Single-Cell Transcriptomics of Human and Mouse Lung Cancers Reveals Conserved Myeloid Populations across Individuals and Species.

Tumor-infiltrating myeloid cells (TIMs) comprise monocytes, macrophages, dendritic cells, and neutrophils, and have emerged as key regulators of cancer growth. These cells can diversify into a spectrum of states, which might promote or limit tumor outgrowth but remain poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to map TIMs in non-small-cell lung cancer patients. We uncovered 25 TIM states, most of which were reproducibly found across patients. To facilitate translational research of these populations, we also profiled TIMs in mice. In comparing TIMs across species, we identified a near-complete congruence of population structures among dendritic cells and monocytes; conserved neutrophil subsets; and species differences among macrophages. By contrast, myeloid cell population structures in patients' blood showed limited overlap with those of TIMs. This study determines the lung TIM landscape and sets the stage for future investigations into the potential of TIMs as immunotherapy targets.

Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-ß Production.

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-ß in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

Withdrawal from 3-Fluoroethamphetamine induces hyperactivity and depression-like behaviors in male mice.

3-Fluoroethamphetamine (3-FEA) belongs to the amphetamine class of stimulant drugs and functions as a releasing agent for the monoamine neurotransmitters norepinephrine, dopamine, and serotonin. 3-FEA acts on the central nervous system and elicits physical and mental side effects, such as euphoria, increased heart rate, and excitement. However, little is known about the withdrawal symptoms and behavioral changes induced by 3-FEA administration. This study aimed to evaluate the short-term consequences of 3-FEA administration (twice a day, 7 days, i.p.; 1 and 10 mg/kg) in C57BL/6J mice (male, 7 weeks old) at three behavioral levels following 1-4 days of withdrawal. The evaluation included (1) withdrawal score, (2) hyperactivity (open field [OF], elevated plus maze [EPM], and cliff avoidance [CA] test), and (3) depression-like behavior (forced-swim test). In the withdrawal score test, withdrawal behavior increased in all 3-FEA groups at 16 and 40 h after withdrawal. In the OF, EPM, and CA tests, the 3-FEA administration group showed significant changes in terms of hyperactivity. In addition, in the forced-swim test, both the 1 mg/kg and 10 mg/kg 3-FEA groups showed increased immobility time. These findings indicate that 3-FEA administration may lead to physical dependence, demonstrated by the withdrawal score increase and significant changes in hyperactivity and depression-like behavior following repeated administration and drug cessation. In conclusion, this study reveals the adverse consequences of 3-FEA administration and highlights the need for awareness raising and regulatory action to control the use of this new psychoactive substance.

Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). METHODS: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. RESULTS: Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D' = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10-5). CONCLUSION: These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.

Deep learning-based prognostication in idiopathic pulmonary fibrosis using chest radiographs.

OBJECTIVES: To develop and validate a deep learning-based prognostic model in patients with idiopathic pulmonary fibrosis (IPF) using chest radiographs. METHODS: To develop a deep learning-based prognostic model using chest radiographs (DLPM), the patients diagnosed with IPF during 2011-2021 were retrospectively collected and were divided into training (n = 1007), validation (n = 117), and internal test (n = 187) datasets. Up to 10 consecutive radiographs were included for each patient. For external testing, three cohorts from independent institutions were collected (n = 152, 141, and 207). The discrimination performance of DLPM was evaluated using areas under the time-dependent receiver operating characteristic curves (TD-AUCs) for 3-year survival and compared with that of forced vital capacity (FVC). Multivariable Cox regression was performed to investigate whether the DLPM was an independent prognostic factor from FVC. We devised a modified gender-age-physiology (GAP) index (GAP-CR), by replacing DLCO with DLPM. RESULTS: DLPM showed similar-to-higher performance at predicting 3-year survival than FVC in three external test cohorts (TD-AUC: 0.83 [95% CI: 0.76-0.90] vs. 0.68 [0.59-0.77], p < 0.001; 0.76 [0.68-0.85] vs. 0.70 [0.60-0.80], p = 0.21; 0.79 [0.72-0.86] vs. 0.76 [0.69-0.83], p = 0.41). DLPM worked as an independent prognostic factor from FVC in all three cohorts (ps < 0.001). The GAP-CR index showed a higher 3-year TD-AUC than the original GAP index in two of the three external test cohorts (TD-AUC: 0.85 [0.80-0.91] vs. 0.79 [0.72-0.86], p = 0.02; 0.72 [0.64-0.80] vs. 0.69 [0.61-0.78], p = 0.56; 0.76 [0.69-0.83] vs. 0.68 [0.60-0.76], p = 0.01). CONCLUSIONS: A deep learning model successfully predicted survival in patients with IPF from chest radiographs, comparable to and independent of FVC. CLINICAL RELEVANCE STATEMENT: Deep learning-based prognostication from chest radiographs offers comparable-to-higher prognostic performance than forced vital capacity. KEY POINTS: • A deep learning-based prognostic model for idiopathic pulmonary fibrosis was developed using 6063 radiographs. • The prognostic performance of the model was comparable-to-higher than forced vital capacity, and was independent from FVC in all three external test cohorts. • A modified gender-age-physiology index replacing diffusing capacity for carbon monoxide with the deep learning model showed higher performance than the original index in two external test cohorts.

Pulse versus non-pulse corticosteroid therapy in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Corticosteroids are commonly used for the treatment of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF); however, the optimal initial dose of corticosteroids remains uncertain due to a lack of sufficient evidence. We evaluated whether the administration of a pulse dose of corticosteroids resulted in improved survival outcomes compared with conventional non-pulse dose of corticosteroids. METHODS: We retrospectively analysed 238 patients with AE-IPF treated with corticosteroids at a tertiary referral hospital between January 2013 and December 2021. Based on whether a pulse dose of corticosteroids (methylprednisolone of ≥250 mg/day or equivalent) was administered within 7 days of hospitalization for AE-IPF, the patients were divided into the pulse and non-pulse regimen groups. The survival outcomes were compared between the two groups using multivariable regression and propensity score-matched analyses. RESULTS: Among the 238 patients, 59 patients received pulse dose of corticosteroids, whereas 179 patients received conventional non-pulse dose of corticosteroids. After adjusting for the confounding factors related to the baseline clinical and radiographic severity, compared with the conventional non-pulse regimen, the pulse regimen of corticosteroids did not reduce the risk of mortality at the 3-month (aHR 0.84, 95% CI 0.45-1.38) or 12-month (aHR 0.96, 95% CI 0.60-1.25) follow-ups. Propensity score-matched analysis revealed similar results. CONCLUSION: The survival outcomes of patients with AE-IPF who received a pulse dose of corticosteroids did not differ from those of patients who received conventional non-pulse dose of corticosteroids. Further prospective studies are required to establish the optimal initial dose of corticosteroids for the treatment of AE-IPF.

Pectoralis Muscle Area as a Predictor of Mortality in Patients Hospitalized with Bronchiectasis Exacerbation.

INTRODUCTION: Data on factors related to mortality in patients with bronchiectasis exacerbation are insufficient. Computed tomography (CT) can measure the pectoralis muscle area (PMA) and is a useful tool to diagnose sarcopenia. This study aimed to evaluate whether PMA can predict mortality in patients with bronchiectasis exacerbation. METHODS: Patients hospitalized due to bronchiectasis exacerbation at a single center were retrospectively divided into survivors and non-survivors based on 1-year mortality. Thereafter, a comparison of the clinical and radiologic characteristics was conducted between the two groups. RESULTS: A total of 66 (14%) patients died at 1 year. In the multivariate analysis, age, BMI <18.4 kg/m2, sex-specific PMA quartile, ≥3 exacerbations in the previous year, serum albumin <3.5 g/dL, cystic bronchiectasis, tuberculosis-destroyed lung, and diabetes mellitus were independent predictors for the 1-year mortality in patients hospitalized with bronchiectasis exacerbation. A lower PMA was associated with a lower overall survival rate in the survival analysis according to sex-specific quartiles of PMA. PMA had the highest area under the curve during assessment of prognostic performance in predicting the 1-year mortality. The lowest sex-specific PMA quartile group exhibited higher disease severity than the highest quartile group. CONCLUSIONS: CT-derived PMA was an independent predictor of 1-year mortality in patients hospitalized with bronchiectasis exacerbation. Patients with lower PMA exhibited higher disease severity. These findings suggest that PMA might be a useful marker for providing additional information regarding prognosis of patients with bronchiectasis exacerbation.

Efficacy and Safety of PrabotulinumtoxinA in Subjects With Benign Masseteric Hypertrophy: A Double-Blind, Randomized, Placebo-Controlled, Multicenter, Phase 3 Trial and Open-Label Extension Study.

BACKGROUND: Despite the widespread use of botulinum toxin (BTX) injection for the treatment of masseter muscle hypertrophy (MMH), there is no standard treatment option. OBJECTIVE: We report the efficacy and safety for BTX in MMH over a period of 48 weeks. METHODS: In double-blinded, placebo-controlled phase 3 trials, 180 patients (randomized 1:1) received treatment with placebo (normal saline) or prabotulinumtoxinA (48 units). Masseter muscle thickness (at maximal clenching and resting positions), 3D imaging analysis, and masseter muscle hypertrophy scale grades were analyzed at each time point. After the 24-week CORE study, all patients who met the same criteria of the CORE study at week 24 ( n = 114) received only prabotulinumtoxinA, regardless of previous treatment, for an additional 24 weeks (48 weeks in total) for the open-label extension study. RESULTS: The largest differences in mean and percent changes from baseline in masseter muscle thickness were observed at 12 weeks, and there were significant differences between the 2 groups at all time points (all p < .001). The effect was independent of the number of injections. No serious adverse event was observed. CONCLUSION: PrabotulinumtoxinA could effectively ameliorate MMH without major complications.

Prediction of dysphagia aspiration through machine learning-based analysis of patients' postprandial voices.

BACKGROUND: Conventional diagnostic methods for dysphagia have limitations such as long wait times, radiation risks, and restricted evaluation. Therefore, voice-based diagnostic and monitoring technologies are required to overcome these limitations. Based on our hypothesis regarding the impact of weakened muscle strength and the presence of aspiration on vocal characteristics, this single-center, prospective study aimed to develop a machine-learning algorithm for predicting dysphagia status (normal, and aspiration) by analyzing postprandial voice limiting intake to 3 cc. METHODS: Conducted from September 2021 to February 2023 at Seoul National University Bundang Hospital, this single center, prospective cohort study included 198 participants aged 40 or older, with 128 without suspected dysphagia and 70 with dysphagia-aspiration. Voice data from participants were collected and used to develop dysphagia prediction models using the Multi-Layer Perceptron (MLP) with MobileNet V3. Male-only, female-only, and combined models were constructed using 10-fold cross-validation. Through the inference process, we established a model capable of probabilistically categorizing a new patient's voice as either normal or indicating the possibility of aspiration. RESULTS: The pre-trained models (mn40_as and mn30_as) exhibited superior performance compared to the non-pre-trained models (mn4.0 and mn3.0). Overall, the best-performing model, mn30_as, which is a pre-trained model, demonstrated an average AUC across 10 folds as follows: combined model 0.8361 (95% CI 0.7667-0.9056; max 0.9541), male model 0.8010 (95% CI 0.6589-0.9432; max 1.000), and female model 0.7572 (95% CI 0.6578-0.8567; max 0.9779). However, for the female model, a slightly higher result was observed with the mn4.0, which scored 0.7679 (95% CI 0.6426-0.8931; max 0.9722). Additionally, the other models (pre-trained; mn40_as, non-pre-trained; mn4.0 and mn3.0) also achieved performance above 0.7 in most cases, and the highest fold-level performance for most models was approximately around 0.9. The 'mn' in model names refers to MobileNet and the following number indicates the 'width_mult' parameter. CONCLUSIONS: In this study, we used mel-spectrogram analysis and a MobileNetV3 model for predicting dysphagia aspiration. Our research highlights voice analysis potential in dysphagia screening, diagnosis, and monitoring, aiming for non-invasive safer, and more effective interventions. TRIAL REGISTRATION: This study was approved by the IRB (No. B-2109-707-303) and registered on clinicaltrials.gov (ID: NCT05149976).

Investigation of changes in DNA methylation associated with alterations in gene expression resulting in differences between lean and obese adipogenesis.

DNA methylation (DNAm) is an important epigenetic regulator controlling various cellular activities, including cell proliferation and differentiation. In the present work, we examined alterations in DNAm associated with obesity using methylome and transcriptome data from 27 purified adipocytes (ACs) and 7 preadipocytes (preACs) in human visceral adipose tissue (VAT) samples. We identified differentially methylated probes (DMPs) using two methods: (i) DMPs that were obtained from a comparison of the DNAm levels between AC and preAC samples (AGDMPs) and (ii) DMPs that were obtained from a comparison of the DNAm levels between obese and lean AC samples (ACDMPs). These two classes of DMPs were obtained to identify a relationship between adipogenesis and obesity. We also investigated how hyper and hypomethylation of the promoter and/or gene body differentially affected changes in gene expression by estimating the odds ratios (ORs) of changes in gene expression without DMPs in the background. Interestingly, the magnitude of DNAm alterations during AC differentiation was greater under lean conditions than under obese conditions. In conclusion, several adipogenesis-related genes were affected by complicated methylation changes and ultimately cause differences in gene expression in ACs under lean and obese conditions.

Should the diameter of the proximal femoral nail be large enough to fill the canal in the treatment of intertrochanteric femoral fracture in patients over fifty?

PURPOSE: Many studies have been conducted to evaluate the effects of nail shape, design, or length on the treatment of intertrochanteric fractures. However, the clinical implications of the nail diameter remain unclear. METHODS: This study was conducted with 191 patients aged ≥ 50 years with unilateral intertrochanteric fractures treated with the same type of short cephalomedullary nail and followed for at least one year. We recorded the reduction type, tip-apex distance, cortical contact of the nail, and nail/canal diameter ratio (NCR) just distal to the locking screw. The effects of nail diameter on the clinical results were evaluated. RESULTS: The average NCR was 68.7. The average union time was 4.78 months. Delayed union or nonunion was seen in 17 patients. Eight patients underwent additional surgery. The mean change in the modified Koval activity score was -0.84. The NCR did not significantly affect the clinical results. Comparisons of cases with NCRs above and below the average and the average - 1 standard deviation revealed no significant difference. The clinical outcome was not related to any variable associated with the nail diameter. CONCLUSION: With this specific proximal femoral nail, a small diameter relative to that of the femoral canal had no adverse effect on the union of osteoporotic intertrochanteric fractures, even in patients with unstable fractures and those who had unsatisfactory reductions.

The Impact of Ulmus macrocarpa Extracts on a Model of Sarcopenia-Induced C57BL/6 Mice.

Aging leads to tissue and cellular changes, often driven by oxidative stress and inflammation, which contribute to age-related diseases. Our research focuses on harnessing the potent anti-inflammatory and antioxidant properties of Korean Ulmus macrocarpa Hance, a traditional herbal remedy, to address muscle loss and atrophy. We evaluated the effects of Ulmus extract on various parameters in a muscle atrophy model, including weight, exercise performance, grip strength, body composition, muscle mass, and fiber characteristics. Additionally, we conducted Western blot and RT-PCR analyses to examine muscle protein regulation, apoptosis factors, inflammation, and antioxidants. In a dexamethasone-induced muscle atrophy model, Ulmus extract administration promoted genes related to muscle formation while reducing those associated with muscle atrophy. It also mitigated inflammation and boosted muscle antioxidants, indicating a potential improvement in muscle atrophy. These findings highlight the promise of Ulmus extract for developing pharmaceuticals and supplements to combat muscle loss and atrophy, paving the way for clinical applications.

Transmembrane protein 150b attenuates BMP signaling in the Xenopus organizer.

The vertebrate organizer is a specified embryonic tissue that regulates dorsoventral patterning and axis formation. Although numerous cellular signaling pathways have been identified as regulators of the organizer's dynamic functions, the process remains incompletely understood, and as-yet unknown pathways remain to be explored for sophisticated mechanistic understanding of the vertebrate organizer. To identify new potential key factors of the organizer, we performed complementary DNA (cDNA) microarray screening using organizer-mimicking Xenopus laevis tissue. This analysis yielded a list of prospective organizer genes, and we determined the role of six-transmembrane domain containing transmembrane protein 150b (Tmem150b) in organizer function. Tmem150b was expressed in the organizer region and induced by Activin/Nodal signaling. In X. laevis, Tmem150b knockdown resulted in head defects and a shortened body axis. Moreover, Tmem150b negatively regulated bone morphogenetic protein (BMP) signaling, likely via physical interaction with activin receptor-like kinase 2 (ALK2). These findings demonstrated that Tmem150b functions as a novel membrane regulatory factor of BMP signaling with antagonistic effects, contributing to the understanding of regulatory molecular mechanisms of organizer axis function. Investigation of additional candidate genes identified in the cDNA microarray analysis could further delineate the genetic networks of the organizer during vertebrate embryogenesis.

Transcriptomes of the tumor-adjacent normal tissues are more informative than tumors in predicting recurrence in colorectal cancer patients.

BACKGROUND: Previous investigations of transcriptomic signatures of cancer patient survival and post-therapy relapse have focused on tumor tissue. In contrast, here we show that in colorectal cancer (CRC) transcriptomes derived from normal tissues adjacent to tumors (NATs) are better predictors of relapse. RESULTS: Using the transcriptomes of paired tumor and NAT specimens from 80 Korean CRC patients retrospectively determined to be in recurrence or nonrecurrence states, we found that, when comparing recurrent with nonrecurrent samples, NATs exhibit a greater number of differentially expressed genes (DEGs) than tumors. Training two prognostic elastic net-based machine learning models-NAT-based and tumor-based in our Samsung Medical Center (SMC) cohort, we found that NAT-based model performed better in predicting the survival when the model was applied to the tumor-derived transcriptomes of an independent cohort of 450 COAD patients in TCGA. Furthermore, compositions of tumor-infiltrating immune cells in NATs were found to have better prognostic capability than in tumors. We also confirmed through Cox regression analysis that in both SMC-CRC as well as in TCGA-COAD cohorts, a greater proportion of genes exhibited significant hazard ratio when NAT-derived transcriptome was used compared to when tumor-derived transcriptome was used. CONCLUSIONS: Taken together, our results strongly suggest that NAT-derived transcriptomes and immune cell composition of CRC are better predictors of patient survival and tumor recurrence than the primary tumor.

Genetic Variants in Histone Modification Regions Predict Clinical Outcomes of Pemetrexed Chemotherapy in Lung Adenocarcinoma.

OBJECTIVE: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. METHODS: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. RESULTS: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36-0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09-1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. CONCLUSION: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.

Classical monocyte-derived macrophages as therapeutic targets of umbilical cord mesenchymal stem cells: comparison of intratracheal and intravenous administration in a mouse model of pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that has no cure. Although mesenchymal stem cells (MSCs) have been reported to ameliorate lung inflammation and fibrosis in mouse models, their mechanisms of action remain unknown. Therefore, we aimed to determine the changes in various immune cells, especially macrophages and monocytes, involved in the effects of MSC treatment on pulmonary fibrosis. METHODS: We collected and analyzed explanted lung tissues and blood from patients with IPF who underwent lung transplantation. After establishing a pulmonary fibrosis model via the intratracheal administration of bleomycin (BLM) to 8-week-old mice, MSCs derived from human umbilical cords were administered intravenously or intratracheally on day 10 and the lungs were immunologically analyzed on days 14 and 21. Flow cytometry was performed to analyze the immune cell characteristics, and gene expression levels were examined using quantitative reverse transcription-polymerase chain reaction. RESULTS: In the histological analysis of explanted human lung tissues, the terminally fibrotic areas contained a larger number of macrophages and monocytes than the early fibrotic areas of the lungs. When human monocyte-derived macrophages (MoMs) were stimulated with interleukin-13 in vitro, the expression of type 2 macrophage (M2) markers was more prominent in MoMs from the classical monocyte subset than in those from intermediate or non-classical monocyte subsets, and MSCs suppressed M2 marker expression independent of MoM subsets. In the mouse model, the increased number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung fibrosis observed in BLM-treated mice were significantly reduced by MSC treatment, which tended to be more prominent with intravenous administration than intratracheal administration. Both M1 and M2 MoMs were upregulated in BLM-treated mice. The M2c subset of M2 MoMs was significantly reduced by MSC treatment. Among M2 MoMs, M2 MoMs derived from Ly6C+ monocytes were most effectively regulated by the intravenous administration, not intratracheal administration, of MSCs. CONCLUSIONS: Inflammatory classical monocytes may play a role in lung fibrosis in human IPF and BLM-induced pulmonary fibrosis. Intravenous rather than intratracheal administration of MSCs may ameliorate pulmonary fibrosis by inhibiting monocyte differentiation into M2 macrophages.

Incidence and risk factors of tuberculosis in patients following gastrectomy or endoscopic submucosal dissection: a cohort analysis of country-level data.

BACKGROUND: Gastric cancer adversely affects nutrition and immunity, while increasing the risk of tuberculosis (TB). This study investigated the incidence and risk factors for TB in gastric cancer patients who had undergone gastrectomy or endoscopic submucosal dissection (ESD). METHODS: This retrospective cohort study was conducted using Korean national insurance claims data. We defined three study groups (total gastrectomy, subtotal gastrectomy, and ESD) of patients diagnosed with gastric cancer plus a cancer-free control group. The latent TB infection (LTBI) screening status, TB incidence, and potential confounders in each cohort were analyzed, and the risk of TB was analyzed using a Cox proportional hazard model. RESULTS: LTBI tests were performed in less than 1% of all patients, and the TB incidence rates were 473.8, 287.4, 199.4, 111.1 events/100,000 person-years in the total gastrectomy, subtotal gastrectomy, ESD, and control cohorts, respectively. Compared to the control cohort, the total gastrectomy cohort showed the highest hazard ratio (HR) for TB incidence (HR: 2.896, 95% CI: 2.559-2.337), while the ESD cohort showed a significantly increased risk (HR: 1.578, 95% CI: 1.957-1.980). Age, body mass index, and lack of exercise were risk factors in all cohorts. Comorbidities were also considered risk factors, depending on the cohort type. CONCLUSIONS: Patients who underwent gastrectomy or ESD had an increased risk of TB, and this risk was correlated with the scope of gastrectomy. Considering the low rate of LTBI diagnostic tests and increased risk of TB in the study cohorts, more specific and practical guidelines for TB management are required for gastric cancer patients.

GSK3 Restrains Germinal Center B Cells to Form Plasma Cells.

B cells in the germinal center (GC) are programmed to form plasma cells (PCs) or memory B cells according to signals received by receptors that are translated to carry out appropriate activities of transcription factors. However, the precise mechanism underlying this process to complete the GC reaction is unclear. In this study, we show that both genetic ablation and pharmacological inhibition of glycogen synthase kinase 3 (GSK3) in GC B cells of mice facilitate the cell fate decision toward PC formation, accompanied by acquisition of dark zone B cell properties. Mechanistically, under stimulation with CD40L and IL-21, GSK3 inactivation synergistically induced the transcription factors Foxo1 and c-Myc, leading to increased levels of key transcription factors required for PC differentiation, including IRF4. This GSK3-mediated alteration of transcriptional factors in turn facilitated the dark zone transition and consequent PC fate commitment. Our study thus reveals the upstream master regulator responsible for interpreting external cues in GC B cells to form PCs mediated by key transcription factors.

First-principles study on the design of nickel based bimetallic catalysts for xylose to xylitol conversion.

A significant challenge for effective biomass utilization and upgrading is catalysis. This research paper focuses on the conversion of xylose into xylitol, a valuable chemical used in the pharmaceutical and food industries. The primary objective is to design more efficient and cost-effective catalysts for this conversion process. The study investigates the use of Ni-bimetallic catalysts by employing a first-principles technique. Catalyst models derived from subsets of Ni (111) surfaces with various transition metals (M = Ti, V, Cr, Fe, Co, and Cu) are examined. The catalyst surfaces are screened based on the rate-determining step (RDS) involved in the conversion of xylose to xylitol, with Ni (111) serving as a reference. Electronic structure calculations are used to analyze the activities of the investigated Ni-bimetallic catalysts relative to the RDS. The results show that certain bimetallic surfaces exhibit significantly lower kinetic barriers compared to the Ni (111) surface. The hydrogenation process when investigated using different transition state paths, reveals that hydrogenation commences at the carbon atom of the carbonyl group of xylose after the ring-opening step. Stability segregation tests demonstrate varying behaviors among the screened catalysts, with Ni (111)/Cr/Ni showing greater stability than Ni (111)/Co. This study sheds light on the theoretical design of catalysts for xylose conversion, providing insights for the development of more efficient and active catalysts for industrial applications. The research highlights the significance of theoretical methodologies in tailoring catalyst surfaces to optimize their performance in biomass upgrading.