a detailed review of the clinical applications of acellular dermal matrix.

Abstract Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (

Organoid culture technique has been taking center stage as a next-generation ex-vivo model due to advancement of stem cell research techniques. The importance of the laboratory-based ex vivo model has increasingly been recognized for recapitulating histological, and physioglocal conditions of in vivo microenviorment. Accordingly, the use of this technique has also broadened the understanding of intratumoral heterogeneity which is closely associated with varied drug responses observed in patients. Likewise, studies on heterogeneity within a single tumor tissue have drawn much attention. Here, we isolated 15 single clones from 4 tumor organoid lines from 1 patient at a primary passage from one patient. Each organoid line showed variable alterations in both genotype and phenotype. Furthermore, our methodological approach on drug test employing a high-throughput screening system enabled us to pinpoint the optimal time frame for anti-cancer drugs within a single tumor. We propose that our method can effectively reveal the heterogeneity of time-point in drug response, and the most optimal therapeutic strategies for individual patient.

Ultraviolet B (UVB) irradiation generates reactive oxygen species (ROS), which can damage exposed skin cells. Mitochondria and NADPH oxidase are the two principal producers of ROS in UVB-irradiated keratinocytes. Peroxiredoxin V (PrxV) is a mitochondrial and cytosolic cysteine-dependent peroxidase enzyme that robustly removes H2O2. We investigated PrxV’s role in protecting epidermal keratinocytes against UVB-induced ROS damage. We separated mitochondrial and cytosolic H2O2 levels from other types of ROS using fluorescent H2O2 indicators. Upon UVB irradiation, PrxV-knockdown HaCaT human keratinocytes showed higher levels of mitochondrial and cytosolic H2O2 than PrxV-expressing controls. PrxV depletion enhanced hyperoxidation-mediated inactivation of mitochondrial PrxIII and cytosolic PrxI and PrxII in UVB-irradiated keratinocytes. PrxV-depleted keratinocytes exhibited mitochondrial dysfunction and were more susceptible to apoptosis through decreased oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, cytochrome C release, and caspase activation. Our findings show that PrxV serves to protect epidermal keratinocytes from UVB-induced damage such as mitochondrial dysfunction and apoptosis, not only by directly removing mitochondrial and cytosolic H2O2 but also by indirectly improving the catalytic activity of mitochondrial PrxIII and cytosolic PrxI and PrxII. It is possible that strengthening PrxV defenses could aid in preventing UVB-induced skin damage.

Nitric oxide (NO) (co)regulates many physiological processes in the body. Its short-lived free radicals force synthesis in situ and on-demand, without storage possibility. Local oxygen availability determines the origin of NO—either by synthesis by nitric oxide synthases (NOS) or by the reduction of nitrate to nitrite to NO by nitrate/nitrite reductases. The existence of nitrate reservoirs, mainly in skeletal muscle, assures the local and systemic availability of NO. Aging is accompanied by changes in metabolic pathways, leading to a decrease in NO availability. We explored age-related changes in various rat organs and tissues. We found differences in nitrate and nitrite contents in tissues of old and young rats at baseline levels, with nitrate levels being generally higher and nitrite levels being generally lower in old rats. However, there were no differences in the levels of nitrate-transporting proteins and nitrate reductase between old and young rats, with the exception of in the eye. Increased dietary nitrate led to significantly higher nitrate enrichment in the majority of old rat organs compared to young rats, suggesting that the nitrate reduction pathway is not affected by aging. We hypothesize that age-related NO accessibility changes originate either from the NOS pathway or from changes in NO downstream signaling (sGC/PDE5). Both possibilities need further investigation.

Evaluation of hepatic fibrosis is essential to prevent liver-related morbidity and mortality. Although various types of ultrasound shear wave elastography (SWE) have been used and validated, there are limited studies on the relatively newer technique, two-dimensional SWE (2D-SWE). Therefore, this study aimed to compare the diagnostic performances of 2D-SWE and point SWE (p-SWE) for evaluating liver fibrosis using histology as the reference standard. To measure liver stiffness (LS) values, 87 patients underwent 2D-SWE and p-SWE using the same machine. Technical failures and unreliable measurements were also evaluated. The diagnostic performances of 2D-SWE and p-SWE were compared using area under the receiver operating characteristic (AUROC) curve analysis. No technical failures were observed in either method; however, unreliable measurements were less frequent in 2D-SWE (1/87 [1.1%]) than in p-SWE (8/87 [9.2%]) (p < 0.001). The AUROC of the LS values of 2D-SWE were significantly higher than those of p-SWE for diagnosing significant fibrosis (0.965 vs. 0.872, p = 0.022) and cirrhosis (0.994 vs. 0.886, p = 0.042). In conclusion, 2D-SWE is more reliable and accurate than p-SWE for diagnosing hepatic fibrosis.

Background This study aimed to investigate the demographic characteristics of patients with knee pain caused by traffic accidents and test the effectiveness of Korean medicine (KM) treatment. Methods The medical charts of 114 inpatients with knee pain caused by a traffic accident were reviewed from July 1, 2019 to October 31, 2019 at Bucheon Jaseng Hospital of KM. The patients’ demographics including gender, age, period of hospitalization, and type of pharmacopuncture and herbal medicine prescribed were reviewed. The Numeric Rating Scale scores and Western Ontario and McMaster Universities Osteoarthritis Index scores were used to assess subjective knee pain. Results There were more females (55%) than males in this study. Patients were more likely to be in their 30s (27.2%), be hospitalized for 11–14 days (41.2%), treated with Hwangryunhaedok pharmacopuncture (78.1%), and be prescribed Hwalhyeoljitong decoction (62.3%).The mean Numeric Rating Scale score for patients with knee pain caused by a traffic accident decreased significantly from 4.26 ± 1.39 to 2.53 ± 1.60 (p < 0.001), and the mean Western Ontario and McMaster Universities Osteoarthritis Index score also decreased significantly from 32.72 ± 18.36 to 23.40 ± 15.80 (p < 0.001) following KM treatment. Conclusion As a result of analyzing 114 hospitalized patients with knee joint pain due to TAs, inpatients were more likely to be female (55%), a patient in their 30s (27.2%), and be a patient hospitalized for 11–14 days (41.2%). KM treatment of traumatic knee injury using pharmacopuncture therapy and herbal medicine can be an may be effective at reducing pain, and healing functional disorders of the knee.

Abstract To identify low anterior resection syndrome (LARS) patterns and their associations with risk factors and quality of life (QOL). This cross-sectional study analyzed patients who underwent restorative anterior resection for left-sided colorectal cancer at Seoul National University Hospital, Seoul, Republic of Korea. We administered LARS questionnaires to assess bowel dysfunction and quality of life between April 2017 and November 2019. LARS patterns were classified based on factor analyses. Variable effects on LARS patterns were estimated using logistic regression analysis. The risk factors and quality of life associated with dominant LARS patterns were analyzed. Data of 283 patients with a median follow-up duration of 24 months were analyzed. Major LARS was observed in 123 (43.3%) patients. Radiotherapy (odds ratio [OR]: 2.851, 95% confidence interval [95% CI]: 2.504–43.958, p = 0.002), low anastomosis (OR: 10.492, 95% CI: 2.504–43.958, p = 0.001), and complications (OR: 2.163, 95% CI: 1.100–4.255, p = 0.025) were independently associated with major LARS. LARS was classified into incontinence- or frequency-dominant types. Risk factors for incontinence-dominant LARS were radiotherapy and complications, whereas those for frequency-dominant LARS included low tumor location. Patients with incontinence-dominant patterns showed lower emotional function, whereas those with frequency-dominant patterns showed lower global health QOL, lower emotional, cognitive, and social functions, and higher incidence of pain and diarrhea. Frequency-dominant LARS had a greater negative effect on QOL than incontinence-dominant LARS. These patterns could be used for preoperative prediction and postoperative treatment of LARS.

Peptidyl arginine deiminases (PAD) enzymes have been investigated in various cancers. Recently, PAD enzyme, in particular PAD2, has been further implicated in cancers. Although the expression of PAD2 was significantly higher in hepatocellular carcinoma (HCC) tissue, its diagnostic or prognostic role of PAD2 in HCC patients is unknown. This study investigated whether the expression of PAD2 affects recurrence and survival in HCC patients who underwent hepatic resection. One hundred and twenty-two HCC patients after hepatic resection were enrolled. The median follow-up was 41 months (range 1–213 months) in enrolled patients. To investigate an association between PAD2 expression level and the clinical characteristics of enrolled patients, the recurrence of HCC following surgical resection and survival of the patients were examined. Ninety-eight cases (80.3%) of HCC demonstrated a higher expression of PAD2. The expression of PAD2 was correlated with age, hepatitis B virus positivity, hypertension, and higher alpha-fetoprotein level. There was no association between PAD2 expression and sex, diabetes mellitus, Child–Pugh class, major portal vein invasion, HCC size or number. The recurrence rates in patients with lower PAD2 expression were higher than those with higher PAD2 expression. The cumulative survival rates of patients with higher PAD2 expression were better than those of patients with lower PAD2 expression, but it was not statistically significant. In conclusion, PAD2 expression is closely associated with recurrence of HCC patients following surgical resection.

Abstract Sepsis, one of the most fatal diseases in the world, is known to culminate in multiple organ failure due to an uncontrolled inflammatory response. Hence, the use of animal models in sepsis research is very important to study complex immune responses. The current study was undertaken to compare commercial stocks with KFDA stocks of DBA/2 mice as an animal model for sepsis study. To compare responses of DBA/2 mice to lipopolysaccharides (LPS)-induced sepsis, we measured altered characteristics of various factors associated with sepsis, including survival curves, organ failure and inflammatory response, in DBA/2Korl stock and two commercial stocks (DBA/2A and DBA/2B). Survival rates after LPS exposure were similar for DBA/2Korl and DBA/2B; however, for times over 20 h, survival rates were reduced and concentration dependent in DBA/2A. In order to evaluate multiple organ failure caused by sepsis, H&E stains were evaluated for liver and spleen tissues obtained in the early (2 h) and later (20 h) stages after exposure to LPS; no significant differences were observed between the three stocks. mRNA and protein levels of proinflammatory cytokines were assessed for evaluating inflammatory reactions, and were found to increase in a dose-dependent manner in most DBA/2 mice after LPS treatment. However, no changes were observed in the mRNA levels of proinflammatory cytokines at 20 h after LPS exposure in the DBA/2A stock. The induction of inflammation-mediated factors by LPS exposure did not induce alterations in the mRNA levels of COX-2 and iNOS in all three DBA/2 stocks. Our results indicate that response of DBA/2Korl to LPS-induced sepsis is similar to the two commercial DBA/2 stocks, thus representing its potential as a useful biological resource established in Korea.

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5–2124.9 vs. 161.7–1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5–392.7 vs. 116.9–240.1 μm; 291.2–551.2 vs. 250.5–362.4 μm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Abstract Intratumor heterogeneity (ITH) stands as one of the main difficulties in the treatment of colorectal cancer (CRC) as it causes the development of resistant clones and leads to heterogeneous drug responses. Here, 12 sets of patient‐derived organoids (PDOs) and cell lines (PDCs) isolated from multiple regions of single tumors from 12 patients, capturing ITH by multiregion sampling of individual tumors, are presented. Whole‐exome sequencing and RNA sequencing of the 12 sets are performed. The PDOs and PDCs of the 12 sets are also analyzed with a clinically relevant 24‐compound library to assess their drug responses. The results reveal unexpectedly widespread subregional heterogeneity among PDOs and PDCs isolated from a single tumor, which is manifested by genetic and transcriptional heterogeneity and strong variance in drug responses, while each PDO still recapitulates the major histologic, genomic, and transcriptomic characteristics of the primary tumor. The data suggest an imminent drawback of single biopsy‐originated PDO‐based clinical diagnosis in evaluating CRC patient responses. Instead, the results indicate the importance of targeting common somatic driver mutations positioned in the trunk of all tumor subregional clones in parallel with a comprehensive understanding of the molecular ITH of each tumor.